The human immunodeficiency virus (HIV) is a lentivirus (a subgroup of
retrovirus) that causes
HIV infection and over time acquired
immunodeficiency syndrome (AIDS).
AIDS is a condition in humans
in which progressive failure of the immune system allows
life-threatening opportunistic infections and cancers to thrive.
Without treatment, average survival time after infection with
estimated to be 9 to 11 years, depending on the
In most cases,
HIV is a sexually transmitted infection and occurs by
contact with or transfer of blood, pre-ejaculate, semen, and vaginal
fluids. Non-sexual transmission can occur from an infected mother to
her infant through breast milk. An HIV-positive mother can
HIV to her baby both during pregnancy and childbirth due to
exposure to her blood or vaginal fluid. Within these bodily fluids,
HIV is present as both free virus particles and virus within infected
HIV infects vital cells in the human immune system such as helper T
cells (specifically CD4+ T cells), macrophages, and dendritic
HIV infection leads to low levels of CD4+
T cells through a
number of mechanisms, including pyroptosis 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 is lost, and the body becomes progressively more susceptible
to opportunistic infections, leading to the development of AIDS.
1.2 Structure and genome
1.4 Replication cycle
1.4.1 Entry to the cell
1.4.2 Replication and transcription
1.4.4 Assembly and release
1.5 Spread within the body
1.6 Genetic variability
6 See also
8 Further reading
9 External links
See also: Subtypes of HIV
HIV is a member of the genus Lentivirus, part of the family
Retroviridae. 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. Lentiviruses are transmitted as
single-stranded, positive-sense, enveloped
RNA viruses. Upon entry
into the target cell, the viral
RNA genome 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, allowing the virus and its host cell to
avoid detection by the immune system, for an indiscriminate amount of
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.
the virus that was initially discovered and termed both LAV
Lymphadenopathy Associated Virus) and HTLV-III (Human T cell
HIV-1 is more virulent and more infective
than HIV-2, and is the cause of the majority of
globally. The lower infectivity of
HIV-2 compared to
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.
Structure and genome
Main article: Structure and genome of HIV
Diagram of the
HIV is different in structure from other retroviruses. It is roughly
spherical with a diameter of about 120 nm, around
60 times smaller than a red blood cell. It is composed of two
copies of positive-sense single-stranded
RNA that codes for the
virus's nine genes enclosed by a conical capsid composed of 2,000
copies of the viral protein p24. The single-stranded
tightly bound to nucleocapsid proteins, p7, and enzymes needed for the
development of the virion such as reverse transcriptase, proteases,
ribonuclease and integrase. A matrix composed of the viral protein p17
surrounds the capsid ensuring the integrity of the virion
This is, in turn, surrounded by the viral envelope, that is composed
of the lipid bilayer 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 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 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
The molecular structure of the viral spike has now been determined by
X-ray crystallography and cryo-electron microscopy. 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 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 epitopes than
recombinant monomeric gp120, which act to suppress the immune response
to target epitopes.
Structure of the
RNA genome of HIV-1
RNA genome consists of at least seven structural landmarks (LTR,
TAR, RRE, 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 microRNAs that regulate the apoptosis genes
ERCC1 and IER3. The Rev protein (p19) is involved in shuttling
RNAs from the nucleus and the cytoplasm by binding to the RRE RNA
element. The Vif protein (p23) prevents the action of
cellular protein that deaminates Cytidine to Uridine in the single
DNA and/or interferes with reverse transcription).
Vpr protein (p14) arrests cell division at G2/M. The Nef protein
CD4 (the major viral receptor), as well as the
MHC class I
MHC class I and class II molecules.
Nef also interacts with SH3 domains. The Vpu protein (p16) influences
the release of new virus particles from infected cells. The ends
of each strand of
RNA contain an
RNA sequence called the long
terminal repeat (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
(TTTTTT) is involved in the frameshift in the Gag-Pol reading frame
required to make functional Pol.
Diagram of the immature and mature forms of HIV
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 cells.
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 co-receptors.
Macrophage-tropic (M-tropic) strains of HIV-1, or
non-syncytia-inducing strains (NSI; now called R5 viruses) use the
CCR5 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
HIV infection. They appear to be the first cells infected
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. In tonsils and
adenoids of HIV-infected patients, macrophages fuse into
multinucleated giant cells that produce huge amounts of virus.
T-tropic strains of HIV-1, or syncytia-inducing (SI; now called X4
viruses) strains replicate in primary CD4+
T cells as well as in
macrophages and use the α-chemokine receptor, CXCR4, for
HIV-1 strains are thought to be transitional strains of
HIV-1 and thus are able to use both
CXCR4 as co-receptors for
The α-chemokine SDF-1, a ligand for CXCR4, suppresses replication of
HIV-1 isolates. It does this by down-regulating the
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
CXCR4 are termed X4, and those that use both, X4R5. However, the
use of co-receptor alone does not explain viral tropism, as not all R5
viruses are able to use
CCR5 on macrophages for a productive
HIV can also infect a subtype of myeloid dendritic
cells, which probably constitute a reservoir that maintains
infection when CD4+ T cell numbers have declined to extremely low
Some people are resistant to certain strains of HIV. For example,
people with the
CCR5-Δ32 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
HIV are present in the seminal fluid, which enables the virus to be
transmitte from a male to his sexual partner. 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
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. 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
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. The adoption of "accessory
HIV-2 and its more promiscuous 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 organism. Having achieved a
low pathogenicity, over time, variants that are more successful at
transmission will be selected.
HIV replication cycle
Entry to the cell
Mechanism of viral entry: 1. Initial interaction between gp120 and
CD4. 2. Conformational change in gp120 allows for secondary
interaction with CCR5. 3. The distal tips of gp41 are inserted into
the cellular membrane. 4. gp41 undergoes significant conformational
change; folding in half and forming coiled-coils. This process pulls
the viral and cellular membranes together, fusing them.
HIV virion enters macrophages and CD4+
T cells by the adsorption
of glycoproteins on its surface to receptors on the target cell
followed by fusion of the viral envelope 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 and a
chemokine co-receptor (generally either
CCR5 or CXCR4, but others are
known to interact) on the target cell surface.
Gp120 binds to
integrin α4β7 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-terminal fusion
peptide gp41 to penetrate the cell membrane. Repeat sequences
in gp41, HR1, and HR2 then interact, causing the collapse of the
extracellular portion of gp41 into a hairpin. This loop structure
brings the virus and cell membranes close together, allowing fusion of
the membranes and subsequent entry of the viral capsid.
HIV has bound to the target cell, the
RNA and various
enzymes, including reverse transcriptase, integrase, ribonuclease, and
protease, are injected into the cell.[not in citation given]
During the microtubule-based transport to the nucleus, the viral
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 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
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.
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-dependent endocytosis of
HIV-1 has also been reported and was
recently suggested to constitute the only route of productive
Replication and transcription
Reverse transcription of the
HIV genome into double-stranded DNA
Shortly after the viral capsid enters the cell, an enzyme called
reverse transcriptase liberates the positive-sense single-stranded RNA
genome from the attached viral proteins and copies it into a
DNA (cDNA) molecule. The process of reverse
transcription is extremely error-prone, and the resulting mutations
may cause 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 DNA
from the antisense cDNA. Together, the c
DNA 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 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 factors need to be present, the most important of which
NF-κB (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
currently fighting infection.
During viral replication, the integrated
DNA provirus is transcribed
into RNA, some of which then undergo
RNA splicing to produce mature
mRNAs. These mRNAs are exported from the nucleus into the cytoplasm,
where they are translated into the regulatory proteins Tat (which
encourages new virus production) and 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 new copies
of the virus genome, while others 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-2 appear to package their
HIV-1 will bind to any appropriate RNA. HIV-2
will preferentially bind to the m
RNA that was used to create the Gag
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 (+)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
Viral recombination produces genetic variation that likely contributes
to the evolution of resistance to 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
Bonhoeffer et al. suggested that template switching by reverse
transcriptase acts as a repair process to deal with breaks in the
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
RNA genome copies. This view of the adaptive
benefit of recombination in
HIV could explain why each
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 ongoing inflammation and production of
reactive oxygen species. Thus, the
HIV genome may be vulnerable to
oxidative damages, including breaks in the single-stranded RNA. For
HIV, as well as for viruses generally, successful infection depends on
overcoming host defensive strategies that often include production of
genome-damaging reactive oxygen. Thus, Michod et al. suggested
that recombination by viruses is an adaptation for repair of genome
damages, and that recombinational variation is a byproduct that may
provide a separate benefit.
Assembly and release
HIV assembling on the surface of an infected macrophage. The HIV
virions have been marked with a green fluorescent tag and then viewed
under a fluorescent microscope.
The final step of the viral cycle, assembly of new
begins at the plasma membrane of the host cell. The Env polyprotein
(gp160) goes through the endoplasmic reticulum and is transported to
the Golgi complex where it is cleaved by furin resulting in the two
HIV envelope glycoproteins, gp41 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
RNA as the forming virion begins
to bud from the host cell. The budded virion is still immature as the
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 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
Animation demonstrating cell-free spread of HIV.
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
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. Secondly, an antigen-presenting cell (APC), such as a
macrophage or dendritic cell, can transmit
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
receptors on the target cell to the contact zone. Cell-to-cell
spread is thought to be particularly important in lymphoid tissues
T cells are densely packed and likely to interact
frequently. Intravital imaging studies have supported the concept
HIV virological synapse in vivo. The hybrid spreading
HIV contribute to the virus' ongoing replication in
spite of anti-retroviral therapies.
Further information: Subtypes of HIV
The phylogenetic tree of the SIV and HIV
HIV differs from many viruses in that it has very high genetic
variability. 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 of approximately 3 x 10−5 per nucleotide base per
cycle of replication and recombinogenic properties of reverse
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
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
African green monkey
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
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's function in non-pathogenic forms of SIV is to downregulate
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 SIV (SIVgor), first isolated from
western lowland gorillas in 2006.
HIV-2's closest relative is SIVsm, a strain of SIV found in sooty
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.
Main article: Diagnosis of HIV/AIDS
A generalized graph of the relationship between
HIV copies (viral
CD4 counts over the average course of untreated HIV
infection; any particular individual's disease course may vary
CD4+ T cell count (cells per µL)
RNA copies per mL of plasma
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 attending urban health facilities were counselled,
tested or receive 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 (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.
HIV deaths (other than U.S.) in 2014.
South Africa (12.51%)
DR Congo (2.17%)
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
HIV testing is extremely accurate. A single screening test is
correct more than 99% of the time.[needs update] The chance of a
false-positive result in 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 CDC show that
HIV testing must start
with an immunoassay combination test for
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:
HIV-1 (+) &
HIV-1 antibodies detected
HIV-1 (−) &
HIV-2 antibodies detected
HIV-1 (+) &
HIV-2 (+): both
HIV-2 antibodies detected
HIV-1 (−) or indeterminate &
Nucleic acid test
must be carried out to detect the acute infection of
HIV-1 or its
An updated algorithm published by the CDC in June 2014 recommends that
diagnosis starts with the p24 antigen test. A negative result rules
out infection, while a positive one must be followed by an HIV-1/2
antibody differentiation immunoassay. A positive differentiation test
confirms diagnosis, while a negative or indeterminate result must be
followed by nucleic acid test (NAT). A positive NAT result confirms
HIV-1 infection whereas a negative result rules out infection (false
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 vaccines, and
anti-retroviral drugs. Other medical research areas include the
topics of pre-exposure prophylaxis, post-exposure prophylaxis,
circumcision and HIV, and accelerated aging effects.
After many years of research, an untested
HIV vaccine has been
created. Bi-specific antibodies, that target both the surface of
T-cells and viral epitopes, can prevent entry of the virus into human
cells. Another group has utilised the same technology to develop
a bi-specific antibody that neutralises viral particles by
cross-linking of envelope glycoproteins.
Main article: Management of HIV/AIDS
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 is greatly reduced when an HIV-infected person has a
suppressed or undetectable viral load (<50 copies/ml) due to
prolonged and successful anti-retroviral treatment. Hence, it can be
said to be almost impossible (but still non-zero) for an HIV-infected
person who has an undetectable viral load to transmit the virus, even
during unprotected sexual intercourse, as there would be a negligible
HIV present in the seminal fluid, vaginal secretions or
blood, for transmission to occur. This does not mean
however, that prolonged anti-retroviral treatment will result in a
suppressed viral load. An undetectable viral load, generally agreed as
less than 50 copies per milliliter of blood, can only be proven by a
polymerase chain reaction (PCR) test.
At the same time, it is important to recognise that reaching an
undetectable viral load is determined by many factors, including
HIV resistance to certain anti-retroviral drugs,
stigma, and inadequate health systems.
Main article: History of HIV/AIDS
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 carinii pneumonia (PCP), a rare opportunistic infection
that was known to occur in people with very compromised immune
systems. Soon thereafter, additional gay men developed a
previously rare skin cancer called
Kaposi's sarcoma (KS).
Many more cases of PCP 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
AIDS is believed to have been in Norway beginning in
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, 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.
Françoise Barré-Sinoussi, co-discoverer of HIV
In 1983, two separate research groups led by American
Robert Gallo and
Françoise Barré-Sinoussi 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. Gallo claimed that a virus his group
had isolated from a person with
AIDS was strikingly similar in shape
to other human T-lymphotropic viruses (HTLVs) his group had been the
first to isolate. Gallo's group called their newly isolated virus
HTLV-III. At the same time, 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 AIDS. 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
Another group working contemporaneously with the Montagnier and Gallo
groups was that of Dr. Jay 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
HIV isolates and several of these remain classic
examples of the
AIDS virus found in the United States.
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
HIV-1 appears to have originated in southern
Cameroon through the
evolution of SIV(cpz), a simian immunodeficiency virus (SIV) that
infects wild chimpanzees (
HIV-1 descends from the SIV(cpz) endemic in
the chimpanzee subspecies Pan troglodytes troglodytes). The
closest relative of
HIV-2 is SIV (smm), a virus of the sooty mangabey
(Cercocebus atys atys), an
Old World monkey
Old World monkey living in littoral West
Africa (from southern
Senegal to western Côte d'Ivoire). New
World monkeys such as the owl monkey are resistant to
possibly because of a genomic fusion of two viral resistance
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.
Left to right: the
African green monkey
African green monkey source of SIV, the sooty
mangabey source of HIV-2, and the chimpanzee source of HIV-1
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
group dates back to circa 1910. Proponents of this dating link
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 many fold if one of
the partners suffers from a sexually transmitted infection resulting
in genital ulcers. Early 1900s colonial cities were notable due to
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 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.
An alternative view — unsupported by evidence — holds
that 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, were
the initial vector that allowed the virus to adapt to humans and
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 1950s, as a sixteen-year-old
male presented with symptoms in 1966 died in 1969.
Discovery and development of HIV-protease inhibitors
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Simian foamy virus
Human foamy virus
Hepatitis B virus)
Human teratocarcinoma-derived virus
Breakthrough of the Year
1997: Dolly the sheep
1998: Accelerating universe
1999: Stem cell
2000: Whole genome sequencing
2001: Nanocircuits or Molecular circuit
2003: Dark energy
2004: Spirit rover
Evolution in action
Poincaré conjecture proof
2007: Human genetic variation
2008: Cellular reprogramming
2010: First quantum machine
HPTN 052 clinical trial
Higgs boson discovery
2014: Rosetta comet mission
CRISPR genome-editing method
2016: First observation of gravitational waves
GW170817 (neutron star merger)
BNF: cb12066922x (d