Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS),[1][2] a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells. The four major routes of transmission are unsafe sex, contaminated needles, breast milk, and transmission from an infected mother to her baby at birth (perinatal transmission). Screening of blood products for HIV has largely eliminated transmission through blood transfusions or infected blood products in the developed world.
HIV infection in humans is considered pandemic by the World Health Organization (WHO).[3] Nevertheless, complacency about HIV may play a key role in HIV risk.[4][5] From its discovery in 1981 to 2006, AIDS killed more than 25 million people.[6] HIV infects about 0.6% of the world's population.[6] In 2009, AIDS claimed an estimated 1.8 million lives, down from a global peak of 2.1 million in 2004.[7] Approximately 260,000 children died of AIDS in 2009.[7] A disproportionate number of AIDS deaths occur in Sub-Saharan Africa, retarding economic growth and exacerbating the burden of poverty.[8] An estimated 22.5 million people (68% of the global total) live with HIV in sub-Saharan Africa, which is also home to 90% of the world's 16.6 million children orphaned by HIV.[7] Treatment with antiretroviral drugs reduces both the mortality and the morbidity of HIV infection.[9] Although antiretroviral medication is still not universally available, expansion of antiretroviral therapy programs since 2004 has helped to turn the tide of AIDS deaths and new infections in many parts of the world.[7] Intensified awareness and preventive measures, as well as the natural course of the epidemic, have also played a role. Nevertheless, an estimated 2.6 million people were newly infected in 2009.[7]
HIV infects vital cells in the human immune system such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells.[10] HIV infection leads to low levels of CD4+ T cells through three main mechanisms: First, direct viral killing of infected cells; second, increased rates of apoptosis in infected cells; and third, 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.
Most untreated people infected with HIV-1 eventually develop AIDS.[11] These individuals mostly die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[12] HIV progresses to AIDS at a variable rate affected by viral, host, and environmental factors; most will progress to AIDS within 10 years of HIV infection: some will have progressed much sooner, and some will take much longer.[13][14] Treatment with anti-retrovirals increases the life expectancy of people infected with HIV. Even after HIV has progressed to diagnosable AIDS, the average survival time with antiretroviral therapy was estimated to be more than 5 years as of 2005[update].[15] Without antiretroviral therapy, someone who has AIDS typically dies within a year.[16]
Infection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load, the level of HIV in the blood. The stage of infection can be determined by measuring the patient's CD4+ T cell count and viral load.
The stages of HIV infection are acute infection (also known as primary infection), latency and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, lymphadenopathy (swollen lymph nodes), pharyngitis (sore throat), rash, myalgia (muscle pain), malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts (fewer than 200 per microliter), various opportunistic infections, cancers and other conditions.
A small percentage of HIV-1 infected individuals retain high levels of CD4+ T-cells without antiretroviral therapy. However, most have detectable viral load and will eventually progress to AIDS without treatment, albeit more slowly than others. These individuals are classified as HIV controllers or long-term nonprogressors (LTNP). People who maintain CD4+ T cell counts and also have low or clinically undetectable viral load without anti-retroviral treatment are known as elite controllers or elite suppressors (ES).[17][18]
Main symptoms of acute HIV infection
Infection with HIV generally occurs by introduction of bodily fluids from an infected person into the body of an uninfected person. A period of rapid viral replication ensues, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood.[19]
This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viremia is associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4+ T cell counts rebound. A good CD8+ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.[20]
During this period (usually 2–4 weeks post-exposure) many individuals develop an influenza or mononucleosis-like illness called acute HIV infection, the most common symptoms of which may include fever, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophageal sores, and may also include, but less commonly, headache, nausea and vomiting, enlarged liver/spleen, weight loss, thrush, and neurological symptoms. Infected individuals may experience all, some, or none of these symptoms. The duration of symptoms varies, averaging 28 days and usually lasting at least a week.[21]
Because of the nonspecific nature of these symptoms, they are often not recognized as signs of HIV infection. Even if patients go to their doctors or a hospital, they will often be misdiagnosed as having one of the more common infectious diseases with the same symptoms. As a consequence, these primary symptoms are not used to diagnose HIV infection, as they do not develop in all cases and because many are caused by other more common diseases. However, recognizing the syndrome can be important because the patient is much more infectious during this period.[22]
A strong immune defense reduces the number of viral particles in the blood stream, marking the start of secondary or chronic HIV infection. The secondary stage of HIV infection can vary between two weeks and 20 years. During this phase of infection, HIV is active within lymph nodes, which typically become persistently swollen, in response to large amounts of virus that become trapped in the follicular dendritic cells (FDC) network.[23] The surrounding tissues that are rich in CD4+ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4+ CD45RO+ T cells carry most of the proviral load.[24]
During this stage of infection early initiation of antiretroviral therapy significantly improves survival, as compared with deferred therapy.[25]
When CD4+ T cell numbers decline below a critical level of 200 cells per µL, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis, skin rashes, and oral ulcerations.
Common opportunistic infections and tumors, most of which are normally controlled by robust CD4+ T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein-Barr virus-induced B-cell lymphomas, or Kaposi's sarcoma.
Pneumonia caused by the fungus Pneumocystis jirovecii is common and often fatal. In the final stages of AIDS, infection with cytomegalovirus (another herpes virus) or Mycobacterium avium complex is more prominent. Not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant.
Average per act risk for acquisition
of HIV by exposure route to an infected source
| Exposure Route |
Chance of infection |
| Blood Transfusion |
90% [26] |
| Childbirth (to child) |
25%[27] |
| Needle-sharing injection drug use |
0.67%[26] |
| Percutaneous needle stick |
0.30%[28] |
| Receptive anal intercourse* |
0.04–3.0%[29] |
| Insertive anal intercourse* |
0.06–0.056%[29] |
| Receptive penile-vaginal intercourse* |
0.05–0.30%[29][30] |
| Insertive penile-vaginal intercourse* |
0.01–0.38% [29][30] |
| Receptive oral intercourse*§ |
0–0.04% [29] |
| Insertive oral intercourse*§ |
0-0.005%[31] |
* assuming no condom use
§ source refers to oral intercourse
performed on a man |
Risk increases substantially in the presence of genital ulcers, mucosal lacerations, concurrent sexually transmitted infections, or a partner with a high viral load of HIV.[32] [33] Commercial sex exposure and national income levels may also impact risk.[34]
Three main transmission routes for HIV have been identified. HIV-2 is transmitted much less frequently by the mother-to-child and sexual route than HIV-1.
The majority of HIV infections are acquired through unprotected sexual relations. Complacency about HIV plays a key role in HIV risk.[4][5] Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal mucous membranes of another. In high-income countries, the risk of female-to-male transmission is 0.04% per act and male-to-female transmission is 0.08% per act. For various reasons, these rates are 4 to 10 times higher in low-income countries.[34] The rate for receptive anal intercourse is much higher, 1.7% per act.[34]
In general, if infected blood comes into contact with any open wound, HIV may be transmitted. This transmission route can account for infections in intravenous drug users, hemophiliacs, and recipients of blood transfusions (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. Health care workers such as nurses, laboratory workers, and doctors have also been infected, although this occurs more rarely. Since transmission of HIV by blood became known medical personnel are required to protect themselves from contact with blood by the use of universal precautions. People giving and receiving tattoos, piercings, and scarification procedures can also be at risk of infection.
HIV has been found at low concentrations in the saliva, tears, and urine of infected individuals, but there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible.[35] It is not possible for mosquitoes to transmit HIV.[36]
The transmission of the virus from the mother to the child can occur in utero (during pregnancy), intrapartum (at childbirth), or via breast feeding. In the absence of treatment, the transmission rate up to birth between the mother and child is around 25%.[27] However, where combination antiretroviral drug treatment and Cesarian section are available, this risk can be reduced to as low as one percent.[27] Postnatal mother-to-child transmission may be largely prevented by complete avoidance of breast feeding; however, this has significant associated morbidity, particularly in low-income settings (where hazards of avoiding breast-feeding may include lack of access to safe water and/or a lack of affordable formula). Exclusive breast feeding and the provision of extended antiretroviral prophylaxis to the infant are also efficacious in avoiding transmission.[37] UNAIDS estimate that 430,000 children were infected worldwide in 2008 (19% of all new infections), primarily by this route, and that a further 65,000 infections were averted through the provision of antiretroviral prophylaxis to HIV-positive women.[38]
Unlike some other viruses, infection with HIV does not provide immunity against additional infections, in particular, in the case of more genetically distant viruses. Both inter- and intra-clade multiple infections have been reported,[39] and even associated with more rapid disease progression.[40] Multiple infections are divided into two categories depending on the timing of the acquisition of the second strain. Coinfection refers to two strains that appear to have been acquired at the same time (or too close to distinguish). Reinfection (or superinfection) is infection with a second strain at a measurable time after the first. Both forms of dual infection have been reported for HIV in both acute and chronic infection around the world.[41][42][43][44]
HIV is a member of the genus Lentivirus,[45] part of the family of Retroviridae.[46] 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.[47] 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 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 integrase and host co-factors.[48] Once integrated, the virus may become latent, allowing the virus and its host cell to avoid detection by the immune system. Alternatively, the virus may be transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new virus particles that 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 LAV and HTLV-III. It is more virulent, more infective,[49] 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. Because of its relatively poor capacity for transmission, HIV-2 is largely confined to West Africa.[50]
| Human immunodeficiency virus |
 |
| Scanning electron micrograph of HIV-1 (in green) budding from cultured lymphocyte. Multiple round bumps on cell surface represent sites of assembly and budding of virions. |
| Virus classification |
| Group: |
Group VI (ssRNA-RT) |
| Family: |
Retroviridae |
| Genus: |
Lentivirus |
| Species |
- Human immunodeficiency virus 1
- Human immunodeficiency virus 2
|
HIV is different in structure from other retroviruses. It is roughly spherical[51] with a diameter of about 120 nm, around 60 times smaller than a red blood cell, yet large for a virus.[52] It is composed of two copies of positive 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.[53] The single-stranded RNA is 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 particle.[53]
This is, in turn, surrounded by the viral envelope that is composed of two layers of fatty molecules called phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and about 70 copies of a complex HIV protein that protrudes through the surface of the virus particle.[53] This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure into the viral envelope.[54] This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle.[54] Both these surface proteins, especially gp120, have been considered as targets of future treatments or vaccines against HIV.[55]
The 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.[53] For example, env codes for a protein called gp160 that is broken down 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.[53]
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.[56][57] 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 APOBEC3G (a cell protein that deaminates DNA:RNA hybrids and/or interferes with the Pol protein). The Vpr protein (p14) arrests cell division at G2/M. The Nef protein (p27) down-regulates CD4 (the major viral receptor), as well as the MHC class I and class II molecules.[58][59][60]
Nef also interacts with SH3 domains. The Vpu protein (p16) influences the release of new virus particles from infected cells.[53] The ends of each strand of HIV 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.[53]
Main article:
HIV tropism
Diagram of the immature and mature forms of HIV
The term viral tropism refers to which cell types HIV 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 and also with chemokine coreceptors.[54]
Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the β-chemokine receptor CCR5 for entry and are, thus, able to replicate in macrophages and CD4+ T cells.[61] This CCR5 coreceptor 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. In tonsils and adenoids of HIV-infected patients, macrophages fuse into multinucleated giant cells that produce huge amounts of virus.
T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4+ T cells as well as in macrophages and use the α-chemokine receptor, CXCR4, for entry.[61][62][63] 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 for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by down-regulating the expression of CXCR4 on the surface of these cells. HIV 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 coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection[61] and HIV can also infect a subtype of myeloid dendritic cells,[64] which probably constitute a reservoir that maintains infection when CD4+ T cell numbers have declined to extremely low levels.
Some people are resistant to certain strains of HIV.[65] For example, people with the CCR5-Δ32 mutation are resistant to infection with R5 virus, as the mutation stops HIV from binding to this coreceptor, reducing its ability to infect target cells.
Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal fluid, which is passed 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.[66][67][68] How this selective process works is still under investigation, but one model is that spermatozoa may selectively carry R5 HIV as they possess both CCR3 and CCR5 but not CXCR4 on their surface[69] and that genital epithelial cells preferentially sequester X4 virus.[70] In patients infected with subtype B HIV-1, there is often a co-receptor switch in late-stage disease and T-tropic variants appear that can infect a variety of T cells through CXCR4.[71] 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.[72] 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% of AIDS patients can harbour viruses of the SI and, it is presumed, the X4 phenotypes.[73][74]
HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution. The adoption of "accessory genes" by HIV-2 and its more promiscuous pattern of coreceptor 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 more successful at transmission will be selected.[75]
The HIV replication cycle
HIV 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 cell membrane and the release of the HIV capsid into the cell.[76][77]
Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4, but others are known to interact) on the cell surface.[76][77] 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.[78] The gp160 spike contains binding domains for both CD4 and chemokine receptors.[76][77]
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 binding domains of gp120 and allowing them to interact with the target chemokine receptor.[76][77] This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.[76][77] 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.[76][77]
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.[76] During the microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed into double-strand DNA, which is then integrated into a host chromosome.
HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using mannose-specific C-type lectin receptors such as DC-SIGN can also be used.[79] 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.[79] The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the infection of cells by HIV.[80]
Shortly after the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule.[81] 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.[82] Together, the cDNA and its complement form a double-stranded viral DNA that is then transported into the cell nucleus. The integration of the viral DNA into the host cell's genome is carried out by another viral enzyme called integrase.[81]
Reverse transcription of the HIV genome into double strand DNA
This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.[81] To actively produce the virus, certain cellular transcription factors need to be present, the most important of which is NF-κB (NF kappa B), which is upregulated when T-cells become activated.[83] This means that those cells most likely to be killed by HIV are those currently fighting infection.
During viral replication, the integrated DNA provirus is transcribed into mRNA, which is then spliced into smaller pieces. These small pieces 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 accumulates in the nucleus, it binds to viral mRNAs and allows unspliced RNAs to leave the nucleus, where they are otherwise retained until spliced.[84] At this stage, the structural proteins Gag and Env are produced from the full-length mRNA. The full-length RNA is actually the virus genome; it binds to the Gag protein and is packaged into new virus particles.
HIV-1 and HIV-2 appear to package their RNA differently; HIV-1 will bind to any appropriate RNA, whereas HIV-2 will preferentially bind to the mRNA that was used to create the Gag protein itself. This may mean that HIV-1 is better able to mutate (HIV-1 infection progresses to AIDS faster than HIV-2 infection and is responsible for the majority of global infections).
The final step of the viral cycle, assembly of new HIV-1 virons, 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 protease and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the 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. Maturation occurs either in the forming bud or in the immature virion after it buds from the host cell. During maturation, HIV proteases cleave the polyproteins into individual functional HIV proteins and enzymes. The various structural components then assemble to produce a mature HIV virion.[85] This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.
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 transcriptase.[86][87][88]
This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[86] This variability is compounded when a single cell is simultaneously infected by two or more different strains of HIV. When simultaneous infection occurs, the genome of progeny virions may be composed of RNA strands from two different strains. This hybrid virion then infects a new cell where it undergoes replication. As this happens, the reverse transcriptase, by jumping back and forth between the two different RNA templates, will generate a newly synthesized retroviral DNA sequence that is a recombinant between the two parental genomes.[86] This recombination is most obvious when it occurs between subtypes.[86]
The closely related simian immunodeficiency virus (SIV) has evolved into many strains, classified by the natural host species. SIV strains of the African green monkey (SIVagm) and sooty mangabey (SIVsmm) are thought to have a long evolutionary history with their hosts. These hosts have adapted to the presence of the virus,[89] which is present at high levels in the host's blood but evokes only a mild immune response,[90] does not cause the development of simian AIDS,[91] and does not undergo the extensive mutation and recombination typical of HIV infection in humans.[92]
In contrast, when these strains infect species that have not adapted to SIV ("heterologous" hosts such as rhesus or cynomologus macaques), the animals develop AIDS and the virus generates genetic diversity similar to what is seen in human HIV infection.[93] Chimpanzee SIV (SIVcpz), the closest genetic relative of HIV-1, is associated with increased mortality and AIDS-like symptoms in its natural host.[94] SIVcpz appears to have been transmitted relatively recently to chimpanzee and human populations, so their hosts have not yet adapted to the virus.[89] This virus has also lost a function of the Nef gene that is present in most SIVs; without this function, T cell depletion is more likely, leading to immunodeficiency.[94]
Three groups of HIV-1 have been identified on the basis of differences in the envelope (env) region: M, N, and O.[95] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.[96] 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 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.[97] Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[98] The existence of a fourth group, "P", has been hypothesised based on a virus isolated in 2009.[99][100][101] The strain is apparently derived from gorilla SIV (SIVgor), first isolated from western lowland gorillas in 2006.[99]
The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIVsmm.
A generalized graph of the relationship between HIV copies (viral load) and CD4 counts over the average course of untreated HIV infection; any particular individual's disease course may vary considerably.
CD4+ T cell count (cells per µL) HIV RNA copies per mL of plasma
Many HIV-positive people are unaware that they are infected with the virus.[102] For example, in 2001 less than 1% of the sexually active urban population in Africa have been tested and this proportion is even lower in rural populations.[102] Furthermore, in 2001 only 0.5% of pregnant women attending urban health facilities are counselled, tested or receive their test results.[102] Again, this proportion is even lower in rural health facilities.[102] 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.[103]
HIV-1 testing is initially by an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV-1. Specimens with a nonreactive 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.[104] 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., Western blot or, less commonly, an immunofluorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA 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.[105]
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.[104] 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. A single screening test is correct more than 99% of the time.[106] 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.[106] Testing post exposure is recommended initially and at six week, three months, and six months.[107]
The South African government announced a plan to start HIV testing in secondary schools by March 2011[108] but this plan was eventually scrapped because doing so would invade pupil's privacy at schools, schools typically don't have the facilities to securely store such information, and schools generally do not have the capacity to provide counselling for HIV positive pupils. In South Africa, anyone over the age of 12 may request an HIV test without parental knowledge or consent. Some 80,000 pupils in three provinces were tested under this programme before it was cancelled.[109]
AIDS Clinic,
McLeod Ganj, Himachel Pradesh, India, 2010
Consistent condom use reduces the risk of heterosexual HIV transmission by approximately 80% over the long-term.[110] Where one partner of a couple is infected, consistent condom use results in rates of HIV infection for the uninfected person of below 1% per year.[111] Some data supports the equivalence of female condoms to latex condoms however the evidence is not definitive.[112] The use of the spermicidenonoxynol-9may increase the risk of transmission due to the fact that it causes vaginal and rectal irritation.[113] A vaginal gel containing tenofovir, areverse transcriptase inhibitor, when used immediately before sex, reduce infection rates by approximately 40% among Africa women.[114]
Circumcision in sub-Saharan Africa reduces the risk of HIV infection in heterosexual men by 38 percent and 66 percent over two years.[115] Based on these studies, the World Health Organizatio and UNAIDS both recommended male circumcision as a method of preventing female-to-male HIV transmission in 2007.[116] Whether it protects against male-to-female transmission is disputed[117][118] and whether it is of benefit in developed countries and among men who have sex with men is undetermined.[119][120][121] Some experts fear that a lower perception of vulnerability among circumcised men may result in more sexual risk-taking behavior, thus negating its preventive effects.[122] Women who have undergonefemale genital cutting have an increased risk of HIV.[123]
Programs encouraging sexual abstinence do not appear to effect subsequent HIV risk.[124] Evidence for a benefit from peer education is equally poor.[125] Comprehensive sexual education provided at school may decrease high risk behavior.[126] A substantial minority of young people continue to engage in high-risk practices despite HIV/AIDS knowledge, underestimating their own risk of becoming infected with HIV.[127]
Early treatment of HIV-infected people with antiretrovirals protected 96% of partners from infection.[128] Pre-exposure prophylaxis with a daily dose of the medications tenofovir with or without emtricitabine is effective in a number of groups including: men who have sex with men, by couples where one is HIV positive, and by young heterosexuals in Africa.[114]
Universal precautions within the health care environment are believed to be effective in decreasing the risk of HIV.[129] Intravenous drug use is an important risk factor and harm reduction strategies such as needle-exchange programmes and opioid substitution therapy appear effective in decreasing this risk.[130]
A course of antiretrovirals administered within 48 to 72 hours after exposure to HIV positive blood or genital secretions is referred to as post-exposure prophylaxis.[114] The use of the single agentzidovudine reduces the risk of subsequent HIV infection five fold.[114] Current treatment regimes typical use lopinavir/ritonavirand lamivudine/zidovudine or emtricitabine/tenofovir and may decrease the risk further.[114]The duration of treatment is usually four week[131] and is associated with significant rates of adverse effects (for zidovudine ~70% including: nausea 24%, fatigue 22%, emotional distress 13%, headaches 9%).[28]
Programs to prevent the transmission of HIV from mothers to children can reduce rates of transmission by 92-99%.[130][132] This primarily involves the use of a combination of antivirals during pregnancy and after birth in the infant but also potentially include bottle feeding rather thanbreastfeeding.[133][132] If replacement feeding is acceptable, feasible, affordable, sustainable and safe mothers should avoid breast-feeding their infants however exclusive breast-feeding is recommended during the first months of life if this is not the case.[134]
As of 2012 there is no effective vaccine for HIV or AIDS.[135] A single trial of the vaccine RV 144 published in 2009 found a partial efficacy rate of ~30% and has stimulated optimism in the research community regarding developing a truly effective vaccine.[136] Further trials of the vaccine are ongoing.[137][138]
Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
There is currently no cure for HIV infection. Treatment consists of highly active antiretroviral therapy, or HAART.[139] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996, when the protease inhibitor-based HAART initially became available.[140] Current HAART options are combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents. Typically, these classes are two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI).
There is no empirical evidence for withholding treatment at any stage of HIV infection,[141] and death rates are almost twice as high when therapy is deferred (until the CD4 count falls below 500) compared to starting therapy when the CD4 count is above 500.[25] However, the timing for starting HIV treatment is still subject to debate.[142]
The United States Panel on Antiretroviral Guidelines for Adults and Adolescents in 2009 recommended that antiretroviral therapy should be initiated in all patients with a CD4 count less than 350, with treatment also recommended for patients with CD4 counts between 350 and 500. However, for patients with CD4 counts over 500, the expert Panel was evenly divided, with 50% in favor of starting antiretroviral therapy at this stage of HIV disease, and 50% viewing initiating therapy at this stage as optional. They noted that "Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence".[143]
New classes of drugs such as entry inhibitors provide treatment options for patients infected with viruses already resistant to common therapies, although they are not widely available and not typically accessible in resource-limited settings. Because AIDS progression in children is more rapid and less predictable than in adults, in particular, in young infants, more aggressive treatment is recommended for children than adults.[144] In developed countries where HAART is available, doctors assess their patients thoroughly: measuring the viral load, how fast CD4 declines, and patient readiness. They then decide when to recommend starting treatment.[145]
HAART neither cures the patient nor uniformly removes all symptoms; high levels of HIV-1, often HAART-resistant, return if treatment is stopped.[146][147] Moreover, it would take more than a lifetime for HIV infection to be cleared using HAART.[148] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to a large reduction in HIV-associated morbidity and mortality in the developed world.[140][149][150] One study suggests the average life expectancy of an HIV infected individual is 32 years from the time of infection if treatment is started when the CD4 count is 350/µL.[151] Life expectancy is further enhanced if antiretroviral therapy is initiated before the CD4 count falls below 500/µL.[25]
In the absence of HAART, progression from HIV infection to AIDS has been observed to occur at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months.[16] However, HAART sometimes achieves far less than optimal results, in some circumstances being effective in less than fifty percent of patients.[citation needed] This is due to a variety of reasons such as medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. However, non-adherence and non-persistence with antiretroviral therapy is the major reason most individuals fail to benefit from HAART.[152]
The reasons for non-adherence and non-persistence with HAART are varied and overlapping. Major psychosocial issues, such as poor access to medical care, inadequate social supports, psychiatric disease and drug abuse contribute to non-adherence. The complexity of these HAART regimens, whether due to pill number, dosing frequency, meal restrictions or other issues along with side effects that create intentional non-adherence also contribute to this problem.[153][154][155] The side effects include lipodystrophy, dyslipidemia, insulin resistance, an increase in cardiovascular risks, and birth defects.[156][157]
Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.[158] Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. Unfortunately, only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus being affordable for developing countries, and would not require daily treatment.[158] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.[158]
Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype,[159] and the average survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months.[160] HAART reduced the death rate from this disease by 80%, and raised the life expectancy for a newly diagnosed HIV-infected person to 20–50 years.[161][162]
As new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year after the individual progresses to AIDS.[16] Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[12] The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function[65] health care and co-infections,[12][16] as well as which particular strain of the virus is involved.[163][164]
Estimated prevalence of HIV among young adults (15–49) per country at the end of 2005
Numbers of people living with or newly infected with HIV, and the number killed by AIDS (1990–2008)
[165]
HIV infections are considered pandemic by the World Health Organization (WHO).[3] As of 2010 approximately 34 million people have HIV globally.[166] Other these approximately 16.8 million are women and 3.4 million are less than 15 years old.[166] It results in about 1.8 million death in 2010 down from 3.1 million in 2001.[166]
Sub-Saharan Africa is the region most effected. In 2010, an estimated 68% (22.9 million) of all HIV cases and 66% of all deaths (1.2 million) occurred in this region.[167] This means that about 5% of the adult populations is infected.[168] Here in contrast to other regions women compose nearly 60% of cases.[167] South Africa has the largest population of people with HIV of any country in the world at 5.9 million.[167]
South & South East Asia is the second most affected; in 2010 this region contained an estimated 4 million cases or 12% of all people living with HIV resulting in approximately 250,000 deaths.[168] Approximately 2.4 million of these cases are in India.[167]Prevalence is lowest in Western and Central Europe at 0.2% and East Asia at 0.1%.[168]
In 2008 approximately 1.2 million people have HIV in the United States of which 20% do not realize that they are infected.[169] It resulted in about 17,500 deaths.[169] In the United Kingdom as of 2009 there where approximately 86,500 cases which resulted in 516 deaths.[170] In Canada as of 2008 there where about 65,000 cases which results in 53 deaths.[171] Since AIDS was first recognized in 1981 and 2009 it has led to nearly 30 million deaths.[172]
AIDS was first clinically observed between in 1981 in the United States.[173] Injection drug users and gay men with no known cause of impaired immunity showed symptoms of Pneumocystis carinii pneumonia (PCP), a rare opportunistic infection that was known to present itself in people with very compromised immune systems.[174][175][176] Soon thereafter, additional gay men developed a previously rare skin cancer called Kaposi's sarcoma (KS).[177][178] Many more cases of PCP and KS quickly emerged, alerting U.S. Centers for Disease Control and Prevention (CDC). A CDC task force was formed to monitor the outbreak. After recognizing a pattern of anomalous symptoms presenting themselves in patients, the task force named the condition acquired immune deficiency syndrome (AIDS).[179]
Robert Gallo, co-discoverer of HIV
In 1983, two separate research groups led by Robert Gallo 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.[180][181] Gallo claimed that a virus his group had isolated from an AIDS patient 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 lymphadenopathy (swelling of the lymph nodes) of the neck andphysical 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).[179] HIV was chosen as a compromise between the two claims (LAV and HTLV-III).
Whether Gallo or Montagnier deserve more credit for the discovery of the virus that causes AIDS has been a matter ofconsiderable controversy. Together with his colleagueFrançoise Barré-Sinoussi, Montagnier was awarded one half of the 2008 Nobel Prize in Physiology or Medicine for his "discovery of human immunodeficiency virus".[182] Harald zur Hausen also shared the Prize for his discovery that human papilloma virus leads to cervical cancer, but Gallo was left out.[183] Gallo said that it was "a disappointment" that he was not named a co-recipient.[184] Montagnier said he was "surprised" Gallo was not recognized by the Nobel Committee: "It was important to prove that HIV was the cause of AIDS, and Gallo had a very important role in that. I'm very sorry for Robert Gallo."[183]
HIV is thought to have originated in non-human primates in sub-Saharan Africa and was transferred to humans late in the 19th or early in the 20th century.[185][186][187] The first paper recognizing a pattern of opportunistic infections characteristic of AIDS was published in 1981.[188]
Both HIV-1 and HIV-2 are believed to have originated in West-Central Africa and to have jumped species (a process known as zoonosis) from non-human primates to humans. 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 SIVcpz endemic in the chimpanzee subspecies Pan troglodytes troglodytes).[189][190] The closest relative of HIV-2 is SIV(smm), a virus of the sooty mangabey (Cercocebus atys atys), an Old World monkey living in litoral West Africa (from southern Senegal to western Ivory Coast).[50] New World monkeys such as the owl monkey are resistant to HIV-1 infection, possibly because of a genomic fusion of two viral resistance genes.[191] 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.[192]
There is evidence that humans who participate in bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV.[193] However, SIV is a weak virus, 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.[194] 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 of 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.[195] 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 a higher degree of sexual promiscuity, the spread of prostitution, and the concomitant high frequency of genital ulcer diseases (such as syphilis) in nascent colonial cities.[196] There is evidence that transmission rates of HIV during vaginal intercourse, while quite low under regular circumstances, may be increased tens, if not hundreds of times, if one of the partners suffers from an STD resulting in genital ulcers. Early 1900s colonial cities were notable due to their high prevalence of prostitution and genital ulcer STDs, to the degree that, as of 1928, as many as 45% of female residents of eastern 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.[196]
An alternative view 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 spread.[194][197][198]
The earliest well documented case of HIV in a human dates back to 1959.[199] The virus may have been present in the United States as early as 1966,[200] but the vast majority of infections occurring outside sub-Saharan Africa (including the U.S.) can be traced back to a single unknown individual who got infected with HIV in Haiti and then brought the infection to the United States some time around 1969.[201] The epidemic then rapidly spread among high-risk groups (initially, sexually promiscuous gay men). By 1978, the prevalence of HIV-1 among gay male residents of New York and San Francisco was estimated at 5%, suggesting that several thousand individuals in the country had been infected by then.[201]
In 2007, Timothy Ray Brown,[202] a 40-year-old HIV-positive man, was given a stem cell transplant as part of his treatment for acute myeloid leukemia (AML).[203] A second transplant was made a year later after a relapse. The donor was chosen not only for genetic compatibility but also for being homozygous for a CCR5-Δ32 mutation that confers resistance to HIV infection.[204][205] After 20 months without antiretroviral drug treatment, it was reported that HIV levels in Brown's blood, bone marrow, and bowel were below the limit of detection.[205] Virus remained undetectable over three years after the first transplant.[203] Although the researchers and some commentators have characterized this result as a cure, others suggest that the virus may remain hidden in tissues[206] such as the brain (a viral reservoir).[207] Stem cell treatment remains investigational because of its anecdotal nature, the disease and mortality risk associated with stem cell transplants, and the difficulty of finding suitable donors.[206][208]
Complementing efforts to control viral replication, immunotherapies that may assist in the recovery of the immune system have been explored in past and ongoing trials, including IL-2 and IL-7.[209] T
The failure of vaccine candidates to protect against HIV infection and progression to AIDS has led to a renewed focus on the biological mechanisms responsible for HIV latency. A limited period of therapy combining anti-retrovirals with drugs targeting the latent reservoir may one day allow for total eradication of HIV infection.[210]
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