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The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause
acquired immunodeficiency syndrome Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ma ...
(AIDS), a condition in which progressive failure of the
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...
allows life-threatening opportunistic infections and
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. In most cases, HIV is a sexually transmitted infection and occurs by contact with or transfer of
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...
,
pre-ejaculate Pre-ejaculate (also known as pre-ejaculatory fluid, pre-seminal fluid or Cowper's fluid, and colloquially as ''pre-cum'') is a clear, colorless, viscous fluid that is emitted from the urethra of the penis during sexual arousal. It is similar in c ...
,
semen Semen, also known as seminal fluid, is an organic bodily fluid created to contain spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals and can fertilize the female ovum. Sem ...
, and vaginal fluids. Non-sexual transmission can occur from an infected mother to her infant during
pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...
, during
childbirth Childbirth, also known as labour and delivery, is the ending of pregnancy where one or more babies exits the internal environment of the mother via vaginal delivery or caesarean section. In 2019, there were about 140.11 million births glob ...
by exposure to her blood or vaginal fluid, and through breast milk. Within these bodily fluids, HIV is present as both free
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...
particles and virus within infected
immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
. Research has shown (for both same-sex and opposite-sex couples) that HIV is untransmittable through condomless sexual intercourse if the HIV-positive partner has a consistently undetectable
viral load Viral load, also known as viral burden, is a numerical expression of the quantity of virus in a given volume of fluid, including biological and environmental specimens. It is not to be confused with viral titre or viral titer, which depends on the ...
. HIV infects vital cells in the human immune system, such as
helper T cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
(specifically CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells through a number of mechanisms, including
pyroptosis Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of va ...
of abortively infected T cells, apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4+ T cells by CD8+ cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a critical level,
cell-mediated immunity Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in ...
is lost, and the body becomes progressively more susceptible to opportunistic infections, leading to the development of AIDS.


Virology


Classification

HIV is a member of the
genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of living and fossil organisms as well as viruses. In the hierarchy of biological classification, genus comes above species and below family. In binomial nom ...
'' Lentivirus'', part of the family ''
Retroviridae A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
''. Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long
incubation period Incubation period (also known as the latent period or latency period) is the time elapsed between exposure to a pathogenic organism, a chemical, or radiation, and when symptoms and signs are first apparent. In a typical infectious disease, the in ...
. Lentiviruses are transmitted as
single-stranded When referring to DNA transcription, the coding strand (or informational strand) is the DNA strand whose base sequence is identical to the base sequence of the RNA transcript produced (although with thymine replaced by uracil). It is this stra ...
, positive-
sense A sense is a biological system used by an organism for sensation, the process of gathering information about the world through the detection of stimuli. (For example, in the human body, the brain which is part of the central nervous system re ...
, enveloped RNA viruses. Upon entry into the target cell, the viral RNA
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
is converted (reverse transcribed) into double-stranded DNA by a virally encoded enzyme, reverse transcriptase, that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded enzyme, integrase, and host co-factors. Once integrated, the virus may become
latent Latency or latent may refer to: Science and technology * Latent heat, energy released or absorbed, by a body or a thermodynamic system, during a constant-temperature process * Latent variable, a variable that is not directly observed but inferred ...
, allowing the virus and its host cell to avoid detection by the immune system, for an indeterminate amount of time. The HIV virus can remain dormant in the human body for up to ten years after primary infection; during this period the virus does not cause symptoms. Alternatively, the integrated viral DNA may be transcribed, producing new RNA genomes and viral proteins, using host cell resources, that are packaged and released from the cell as new virus particles that will begin the replication cycle anew. Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is the virus that was initially discovered and termed both lymphadenopathy associated virus (LAV) and human T-lymphotropic virus 3 (HTLV-III). HIV-1 is more
virulent Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...
and more infective than HIV-2, and is the cause of the majority of HIV infections globally. The lower infectivity of HIV-2, compared to HIV-1, implies that fewer of those exposed to HIV-2 will be infected per exposure. Due to its relatively poor capacity for transmission, HIV-2 is largely confined to
West Africa West Africa or Western Africa is the westernmost region of Africa. The United Nations defines Western Africa as the 16 countries of Benin, Burkina Faso, Cape Verde, The Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali, M ...
.


Structure and genome

HIV is similar in structure to other retroviruses. It is roughly spherical with a diameter of about 120  nm, around 100,000 times smaller in volume than a
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
.Compared with overview in: It is composed of two copies of positive-
sense A sense is a biological system used by an organism for sensation, the process of gathering information about the world through the detection of stimuli. (For example, in the human body, the brain which is part of the central nervous system re ...
single-stranded When referring to DNA transcription, the coding strand (or informational strand) is the DNA strand whose base sequence is identical to the base sequence of the RNA transcript produced (although with thymine replaced by uracil). It is this stra ...
RNA that codes for the virus's nine
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s enclosed by a conical
capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...
composed of 2,000 copies of the viral protein p24. The single-stranded RNA is tightly bound to nucleocapsid proteins, p7, and enzymes needed for the development of the virion such as reverse transcriptase,
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s,
ribonuclease Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within ...
and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle. This is, in turn, surrounded by the
viral envelope A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. Numerous human pathogenic viruses in circulation are encase ...
, that is composed of the
lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
taken from the membrane of a human host cell when the newly formed virus particle buds from the cell. The viral envelope contains proteins from the host cell and relatively few copies of the HIV envelope protein, which consists of a cap made of three molecules known as glycoprotein (gp) 120, and a stem consisting of three
gp41 Gp41 also known as glycoprotein 41 is a subunit of the envelope protein complex of retroviruses, including human immunodeficiency virus (HIV). Gp41 is a transmembrane protein that contains several sites within its ectodomain that are required fo ...
molecules that anchor the structure into the viral envelope. The envelope protein, encoded by the HIV ''env'' gene, allows the virus to attach to target cells and fuse the viral envelope with the target cell's membrane releasing the viral contents into the cell and initiating the infectious cycle. As the sole viral protein on the surface of the virus, the envelope protein is a major target for
HIV vaccine An HIV vaccine is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine, which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals. It is thought that an HIV ...
efforts. Over half of the mass of the trimeric envelope spike is N-linked glycans. The density is high as the glycans shield the underlying viral protein from neutralisation by antibodies. This is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic and Golgi apparatus. The majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on human glycoproteins that are secreted or present on a cell surface. The unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to, or are adapted to cope with, these envelope glycans. The molecular structure of the viral spike has now been determined by
X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
and
cryogenic electron microscopy Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample so ...
. These advances in structural biology were made possible due to the development of stable recombinant forms of the viral spike by the introduction of an intersubunit disulphide bond and an isoleucine to proline
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
( radical replacement of an amino acid) in gp41. The so-called SOSIP trimers not only reproduce the antigenic properties of the native viral spike, but also display the same degree of immature glycans as presented on the native virus. Recombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
s than recombinant monomeric gp120, which act to suppress the immune response to target epitopes. The RNA genome consists of at least seven structural landmarks ( LTR,
TAR Tar is a dark brown or black viscous liquid of hydrocarbons and free carbon, obtained from a wide variety of organic materials through destructive distillation. Tar can be produced from coal, wood, petroleum, or peat. "a dark brown or black bi ...
,
RRE The Royal Radar Establishment was a research centre in Malvern, Worcestershire in the United Kingdom. It was formed in 1953 as the Radar Research Establishment by the merger of the Air Ministry's Telecommunications Research Establishment (TRE) a ...
, PE, SLIP, CRS, and INS), and nine genes (''gag'', ''pol'', and ''env'', ''tat'', ''rev'', ''nef'', ''vif'', ''vpr'', ''vpu'', and sometimes a tenth ''tev'', which is a fusion of ''tat'', ''env'' and ''rev''), encoding 19 proteins. Three of these genes, ''gag'', ''pol'', and ''env'', contain information needed to make the structural proteins for new virus particles. For example, ''env'' codes for a protein called gp160 that is cut in two by a cellular protease to form gp120 and gp41. The six remaining genes, ''tat'', ''rev'', ''nef'', ''vif'', ''vpr'', and ''vpu'' (or ''vpx'' in the case of HIV-2), are regulatory genes for proteins that control the ability of HIV to infect cells, produce new copies of virus (replicate), or cause disease. The two '' tat'' proteins (p16 and p14) are transcriptional transactivators for the LTR promoter acting by binding the TAR RNA element. The TAR may also be processed into
microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. mi ...
s that regulate the apoptosis genes ''
ERCC1 DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination. Many aspects of these two gene ...
'' and ''
IER3 Radiation-inducible immediate-early gene IEX-1 is a protein that in humans is encoded by the ''IER3'' gene. This gene functions in the protection of cells from Fas- or tumor necrosis factor type alpha-induced apoptosis Apoptosis (from grc, ...
''. The ''rev'' protein (p19) is involved in shuttling RNAs from the nucleus and the cytoplasm by binding to the
RRE The Royal Radar Establishment was a research centre in Malvern, Worcestershire in the United Kingdom. It was formed in 1953 as the Radar Research Establishment by the merger of the Air Ministry's Telecommunications Research Establishment (TRE) a ...
RNA element. The ''vif'' protein (p23) prevents the action of
APOBEC3G APOBEC3G (apolipoprotein B mRNA editing enzyme, catalytic subunit 3G) is a human enzyme encoded by the ''APOBEC3G'' gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in ...
(a cellular protein that deaminates
cytidine Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1- glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid. which ...
to
uridine Uridine (symbol U or Urd) is a glycosylated pyrimidine analog containing uracil attached to a ribose ring (or more specifically, a ribofuranose) via a β-N1-glycosidic bond. The analog is one of the five standard nucleosides which make up nucle ...
in the single-stranded viral DNA and/or interferes with reverse transcription). The ''
vpr Vpr is a Human immunodeficiency virus gene and protein product. Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for ...
'' protein (p14) arrests
cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ar ...
at G2/M. The ''nef'' protein (p27) down-regulates CD4 (the major viral receptor), as well as the MHC class I and class II molecules. ''Nef'' also interacts with
SH3 domain The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phos ...
s. The ''vpu'' protein (p16) influences the release of new virus particles from infected cells. The ends of each strand of HIV RNA contain an RNA sequence called a
long terminal repeat A long terminal repeat (LTR) is a pair of identical sequences of DNA, several hundred base pairs long, which occur in eukaryotic genomes on either end of a series of genes or pseudogenes that form a retrotransposon or an endogenous retrovirus or ...
(LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell. The Psi element is involved in viral genome packaging and recognized by ''gag'' and ''rev'' proteins. The SLIP element () is involved in the
frameshift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
in the ''gag''-''pol''
reading frame In molecular biology, a reading frame is a way of dividing the sequence of nucleotides in a nucleic acid ( DNA or RNA) molecule into a set of consecutive, non-overlapping triplets. Where these triplets equate to amino acids or stop signals during ...
required to make functional ''pol''.


Tropism

The term viral tropism refers to the cell types a virus infects. HIV can infect a variety of immune cells such as CD4+ T cells, macrophages, and
microglial cell Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune d ...
s. HIV-1 entry to macrophages and CD4+ T cells is mediated through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells' membrane and also with
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
co-receptor A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell. Properties The ...
s. Macrophage-tropic (M-tropic) strains of HIV-1, or non-
syncytia A syncytium (; plural syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell which can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleus) ...
-inducing strains (NSI; now called R5 viruses) use the ''β''-chemokine receptor,
CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 p ...
, for entry and are thus able to replicate in both macrophages and CD4+ T cells. This CCR5 co-receptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype. Indeed, macrophages play a key role in several critical aspects of HIV infection. They appear to be the first cells infected by HIV and perhaps the source of HIV production when CD4+ cells become depleted in the patient. Macrophages and microglial cells are the cells infected by HIV in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. In the
tonsil The tonsils are a set of lymphoid organs facing into the aerodigestive tract, which is known as Waldeyer's tonsillar ring and consists of the adenoid tonsil, two tubal tonsils, two palatine tonsils, and the lingual tonsils. These organs play ...
s and
adenoids In anatomy, the adenoid, also known as the pharyngeal tonsil or nasopharyngeal tonsil, is the superior-most of the tonsils. It is a mass of lymphatic tissue located behind the nasal cavity, in the roof of the nasopharynx, where the nose blend ...
of HIV-infected patients, macrophages fuse into multinucleated
giant cell A giant cell (also known as multinucleated giant cell, or multinucleate giant cell) is a mass formed by the union of several distinct cells (usually histiocytes), often forming a granuloma. Although there is typically a focus on the pathologica ...
s that produce huge amounts of virus. T-tropic strains of HIV-1, or
syncytia A syncytium (; plural syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell which can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleus) ...
-inducing strains (SI; now called X4 viruses) replicate in primary CD4+ T cells as well as in macrophages and use the ''α''-chemokine receptor,
CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemokin ...
, for entry. Dual-tropic HIV-1 strains are thought to be transitional strains of HIV-1 and thus are able to use both CCR5 and CXCR4 as co-receptors for viral entry. The ''α''-chemokine SDF-1, a
ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...
for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of HIV target cells. M-tropic HIV-1 isolates that use only the CCR5 receptor are termed R5; those that use only CXCR4 are termed X4, and those that use both, X4R5. However, the use of co-receptors alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection and HIV can also infect a subtype of
myeloid dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
, which probably constitute a
reservoir A reservoir (; from French ''réservoir'' ) is an enlarged lake behind a dam. Such a dam may be either artificial, built to store fresh water or it may be a natural formation. Reservoirs can be created in a number of ways, including contro ...
that maintains infection when CD4+ T cell numbers have declined to extremely low levels. Some people are resistant to certain strains of HIV. For example, people with the
CCR5-Δ32 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 pr ...
mutation are resistant to infection by the R5 virus, as the mutation leaves HIV unable to bind to this co-receptor, reducing its ability to infect target cells. Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the
seminal fluid Semen, also known as seminal fluid, is an organic bodily fluid created to contain spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals and can fertilize the female ovum. Semen is ...
, which enables the virus to be transmitted from a male to his
sexual partner Sexual partners are people who engage in sexual activity together. The sexual partners may be in a committed relationship, either on an exclusive basis or not, or engage in the sexual activity on a casual basis. They may be on intimate terms ...
. The virions can then infect numerous cellular targets and disseminate into the whole organism. However, a selection process leads to a predominant transmission of the R5 virus through this pathway. In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants that can infect a variety of T cells through CXCR4. These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system collapse, and opportunistic infections that mark the advent of AIDS. HIV-positive patients acquire an enormously broad spectrum of opportunistic infections, which was particularly problematic prior to the onset of
HAART The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multip ...
therapies; however, the same infections are reported among HIV-infected patients examined post-mortem following the onset of antiretroviral therapies. Thus, during the course of infection, viral adaptation to the use of CXCR4 instead of CCR5 may be a key step in the progression to AIDS. A number of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes. HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution to
West Africa West Africa or Western Africa is the westernmost region of Africa. The United Nations defines Western Africa as the 16 countries of Benin, Burkina Faso, Cape Verde, The Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali, M ...
. The adoption of "accessory genes" by HIV-2 and its more
promiscuous Promiscuity is the practice of engaging in sexual activity frequently with different partners or being indiscriminate in the choice of sexual partners. The term can carry a moral judgment. A common example of behavior viewed as promiscuous by ma ...
pattern of co-receptor usage (including CD4-independence) may assist the virus in its adaptation to avoid innate restriction factors present in host cells. Adaptation to use normal cellular machinery to enable transmission and productive infection has also aided the establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host, but ultimately become a
commensal Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fro ...
organism. Having achieved a low pathogenicity, over time, variants that are more successful at transmission will be selected.


Replication cycle


Entry to the cell

The HIV virion enters macrophages and CD4+
T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
by the
adsorption Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the ''adsorbate'' on the surface of the ''adsorbent''. This process differs from absorption, in which ...
of glycoproteins on its surface to receptors on the target cell followed by fusion of the
viral envelope A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. Numerous human pathogenic viruses in circulation are encase ...
with the target cell membrane and the release of the HIV capsid into the cell. Entry to the cell begins through interaction of the trimeric envelope complex (
gp160 ''Env'' is a viral gene that encodes the protein forming the viral envelope. The expression of the ''env'' gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane. Analysis of the structur ...
spike) on the HIV viral envelope and both CD4 and a chemokine co-receptor (generally either
CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 p ...
or
CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemokin ...
, but others are known to interact) on the target cell surface. Gp120 binds to
integrin Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle ...
α4β7 activating
LFA-1 Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates ...
, the central integrin involved in the establishment of
virological synapse Viral synapse (or virological synapse) is a molecularly organized cellular junction that is similar in some aspects to immunological synapses. Many viruses including herpes simplex virus (HSV), human immunodeficiency virus (HIV) and human T-lymphot ...
s, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains binding domains for both CD4 and chemokine receptors. The first step in fusion involves the high-affinity attachment of the CD4 binding domains of
gp120 Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1988. The 120 in its name comes from ...
to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a structural change, exposing the chemokine receptor binding domains of gp120 and allowing them to interact with the target chemokine receptor. This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.
Repeat sequences Repeated sequences (also known as repetitive elements, repeating units or repeats) are short or long patterns of nucleic acids (DNA or RNA) that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genom ...
in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranes close together, allowing fusion of the membranes and subsequent entry of the viral capsid. After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse transcriptase, integrase, ribonuclease, and protease, are injected into the cell. During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome. HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as
DC-SIGN DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) also known as CD209 ( Cluster of Differentiation 209) is a protein which in humans is encoded by the ''CD209'' gene. DC-SIGN is a C-type lectin receptor pr ...
can also be used. DCs are one of the first cells encountered by the virus during sexual transmission. They are currently thought to play an important role by transmitting HIV to T cells when the virus is captured in the mucosa by DCs. The presence of FEZ-1, which occurs naturally in
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s, is believed to prevent the infection of cells by HIV. HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at the plasma membrane. More recently, however, productive infection by pH-independent,
clathrin-mediated endocytosis Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This ...
of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.


Replication and transcription

Shortly after the viral capsid enters the cell, an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
called reverse transcriptase liberates the positive-sense single-stranded RNA genome from the attached viral proteins and copies it into a
complementary DNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a spec ...
(cDNA) molecule. The process of reverse transcription is extremely error-prone, and the resulting mutations may cause
drug resistance Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is ...
or allow the virus to evade the body's immune system. The reverse transcriptase also has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA, as well as DNA-dependent DNA polymerase activity that creates a
sense A sense is a biological system used by an organism for sensation, the process of gathering information about the world through the detection of stimuli. (For example, in the human body, the brain which is part of the central nervous system re ...
DNA from the ''antisense'' cDNA. Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cell's
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
is carried out by another viral enzyme called integrase. The integrated viral DNA may then lie dormant, in the latent stage of HIV infection. To actively produce the virus, certain cellular
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s need to be present, the most important of which is NF-''κ''B (nuclear factor kappa B), which is upregulated when T cells become activated. This means that those cells most likely to be targeted, entered and subsequently killed by HIV are those actively fighting infection. During viral replication, the integrated DNA provirus is transcribed into RNA. The full-length genomic RNAs (gRNA) can be packaged into new viral particles in a pseudodiploid form. The selectivity in the packaging is explained by the structural properties of the dimeric conformer of the gRNA. The gRNA dimer is characterized by a tandem three-way junction within the gRNA monomer, in which the SD and AUG hairpins, responsible for splicing and translation respectively, are sequestered and the DIS (dimerization initiation signal) hairpin is exposed.The formation of the gRNA dimer is mediated by a 'kissing' interaction between the DIS hairpin loops of the gRNA monomers. At the same time, certain guanosine residues in the gRNA are made available for binding of the nucleocapsid (NC) protein leading to the subsequent virion assembly. The labile gRNA dimer has been also reported to achieve a more stable conformation following the NC binding, in which both the DIS and the U5:AUG regions of the gRNA participate in extensive base pairing. RNA can also be processed to produce mature messenger RNAs (mRNAs). In most cases, this processing involves RNA splicing to produce mRNAs that are shorter than the full-length genome. Which part of the RNA is removed during RNA splicing determines which of the HIV protein-coding sequences is translated. Mature HIV mRNAs are exported from the nucleus into the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
, where they are
translated Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
to produce HIV proteins, including Rev. As the newly produced Rev protein is produced it moves to the nucleus, where it binds to full-length, unspliced copies of virus RNAs and allows them to leave the nucleus. Some of these full-length RNAs function as mRNAs that are translated to produce the structural proteins Gag and Env. Gag proteins bind to copies of the virus RNA genome to package them into new virus particles. HIV-1 and HIV-2 appear to package their RNA differently. HIV-1 will bind to any appropriate RNA. HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself.


Recombination

Two RNA genomes are encapsidated in each HIV-1 particle (see
Structure and genome of HIV The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the ...
). Upon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur. Recombination occurs as the single-strand, positive-sense RNA genomes are reverse transcribed to form DNA. During reverse transcription, the nascent DNA can switch multiple times between the two copies of the viral RNA. This form of recombination is known as copy-choice. Recombination events may occur throughout the genome. Anywhere from two to 20 recombination events per genome may occur at each replication cycle, and these events can rapidly shuffle the genetic information that is transmitted from parental to progeny genomes. Viral recombination produces genetic variation that likely contributes to the
evolution Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
of resistance to
anti-retroviral therapy The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple ...
. Recombination may also contribute, in principle, to overcoming the immune defenses of the host. Yet, for the adaptive advantages of genetic variation to be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from separate progenitor parental viruses of differing genetic constitution. It is unknown how often such mixed packaging occurs under natural conditions. Bonhoeffer ''et al.'' suggested that template switching by reverse transcriptase acts as a repair process to deal with breaks in the single-stranded RNA genome. In addition, Hu and Temin suggested that recombination is an adaptation for repair of damage in the RNA genomes. Strand switching (copy-choice recombination) by reverse transcriptase could generate an undamaged copy of genomic DNA from two damaged single-stranded RNA genome copies. This view of the adaptive benefit of recombination in HIV could explain why each HIV particle contains two complete genomes, rather than one. Furthermore, the view that recombination is a repair process implies that the benefit of repair can occur at each replication cycle, and that this benefit can be realized whether or not the two genomes differ genetically. On the view that recombination in HIV is a repair process, the generation of recombinational variation would be a consequence, but not the cause of, the evolution of template switching. HIV-1 infection causes
chronic inflammation Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions ...
and production of
reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen () p ...
. Thus, the HIV genome may be vulnerable to
oxidative damage Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
, including breaks in the single-stranded RNA. For HIV, as well as for viruses in general, successful infection depends on overcoming host defense strategies that often include production of genome-damaging reactive oxygen species. Thus, Michod ''et al.'' suggested that recombination by viruses is an adaptation for repair of genome damage, and that recombinational variation is a byproduct that may provide a separate benefit.


Assembly and release

The final step of the viral cycle, assembly of new HIV-1 virions, begins at the plasma membrane of the host cell. The Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ...
where it is cleaved by
furin Furin is a protease, a proteolytic enzyme that in humans and other animals is encoded by the ''FURIN'' gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these s ...
resulting in the two HIV envelope glycoproteins,
gp41 Gp41 also known as glycoprotein 41 is a subunit of the envelope protein complex of retroviruses, including human immunodeficiency virus (HIV). Gp41 is a transmembrane protein that contains several sites within its ectodomain that are required fo ...
and
gp120 Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1988. The 120 in its name comes from ...
. These are transported to the plasma membrane of the host cell where gp41 anchors gp120 to the membrane of the infected cell. The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell. The budded virion is still immature as the
gag A gag is usually an item or device designed to prevent speech, often as a restraint device to stop the subject from calling for help and keep its wearer silent. This is usually done by blocking the mouth, partially or completely, or attemptin ...
polyproteins still need to be cleaved into the actual matrix, capsid and nucleocapsid proteins. This cleavage is mediated by the packaged viral protease and can be inhibited by antiretroviral drugs of the protease inhibitor class. The various structural components then assemble to produce a mature HIV virion. Only mature virions are then able to infect another cell.


Spread within the body

The classical process of infection of a cell by a virion can be called "cell-free spread" to distinguish it from a more recently recognized process called "cell-to-cell spread". In cell-free spread (see figure), virus particles bud from an infected T cell, enter the blood or
extracellular fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a low ...
and then infect another T cell following a chance encounter. HIV can also disseminate by direct transmission from one cell to another by a process of cell-to-cell spread, for which two pathways have been described. Firstly, an infected T cell can transmit virus directly to a target T cell via a
virological synapse Viral synapse (or virological synapse) is a molecularly organized cellular junction that is similar in some aspects to immunological synapses. Many viruses including herpes simplex virus (HSV), human immunodeficiency virus (HIV) and human T-lymphot ...
. Secondly, an antigen-presenting cell (APC), such as a macrophage or dendritic cell, can transmit HIV to T cells by a process that either involves productive infection (in the case of macrophages) or capture and transfer of virions ''in trans'' (in the case of dendritic cells). Whichever pathway is used, infection by cell-to-cell transfer is reported to be much more efficient than cell-free virus spread. A number of factors contribute to this increased efficiency, including polarised virus budding towards the site of cell-to-cell contact, close apposition of cells, which minimizes fluid-phase
diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemica ...
of virions, and clustering of HIV entry receptors on the target cell towards the contact zone. Cell-to-cell spread is thought to be particularly important in
lymphoid tissue The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphatic or lymphoid o ...
s, where CD4+ T cells are densely packed and likely to interact frequently. Intravital imaging studies have supported the concept of the HIV virological synapse ''in vivo''. The many dissemination mechanisms available to HIV contribute to the virus's ongoing replication in spite of anti-retroviral therapies.


Genetic variability

HIV differs from many viruses in that it has very high
genetic variability Genetic variability is either the presence of, or the generation of, genetic differences. It is defined as "the formation of individuals differing in genotype, or the presence of genotypically different individuals, in contrast to environmentally i ...
. This diversity is a result of its fast replication cycle, with the generation of about 1010 virions every day, coupled with a high
mutation rate In genetics, the mutation rate is the frequency of new mutations in a single gene or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates ...
of approximately 3 x 10−5 per
nucleotide base Nucleobases, also known as ''nitrogenous bases'' or often simply ''bases'', are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic b ...
per cycle of replication and recombinogenic properties of reverse transcriptase. This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day. This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes. This recombination is most obvious when it occurs between subtypes. The closely related
simian immunodeficiency virus ''Simian immunodeficiency virus'' (''SIV'') is a species of retrovirus that cause persistent infections in at least 45 species of non-human primates. Based on analysis of strains found in four species of monkeys from Bioko Island, which was iso ...
(SIV) has evolved into many strains, classified by the natural host species. SIV strains of the African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus, which is present at high levels in the host's blood, but evokes only a mild immune response, does not cause the development of simian AIDS, and does not undergo the extensive mutation and recombination typical of HIV infection in humans. In contrast, when these strains infect species that have not adapted to SIV ("heterologous" or similar hosts such as rhesus or cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection. Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host. SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus. This virus has also lost a function of the '' nef'' gene that is present in most SIVs. For non-pathogenic SIV variants, ''nef'' suppresses T cell activation through the CD3 marker. ''Nef'' function in non-pathogenic forms of SIV is to
downregulate In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pr ...
expression of inflammatory cytokines, MHC-1, and signals that affect T cell trafficking. In HIV-1 and SIVcpz, ''nef'' does not inhibit T-cell activation and it has lost this function. Without this function, T cell depletion is more likely, leading to immunodeficiency. Three groups of HIV-1 have been identified on the basis of differences in the envelope (''env'') region: M, N, and O. Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct. The most prevalent are subtypes B (found mainly in North America and Europe), A and D (found mainly in Africa), and C (found mainly in Africa and Asia); these subtypes form branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Co-infection with distinct subtypes gives rise to circulating recombinant forms (CRFs). In 2000, the last year in which an analysis of global subtype prevalence was made, 47.2% of infections worldwide were of subtype C, 26.7% were of subtype A/CRF02_AG, 12.3% were of subtype B, 5.3% were of subtype D, 3.2% were of CRF_AE, and the remaining 5.3% were composed of other subtypes and CRFs. Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes. The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009. The strain is apparently derived from
gorilla Gorillas are herbivorous, predominantly ground-dwelling great apes that inhabit the tropical forests of equatorial Africa. The genus ''Gorilla'' is divided into two species: the eastern gorilla and the western gorilla, and either four or fi ...
SIV (SIVgor), first isolated from
western lowland gorilla The western lowland gorilla (''Gorilla gorilla gorilla'') is one of two Critically Endangered subspecies of the western gorilla (''Gorilla gorilla'') that lives in montane, primary and secondary forest and lowland swampland in central Afri ...
s in 2006. HIV-2's closest relative is SIVsm, a strain of SIV found in sooty mangabees. Since HIV-1 is derived from SIVcpz, and HIV-2 from SIVsm, the genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsm.


Diagnosis

Many HIV-positive people are unaware that they are infected with the virus. For example, in 2001 less than 1% of the sexually active urban population in Africa had been tested, and this proportion is even lower in rural populations. Furthermore, in 2001 only 0.5% of
pregnant women Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
attending urban health facilities were counselled, tested or received their test results. Again, this proportion is even lower in rural health facilities. Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine and medical research are routinely screened for HIV. HIV-1 testing is initially done using an
enzyme-linked immunosorbent assay The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
(ELISA) to detect antibodies to HIV-1. Specimens with a non-reactive result from the initial ELISA are considered HIV-negative, unless new exposure to an infected partner or partner of unknown HIV status has occurred. Specimens with a reactive ELISA result are retested in duplicate. If the result of either duplicate test is reactive, the specimen is reported as repeatedly reactive and undergoes confirmatory testing with a more specific supplemental test (e.g., a
polymerase chain reaction The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) ...
(PCR),
western blot The western blot (sometimes called the protein immunoblot), or western blotting, is a widely used analytical technique in molecular biology and immunogenetics to detect specific proteins in a sample of tissue homogenate or extract. Besides detect ...
or, less commonly, an
immunofluorescence assay Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specif ...
(IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or PCR or reactive by western blot are considered HIV-positive and indicative of HIV infection. Specimens that are repeatedly ELISA-reactive occasionally provide an indeterminate western blot result, which may be either an incomplete antibody response to HIV in an infected person or nonspecific reactions in an uninfected person. Although IFA can be used to confirm infection in these ambiguous cases, this assay is not widely used. In general, a second specimen should be collected more than a month later and retested for persons with indeterminate western blot results. Although much less commonly available,
nucleic acid test A nucleic acid test (NAT) is a technique used to detect a particular nucleic acid sequence and thus usually to detect and identify a particular species or subspecies of organism, often a virus or bacterium that acts as a pathogen in blood, tissu ...
ing (e.g., viral RNA or proviral DNA amplification method) can also help diagnosis in certain situations. In addition, a few tested specimens might provide inconclusive results because of a low quantity specimen. In these situations, a second specimen is collected and tested for HIV infection. Modern HIV testing is extremely accurate, when the
window period In medicine, the window period for a test designed to detect a specific disease (particularly infectious disease) is the time between first infection and when the test can reliably detect that infection. In antibody-based testing, the window period ...
is taken into consideration. A single screening test is correct more than 99% of the time. The chance of a false-positive result in a standard two-step testing protocol is estimated to be about 1 in 250,000 in a low risk population. Testing post-exposure is recommended immediately and then at six weeks, three months, and six months. The latest recommendations of the US
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) show that HIV testing must start with an
immunoassay An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoass ...
combination test for HIV-1 and HIV-2 antibodies and p24
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
. A negative result rules out HIV exposure, while a positive one must be followed by an HIV-1/2 antibody differentiation immunoassay to detect which antibodies are present. This gives rise to four possible scenarios: * 1. HIV-1 (+) & HIV-2 (−): HIV-1 antibodies detected * 2. HIV-1 (−) & HIV-2 (+): HIV-2 antibodies detected * 3. HIV-1 (+) & HIV-2 (+): both HIV-1 and HIV-2 antibodies detected * 4. HIV-1 (−) or indeterminate & HIV-2 (−):
Nucleic acid test A nucleic acid test (NAT) is a technique used to detect a particular nucleic acid sequence and thus usually to detect and identify a particular species or subspecies of organism, often a virus or bacterium that acts as a pathogen in blood, tissu ...
must be carried out to detect the acute infection of HIV-1 or its absence.


Research

HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure
HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV. Many governments and research institutions participate in HIV/AIDS research. This research includes behavioral health interventions, such as research into
sex education Sex education, also known as sexual education, sexuality education or sex ed, is the instruction of issues relating to human sexuality, including emotional relations and responsibilities, human sexual anatomy, sexual activity, sexual reproduc ...
, and
drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for re ...
, such as research into
microbicides for sexually transmitted diseases Microbicides for sexually transmitted diseases are pharmacologic agents and chemical substances that are capable of killing or destroying certain microorganisms that commonly cause human infection (for example, the human immunodeficiency virus) ...
,
HIV vaccine An HIV vaccine is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine, which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals. It is thought that an HIV ...
s, and anti-retroviral drugs. Other medical research areas include the topics of
pre-exposure prophylaxis Pre-exposure prophylaxis (PrEP) is the use of medications to prevent the spread of disease in people who have not yet been exposed to a disease-causing agent, usually a virus. The term typically refers to the use of antiviral drugs as a strateg ...
, post-exposure prophylaxis,
circumcision Circumcision is a procedure that removes the foreskin from the human penis. In the most common form of the operation, the foreskin is extended with forceps, then a circumcision device may be placed, after which the foreskin is excised. Top ...
, and accelerated aging effects.


Treatment and transmission

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs. In many parts of the world, HIV has become a chronic condition in which progression to AIDS is increasingly rare. HIV latency, and the consequent viral reservoir in CD4+ T cells, dendritic cells, as well as macrophages, is the main barrier to eradication of the virus. It is important to note that although HIV is highly virulent, transmission does not occur through sex when an HIV-positive person has a consistently undetectable
viral load Viral load, also known as viral burden, is a numerical expression of the quantity of virus in a given volume of fluid, including biological and environmental specimens. It is not to be confused with viral titre or viral titer, which depends on the ...
(<50 copies/ml) due to anti-retroviral treatment. This was first argued by the Swiss Federal Commission for AIDS/HIV in 2008 in the Swiss Statement, though the statement was controversial at the time. However, following multiple studies, it became clear that the chance of passing on HIV through sex is effectively zero where the HIV-positive person has a consistently undetectable viral load; this is known as U=U, "Undetectable=Untransmittable", also phrased as "can't pass it on". The studies demonstrating U=U are: Opposites Attract, PARTNER 1, PARTNER 2, (for male-male couples) and HPTN052 (for heterosexual couples) when "the partner living with HIV had a durably suppressed viral load." In these studies, couples where one partner was HIV positive and one partner was HIV negative were enrolled and regular HIV testing completed. In total from the four studies, 4097 couples were enrolled over four continents and 151,880 acts of condomless sex were reported; there were zero phylogenetically linked transmissions of HIV where the positive partner had an undetectable viral load. Following this, the U=U consensus statement advocating the use of "zero risk" was signed by hundreds of individuals and organisations, including the US
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
,
British HIV Association The British HIV Association (BHIVA) is an organisation of healthcare professionals interested in the treatment and care of people with HIV. The current BHIVA Chair is Dr Laura Waters. The aims of BHIVA are, to advance: * Promotion of good prac ...
and ''
The Lancet ''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823. The journal publishes original research articles, ...
'' medical journal. The importance of the final results of the PARTNER 2 study were described by the medical director of the
Terrence Higgins Trust Terrence Higgins Trust is a British charity that campaigns about and provides services relating to HIV and sexual health. In particular, the charity aims to end the transmission of HIV in the UK; to support and empower people living with HIV, to ...
as "impossible to overstate", while lead author Alison Rodger declared that the message that "undetectable viral load makes HIV untransmittable ... can help end the HIV pandemic by preventing HIV transmission. The authors summarised their findings in ''The Lancet'' as follows: This result is consistent with the conclusion presented by Anthony S. Fauci, the Director of the
National Institute of Allergy and Infectious Diseases The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's ...
for the U.S.
National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
, and his team in a viewpoint published in the '' Journal of the American Medical Association'', that U=U is an effective HIV prevention method when an undetectable viral load is maintained.
Genital herpes Genital herpes is an infection by the herpes simplex virus (HSV) of the genitals. Most people either have no or mild symptoms and thus do not know they are infected. When symptoms do occur, they typically include small blisters that break open ...
(HSV-2) reactivation in those infected with the virus have an associated increase in CCR-5 enriched CD4+ T cells as well as inflammatory dendritic cells in the submucosa of the genital skin. Tropism of HIV for CCR-5 positive cells explains the two to threefold increase in HIV acquisition among persons with genital herpes. Daily antiviral (e.g. acyclovir) medication do not reduce the sub-clinical post reactivation inflammation and therefore does not confer reduced risk of HIV acquisition.


History


Discovery

The first news story on "an exotic new disease" appeared May 18, 1981, in the gay newspaper ''
New York Native The ''New York Native'' was a biweekly gay newspaper published by Charles Ortleb in New York City from December 1980 until January 13, 1997. It was the only gay paper in New York City during the early part of the AIDS epidemic, and pioneered repor ...
''. AIDS was first clinically observed in 1981 in the United States. The initial cases were a cluster of injection drug users and gay men with no known cause of impaired immunity who showed symptoms of ''
Pneumocystis The Pneumocystidomycetes are a class of ascomycete fungi. It includes the single order Pneumocystidales, which contains the single monotypic family Pneumocystidaceae, which in turn contains the genus Genus ( plural genera ) is a taxonomic r ...
'' pneumonia (PCP or PJP, the latter term recognizing that the causative agent is now called ''Pneumocystis jirovecii''), a rare opportunistic infection that was known to occur in people with very compromised immune systems. Soon thereafter, researchers at the
NYU School of Medicine NYU Grossman School of Medicine is a medical school of New York University, a private research university in New York City. It was founded in 1841 and is one of two medical schools of the university, with the other being the Long Island School ...
studied gay men developing a previously rare skin cancer called
Kaposi's sarcoma Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limit ...
(KS). Many more cases of PJP and KS emerged, alerting U.S.
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) and a CDC task force was formed to monitor the outbreak. The earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966. In the beginning, the CDC did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus. They also used ''Kaposi's Sarcoma and Opportunistic Infections'', the name by which a task force had been set up in 1981. In the general press, the term ''GRID'', which stood for
gay-related immune deficiency AIDS is caused by a human immunodeficiency virus (HIV), which originated in non-human primates in Central and West Africa. While various sub-groups of the virus acquired human infectivity at different times, the present pandemic had its origins ...
, had been coined. The CDC, in search of a name and looking at the infected communities, coined "the 4H disease", as it seemed to single out homosexuals, heroin users, hemophiliacs, and Haitians. However, after determining that AIDS was not isolated to the
gay community The LGBT community (also known as the LGBTQ+ community, GLBT community, gay community, or queer community) is a loosely defined grouping of lesbian, gay, bisexual, transgender, and other queer individuals united by a common culture and ...
, it was realized that the term GRID was misleading and ''AIDS'' was introduced at a meeting in July 1982. By September 1982 the CDC started using the name AIDS. In 1983, two separate research groups led by American
Robert Gallo Robert Charles Gallo (; born March 23, 1937) is an American biomedical researcher. He is best known for his role in establishing the human immunodeficiency virus (HIV) as the infectious agent responsible for acquired immune deficiency syndrome ...
and French investigators and Luc Montagnier independently declared that a novel retrovirus may have been infecting AIDS patients, and published their findings in the same issue of the journal ''
Science Science is a systematic endeavor that Scientific method, builds and organizes knowledge in the form of Testability, testable explanations and predictions about the universe. Science may be as old as the human species, and some of the earli ...
''. Gallo claimed that a virus his group had isolated from a person with AIDS was strikingly similar in
shape A shape or figure is a graphical representation of an object or its external boundary, outline, or external surface, as opposed to other properties such as color, texture, or material type. A plane shape or plane figure is constrained to lie ...
to other
human T-lymphotropic virus The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma an ...
es (HTLVs) his group had been the first to isolate. Gallo admitted in 1987 that the virus he claimed to have discovered in 1984 was in reality a virus sent to him from France the year before. Gallo's group called their newly isolated virus HTLV-III. Montagnier's group isolated a virus from a patient presenting with swelling of the lymph nodes of the neck and physical weakness, two classic symptoms of primary HIV infection. Contradicting the report from Gallo's group, Montagnier and his colleagues showed that core proteins of this virus were immunologically different from those of HTLV-I. Montagnier's group named their isolated virus lymphadenopathy-associated virus (LAV). As these two viruses turned out to be the same, in 1986 LAV and HTLV-III were renamed HIV. Another group working contemporaneously with the Montagnier and Gallo groups was that of Jay A. Levy at the
University of California, San Francisco The University of California, San Francisco (UCSF) is a public land-grant research university in San Francisco, California. It is part of the University of California system and is dedicated entirely to health science and life science. It con ...
. He independently discovered the AIDS virus in 1983 and named it the AIDS associated retrovirus (ARV). This virus was very different from the virus reported by the Montagnier and Gallo groups. The ARV strains indicated, for the first time, the heterogeneity of HIV isolates and several of these remain classic examples of the AIDS virus found in the United States.


Origins

Both HIV-1 and HIV-2 are believed to have originated in non-human
primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians ( monkeys and apes, the latter including ...
s in West-central Africa, and are believed to have transferred to humans (a process known as
zoonosis A zoonosis (; plural zoonoses) or zoonotic disease is an infectious disease of humans caused by a pathogen (an infectious agent, such as a bacterium, virus, parasite or prion) that has jumped from a non-human (usually a vertebrate) to a human. ...
) in the early 20th century. HIV-1 appears to have originated in southern
Cameroon Cameroon (; french: Cameroun, ff, Kamerun), officially the Republic of Cameroon (french: République du Cameroun, links=no), is a country in west-central Africa. It is bordered by Nigeria to the west and north; Chad to the northeast; the C ...
through the evolution of SIVcpz, a
simian immunodeficiency virus ''Simian immunodeficiency virus'' (''SIV'') is a species of retrovirus that cause persistent infections in at least 45 species of non-human primates. Based on analysis of strains found in four species of monkeys from Bioko Island, which was iso ...
(SIV) that infects wild chimpanzees (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies '' Pan troglodytes troglodytes''). The closest relative of HIV-2 is SIVsmm, a virus of the sooty mangabey (''Cercocebus atys atys''), an
Old World monkey Old World monkey is the common English name for a family of primates known taxonomically as the Cercopithecidae (). Twenty-four genera and 138 species are recognized, making it the largest primate family. Old World monkey genera include baboons ...
living in littoral West Africa (from southern
Senegal Senegal,; Wolof: ''Senegaal''; Pulaar: 𞤅𞤫𞤲𞤫𞤺𞤢𞥄𞤤𞤭 (Senegaali); Arabic: السنغال ''As-Sinighal'') officially the Republic of Senegal,; Wolof: ''Réewum Senegaal''; Pulaar : 𞤈𞤫𞤲𞤣𞤢𞥄𞤲𞤣𞤭 ...
to western Côte d'Ivoire).
New World monkey New World monkeys are the five families of primates that are found in the tropical regions of Mexico, Central and South America: Callitrichidae, Cebidae, Aotidae, Pitheciidae, and Atelidae. The five families are ranked together as the Ceboidea ...
s such as the
owl monkey Night monkeys, also known as owl monkeys or douroucoulis (), are nocturnal New World monkeys of the genus ''Aotus'', the only member of the family Aotidae (). The genus comprises eleven species which are found across Panama and much of South Ame ...
are resistant to HIV-1 infection, possibly because of a genomic fusion of two viral resistance genes. HIV-1 is thought to have jumped the species barrier on at least three separate occasions, giving rise to the three groups of the virus, M, N, and O. There is evidence that humans who participate in bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV. However, SIV is a weak virus, and it is typically suppressed by the human immune system within weeks of infection. It is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough time to mutate into HIV. Furthermore, due to its relatively low person-to-person transmission rate, it can only spread throughout the population in the presence of one or more high-risk transmission channels, which are thought to have been absent in Africa prior to the 20th century. Specific proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout the society, depend on the proposed timing of the animal-to-human crossing. Genetic studies of the virus suggest that the most recent common ancestor of the HIV-1 M group dates back to circa 1910. Proponents of this dating link the HIV epidemic with the emergence of
colonialism Colonialism is a practice or policy of control by one people or power over other people or areas, often by establishing colony, colonies and generally with the aim of economic dominance. In the process of colonisation, colonisers may impose the ...
and growth of large colonial African cities, leading to social changes, including different patterns of sexual contact (especially multiple, concurrent partnerships), the spread of prostitution, and the concomitant high frequency of
genital ulcer A genital ulcer is an open sore located on the genital area, which includes the vulva, penis, perianal region, or anus. Genital ulcers are most commonly caused by infectious agents (fungal infections, secondary bacterial infections, or sexually t ...
diseases (such as syphilis) in nascent colonial cities. While transmission rates of HIV during vaginal intercourse are typically low, they are increased manyfold if one of the partners has a sexually transmitted infection resulting in genital ulcers. Early 1900s colonial cities were notable for their high prevalence of prostitution and genital ulcers to the degree that as of 1928 as many as 45% of female residents of eastern Leopoldville (currently Kinshasa) were thought to have been prostitutes and as of 1933 around 15% of all residents of the same city were infected by one of the forms of syphilis. The earliest, well-documented case of HIV in a human dates back to 1959 in the
Belgian Congo The Belgian Congo (french: Congo belge, ; nl, Belgisch-Congo) was a Belgian colony in Central Africa from 1908 until independence in 1960. The former colony adopted its present name, the Democratic Republic of the Congo (DRC), in 1964. Colo ...
. The virus may have been present in the United States as early as the mid- to late 1960s, as a sixteen-year-old male named Robert Rayford presented with symptoms in 1966 and died in 1969. An alternative and likely complementary hypothesis points to the widespread use of unsafe medical practices in Africa during years following World War II, such as unsterile reuse of single-use syringes during mass vaccination, antibiotic, and anti-malaria treatment campaigns. Research on the timing of most recent common ancestor for HIV-1 groups M and O, as well as on HIV-2 groups A and B, indicates that SIV has given rise to transmissible HIV lineages throughout the twentieth century. The dispersed timing of these transmissions to humans implies that no single external factor is needed to explain the cross-species transmission of HIV. This observation is consistent with both of the two prevailing views of the origin of the HIV epidemics, namely SIV transmission to humans during the slaughter or butchering of infected primates, and the colonial expansion of sub-Saharan African cities.


See also

* Antiviral drug *
Discovery and development of HIV-protease inhibitors Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule l ...
*
HIV/AIDS denialism HIV/AIDS denialism is the belief, despite conclusive evidence to the contrary, that the human immunodeficiency virus (HIV) does not cause acquired immune deficiency syndrome (AIDS). Some of its proponents reject the existence of HIV, while othe ...
*
World AIDS Day World AIDS Day, designated on 1 December every year since 1988, is an international day dedicated to raising awareness of the AIDS pandemic caused by the spread of HIV infection and mourning those who have died of the disease. The acquired imm ...


References


Further reading

* * *


External links

* {{DEFAULTSORT:Hiv * Causes of death Discovery and invention controversies IARC Group 2B carcinogens Lentiviruses Sexually transmitted diseases and infections 1983 in biology