Prevention But Not Cure!

Human immunodeficiency virus (HIV) is a retrovirus that can lead to acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections).

Previous names for the virus include human T-lymphotropic virus-III (HTLV-III), lymphadenopathy-associated virus (LAV), or AIDS-associated retrovirus (ARV).[1][2]
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 unprotected sexual intercourse, contaminated needles, and transmission from an infected mother to her baby at birth, or through breast milk.

Screening of blood products for HIV in the developed world has largely eliminated transmission through blood transfusions or infected blood products in these countries.

HIV infection in humans is now pandemic. As of January 2006, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has killed more than 25 million people since it was first recognized on December 1, 1981, making it one of the most destructive pandemics in recorded history. In 2005 alone, AIDS claimed an estimated 2.4–3.3 million lives, of which more than 570,000 were children.

It is estimated that about 0.6% of the world's living population is infected with HIV.[3] A third of these deaths are occurring in sub-Saharan Africa, retarding economic growth and increasing poverty.
[4] According to current estimates, HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.
[5] Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but routine access to antiretroviral medication is not available in all countries.[6]
• Sexual route. The majority of HIV infections are acquired through unprotected sexual relations. Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal mucous membranes of another.
• Blood or blood product route. 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. HIV can also be spread through the sharing of needles. Health care workers such as nurses, laboratory workers, and doctors, have also been infected, although this occurs more rarely. People who give and receive tattoos, piercings, and scarification procedures can also be at risk of infection.
• Mother-to-child transmission (MTCT). The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between the mother and child is 25%.[16] However, where drug treatment and Cesarian section are available, this can be reduced to 1%.[16] Breast feeding also presents a risk of infection for the baby.
HIV-2 is transmitted much less frequently by the MTCT and sexual route than HIV-1.
Replication cycle


Schematic representation of the key structural features of HIV-1 entry into T cells. The two bottom images show alternate models for entry into cells.


The HIV replication cycle
Entry to the cell
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.[48][49]
The interactions of the trimeric envelope complex (gp160 spike, discussed above) and both CD4 and a chemokine receptor (generally either CCR5 or CXCR4 but others are known to interact) on the cell surface.[48][49] The gp160 spike contains binding domains for both CD4 and chemokine receptors.[48][49] 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.[48][49] This allows for a more stable two-pronged attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.[48][49] 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.[48][49]
Once 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.[48]
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.[50] 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 once the virus has been captured in the mucosa by DCs.[50]
Replication and transcription
Once the viral capsid enters the cell, an enzyme called reverse transcriptase liberates the single-stranded (+)RNA from the attached viral proteins and copies it into a complementary DNA.[51] This process of reverse transcription is extremely error-prone and it is during this step that mutations may occur. Such mutations may cause drug resistance. The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (vDNA). This vDNA 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.[51]
This integrated viral DNA may then lie dormant, in the latent stage of HIV infection.[51] 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.[52] This means that those cells most likely to be killed by HIV are in fact those currently fighting infection.


Rev-mediated HIV mRNA transport. Rev (red) binds the Rev response element (RRE, blue) to mediate export of unspliced and singly spliced mRNA from the nucleus to the cytoplasm.
In this replication process, the integrated provirus is copied to mRNA which is then spliced into smaller pieces. These small pieces produce the regulatory proteins Tat (which encourages new virus production) and Rev. As Rev accumulates it gradually starts to inhibit mRNA splicing.[53] 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 which 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).
Assembly and release
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 either occurs 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.[54] This cleavage step can be inhibited by protease inhibitors. The mature virus is then able to infect another cell.
Genetic variability
The phylogenetic tree of the SIV and HIV (click on image for a detailed description).

Map showing HIV-1 subtype prevalence. The bigger the pie chart, the more infections are present.
HIV differs from many other viruses as it has very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of 109 to 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.[55] This complex scenario leads to the generation of many variants of HIV in a single infected patient in the course of one day.[55] 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.[55] This recombination is most obvious when it occurs between subtypes.[55]
The closely related simian immunodeficiency virus (SIV) exhibits a somewhat different behavior: in its natural hosts, African green monkeys and sooty mangabeys, the retrovirus is present in high levels in the blood, but evokes only a mild immune response,[56] does not cause the development of simian AIDS,[57] and does not undergo the extensive mutation and recombination typical of HIV.[58] By contrast, infection of heterologous hosts (rhesus or cynomologus macaques) with SIV results in the generation of genetic diversity that is on the same order as HIV in infected humans; these heterologous hosts also develop simian AIDS.[59] The relationship, if any, between genetic diversification, immune response, and disease progression is unknown.
Three groups of HIV-1 have been identified on the basis of differences in env: M, N, and O.[60] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole genome, which are geographically distinct.[61] 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.[62] Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[63]
The genetic sequence of HIV-2 is only partially homologous to HIV-1 and more closely resembles that of SIV than HIV-1.