The human immunodeficiency viruses (HIV) are two species of ''
Lentivirus
''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
'' (a subgroup of
retrovirus
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 ...
) 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 splinte ...
allows life-threatening
opportunistic infection
An opportunistic infection is an infection caused by pathogens (bacteria, fungi, parasites or viruses) that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune ...
s 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
Sexually transmitted infections (STIs), also referred to as sexually transmitted diseases (STDs) and the older term venereal diseases, are infections that are Transmission (medicine), spread by Human sexual activity, sexual activity, especi ...
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 c ...
,
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. Semen i ...
, 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 ( 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 ...
, 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 globall ...
by exposure to her blood or vaginal fluid, and through
breast milk
Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
.
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 Ivanovsky's 1 ...
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
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
+ T cells),
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s, and
dendritic cell
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. ...
s. HIV infection leads to low levels of CD4
+ T cells through a number of mechanisms, including
pyroptosis Pyroptosis is a highly inflammatory form of Lysis, 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 clearanc ...
of abortively infected T cells,
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
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 extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biological classification, genus com ...
''
Lentivirus
''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
'',
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 e ...
''.
Lentiviruses have many
morphologies and
biological
Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary in ...
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 i ...
.
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 strand ...
, 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 Stimulus (physiology), stimuli. (For example, in the human body, the brain which is part of the cen ...
,
enveloped RNA virus
An RNA virus is a virusother than a retrovirusthat has ribonucleic acid (RNA) as its genetic material. The nucleic acid is usually single-stranded RNA ( ssRNA) but it may be double-stranded (dsRNA). Notable human diseases caused by RNA viruses ...
es. Upon entry into the target cell, the viral
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
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 ge ...
is converted (reverse transcribed) into double-stranded
DNA by a virally encoded enzyme,
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
, that is transported along with the viral genome in the virus particle. The resulting viral DNA is then imported into the
cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
and integrated into the cellular DNA by a virally encoded enzyme,
integrase
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...
, 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 ca ...
and more
infective
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmiss ...
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, Maurit ...
.
Structure and genome
![HI-virion-structure en](https://upload.wikimedia.org/wikipedia/commons/5/5e/HI-virion-structure_en.svg)
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 Stimulus (physiology), stimuli. (For example, in the human body, the brain which is part of the cen ...
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 strand ...
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
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 ba ...
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 may ...
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
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
,
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 the ...
and
integrase
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...
. 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.
![Protein Structure Diagram of Fusion Peptide Epitope on HIV Spike (41863579304)](https://upload.wikimedia.org/wikipedia/commons/8/88/Protein_Structure_Diagram_of_Fusion_Peptide_Epitope_on_HIV_Spike_%2841863579304%29.jpg)
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 v ...
efforts.
Over half of the mass of the trimeric envelope spike is N-linked
glycan
The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate p ...
s. 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
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
and an
isoleucine
Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the deprot ...
to
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
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 or viral replication, mi ...
(
radical replacement
A conservative replacement (also called a conservative mutation or a conservative substitution) is an amino acid replacement in a protein that changes a given amino acid to a different amino acid with similar Amino_acid#Classification, biochemical ...
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.
![HIV-genome](https://upload.wikimedia.org/wikipedia/commons/c/c6/HIV-genome.png)
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 bit ...
,
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. miRN ...
s that regulate the
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
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 i ...
(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 nuclei ...
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 (biology), 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 eukar ...
at
G2/M. The ''nef'' protein (p27) down-regulates
CD4
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
(the major viral receptor), as well as the
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on plat ...
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 nucleic acid sequence, 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 ...
required to make functional ''pol''.
Tropism
![HIV Mature and Immature](https://upload.wikimedia.org/wikipedia/commons/0/00/HIV_Mature_and_Immature.PNG)
The term
viral tropism
Tissue tropism is the range of cells and tissues of a host (biology), host that support growth of a particular pathogen, such as a virus (biology), virus, bacteria, bacterium or parasite.
Some bacteria and viruses have a broad tissue tropism and c ...
refers to the cell types a virus infects. HIV can infect a variety of immune cells such as
CD4+ T cells,
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s, 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 de ...
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 t ...
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 pro ...
, 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 par ...
. 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 an ...
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 blends ...
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 pathological ...
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 electr ...
for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by
down-regulating
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 proce ...
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
Sexual intercourse (or coitus or copulation) is a sexual activity typically involving the insertion and thrusting of the penis into the vagina for sexual pleasure or reproduction.Sexual intercourse most commonly means penile–vaginal penetrat ...
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 i ...
, 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 multiple ...
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, Maurit ...
. The adoption of "accessory genes" by HIV-2 and its more
promiscuous
Promiscuity is the practice of engaging in sexual activity frequently with different Sexual partner, partners or being indiscriminate in the choice of sexual partners. The term can carry a moral judgment. A common example of behavior viewed as pro ...
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
![HIV Membrane fusion panel](https://upload.wikimedia.org/wikipedia/commons/6/61/HIV_Membrane_fusion_panel.svg)
The HIV virion enters
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
s 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 a f ...
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 spike) on the HIV viral envelope and both
CD4
In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...
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 pro ...
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 α
4β
7 activating LFA-1, the central integrin involved in the establishment of virological synapses, 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 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-terminus, N-terminal fusion peptide gp41 to penetrate the cell membrane.
Repeated sequence (DNA), Repeat sequences 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 cell
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. ...
s (DCs) by this CD4-CCR5 route, but another route using Mannose receptor, mannose-specific C-type lectin receptors such as DC-SIGN 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 neurons, is believed to prevent the infection of cells by HIV.
![Itrafig2](https://upload.wikimedia.org/wikipedia/commons/4/47/Itrafig2.jpg)
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 of HIV-1 has also been reported and was recently suggested to constitute the only route of productive entry.
Replication and transcription
![Reverse Transcription](https://upload.wikimedia.org/wikipedia/commons/a/aa/Reverse_Transcription.png)
Shortly after the viral capsid enters the cell, an enzyme called
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
liberates the positive-sense single-stranded
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
genome from the attached viral proteins and copies it into a cDNA, complementary DNA (cDNA) molecule.
The process of reverse transcription is extremely error-prone, and the resulting mutations may cause Resistance to antiviral drugs, drug resistance 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 Stimulus (physiology), stimuli. (For example, in the human body, the brain which is part of the cen ...
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 cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
. 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 ge ...
is carried out by another viral enzyme called
integrase
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...
.
The integrated viral DNA may then lie dormant, in the latent stage of HIV infection.
To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF-κB, 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 Stem-loop, 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 post-transcriptional modification, 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, where they are Translation (genetics), translated to produce HIV proteins, including Rev (HIV), 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). 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 of resistance to Management of HIV/AIDS, anti-retroviral therapy. 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 and production of reactive oxygen species. Thus, the HIV genome may be vulnerable to oxidative damage, 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
![HIV on macrophage](https://upload.wikimedia.org/wikipedia/commons/a/a7/HIV_on_macrophage.png)
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 where it is Bond cleavage, cleaved by furin 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. 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 Group-specific antigen, gag 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 (pharmacology), 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
![Virus infecting lymphocytes](https://upload.wikimedia.org/wikipedia/commons/f/fb/Virus_infecting_lymphocytes.gif)
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 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 Viral synapse, virological synapse.
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 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 tissues, where CD4
+ T cells are densely packed and likely to interact frequently.
Intravital microscopy, 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-SIV-phylogenetic-tree straight](https://upload.wikimedia.org/wikipedia/commons/f/fb/HIV-SIV-phylogenetic-tree_straight.svg)
HIV differs from many viruses in that it has very high genetic variability. This diversity is a result of its fast #Replication cycle, replication cycle, with the generation of about 10
10 virions every day, coupled with a high mutation rate of approximately 3 x 10
−5 per Nucleobase, nucleotide base per cycle of replication and Genetic recombination, 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 Coinfection, 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 (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the Chlorocebus, 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 macaque, rhesus or Crab-eating macaque, cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection. Common chimpanzee, 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 (protein), nef'' gene that is present in most SIVs. For non-pathogenic SIV variants, ''nef'' suppresses T cell activation through the CD3 (immunology), CD3 marker. ''Nef'' function in non-pathogenic forms of SIV is to Downregulation and upregulation, downregulate expression of Proinflammatory cytokine, inflammatory cytokines, MHC class I, 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. Coinfection, 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 gorilla, gorilla SIV (SIVgor), first isolated from western lowland gorillas 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
![Hiv-timecourse copy](https://upload.wikimedia.org/wikipedia/commons/0/0e/Hiv-timecourse_copy.svg)
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 Pregnancy, pregnant women 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, Blood donation, 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 (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 (PCR), western blot or, less commonly, an immunofluorescence assay (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 testing (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 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 (CDC), Centers for Disease Control and Prevention (CDC) show that HIV testing must start with an immunoassay combination test for HIV-1 and HIV-2 Antibody, antibodies and p24 antigen. 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 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, 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, and drug development, such as research into microbicides for sexually transmitted diseases,
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 v ...
s, and antiretroviral drug, anti-retroviral drugs. Other medical research areas include the topics of pre-exposure prophylaxis, post-exposure prophylaxis, circumcision and HIV, circumcision, and Biological clock (aging), accelerated aging effects.
Treatment and transmission
The management of HIV/AIDS normally includes the use of multiple Antiviral drugs, antiretroviral drugs. In many parts of the world, HIV has become a chronic condition in which progression to HIV/AIDS#Acquired immunodeficiency syndrome, 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 (<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 Centers for Disease Control and Prevention, CDC, British HIV Association and ''The Lancet'' medical journal. The importance of the final results of the PARTNER 2 study were described by the medical director of the Terrence Higgins Trust 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 for the U.S. National Institutes of Health, 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 (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''.
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 jirovecii, Pneumocystis'' 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 studied gay men developing a previously rare skin cancer called Kaposi's sarcoma (KS).
Many more cases of PJP and KS emerged, alerting U.S. Centers for Disease Control and Prevention (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, 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, haemophilia, hemophiliacs, and Haitians.
However, after determining that AIDS was not isolated to the gay community,
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 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 (journal), Science''.
Gallo claimed that a virus his group had isolated from a person with AIDS was strikingly similar in virus structure, shape to other human T-lymphotropic viruses (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 asthenia, 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. 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 primates in West-central Africa, and are believed to have transferred to humans (a process known as zoonosis) in the early 20th century.
HIV-1 appears to have originated in southern Cameroon through the evolution of SIVcpz, a simian immunodeficiency virus (SIV) that infects wild common chimpanzee, chimpanzees (HIV-1 descends from the SIVcpz endemic in the chimpanzee subspecies ''Central chimpanzee, Pan troglodytes troglodytes'').
The closest relative of HIV-2 is SIVsmm, a virus of the sooty mangabey (''Cercocebus atys atys''), an Old World monkey living in littoral West Africa (from southern Senegal to western Ivory Coast, Côte d'Ivoire).
New World monkeys such as the Night monkey, owl monkey are resistant to HIV-1 infection, possibly because of a fusion gene, 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.
![SIV primates](https://upload.wikimedia.org/wikipedia/commons/9/93/SIV_primates.jpg)
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 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 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 disease, 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 Kinshasa, 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 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
* HIV/AIDS denialism
* World AIDS Day
References
Further reading
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External links
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{{DEFAULTSORT:Hiv
HIV/AIDS, *
Causes of death
Discovery and invention controversies
IARC Group 2B carcinogens
Lentiviruses
Sexually transmitted diseases and infections
1983 in biology