There are four basic steps in the sexual transmission of HIV from one person to another:

• Contact with mucosal epithelium
• Uptake by dendritic cells (DCs)
• Transport to lymphoid tissues, such as lymph nodes and gut-associated lymphoid tissue
• Infection of CD4+ T cells in lymphoid tissues

Following mucosal contact, HIV breaches the mucosal barrier, most likely following microtrauma, and is captured by DCs in the lamina propria. DCs are antigen-presenting cells that initiate adaptive immune responses by presenting antigens to, and activating, CD4+ T cells. After attachment of HIV, DCs migrate to secondary lymphoid organs where they pass HIV to CD4+ T cells. During this early phase of HIV infection, both CD4 and CCR5 molecules are used as receptors by HIV to enter cells. Other characteristics of HIV that infects cells at mucosal surfaces are different to those of viruses in established infection, such as higher Env content, enhanced cell-free infectivity and interaction with DCs, and relative resistance to IFN-α, suggesting a selective advantage of founder viruses for conditions at the mucosal surface.^[3]

Attachment of HIV to DCs occurs via binding of HIV envelope proteins to a family of molecules called C-type lectin receptors, which include DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), mannose receptors and langerin. Each of these molecules can bind the HIV envelope glycoprotein gp120, and are expressed on different subtypes of DC.^[4-5] DCs not only act as vehicles to transport HIV to lymphoid tissues, where CD4+ T cells becomes infected, they also present HIV antigens to CD4+ T cells leading to CD4+ T cell activation. This potentiates both the infection of, and replication in, CD4+ T cells.^[6] While DCs express both CD4 and CCR5 receptors,^[7] they do not express CXCR4.^[8] This may contribute to the preferential sexual transmission of R5-tropic viral isolates.^[9] Early simian immunodeficiency virus (SIV) infection is associated with massive depletion of CCR5-expressing activated CD4+ T cells from lymphoid tissue, particularly gut-associated lymphoid tissue. ^[10]

Host determinants of HIV transmission

HIV transmission efficiency depends on the size of the virus inoculum from the HIV-infected person and the susceptibility of the exposed person. The most important factor that influences the risk of sexual transmission of HIV-1 is the HIV viral load, as reflected in the number of copies of HIV RNA per millilitre of plasma, with a 2·4 times increased risk of sexual transmission for every 1 log₁₀ increase in plasma HIV RNA level. The sexual activity of people with acute HIV infection, which causes very high plasma HIV viral loads during the first few months of infection, is an important driver of HIV epidemics. A reduction in plasma HIV viral load of 0·7 log₁₀ is estimated to reduce HIV-1 transmission by 50%.^[11]  People with primary and late-stage HIV infection, both of which are associated with a very high HIV viral load, are more likely to transmit HIV.^{[12, 13]} Plasma HIV viral load usually correlates with HIV viral load in genital secretions.^[14] Like plasma HIV viral load, genital fluid HIV viral load is high during primary HIV infection and during the later stages of HIV disease, such as acquired immunodeficiency syndrome (AIDS). Suppression of HIV-1 infection in the anogenital tract resulting from the use of ART, associated with a decline of HIV RNA in secretions, is the most likely mechanism for the prevention of HIV-1 transmission that was observed in HIV-1 sero-discordant couples in the HPTN 052 clinical trial.^[15] Other host factors that influence HIV transmission are listed in Table 1.

Studies of HIV DNA sequences during acute and early infection suggest that there is a bottleneck in the virus population during transmission, regardless of route of transmission. In contrast to the extensive sequence diversity present during chronic infection, the sequence diversity in acute infection is much more limited; typically only one or a few genetic variants of HIV can be detected.^[16]

Role of sexually transmissible infections in transmission of HIV

Transmission and acquisition of HIV may be increased in people with concurrent sexually transmissible infections (STIs).^{[17], [18]} Concurrent STIs also have a strong epidemiological link with increased risk of HIV acquisition. Two of the best described STIs that increase HIV risk are herpes simplex virus type 2 (HSV-2) and human papilloma virus (HPV) infections; each has been associated with a 2–3 fold increased rate of HIV acquisition in large meta-analyses.^[19]

Ulcerative STIs are particularly associated with increased transmission of HIV.^[12]  Both symptomatic and asymptomatic STIs increase anogenital tract HIV viral load and the numbers of cells expressing CCR5.^[20] Mathematical models suggest that intercurrent STIs may increase the likelihood of HIV transmission ten-fold.^[21]  Treatment of STIs has been associated with a decline in genital secretion HIV viral load, which may explain the dramatic reductions in HIV transmission observed following treatment of STIs.^[22]

There is epidemiological evidence and biological plausibility to support an association between prevalent HSV-2 infection and HIV acquisition in both men and women.^[23] HSV-2 infection was found to have the strongest association with HIV acquisition in women in Tanzania compared with other STIs.^[24] The relative risk of HIV acquisition was higher for incident than for prevalent HSV-2 infection in this study. Valacyclovir has been demonstrated to decrease plasma, vaginal and rectal HIV viral load in individuals with both HIV and HSV-2 infection.^[25], ^[26] However, two large randomised trials failed to show a reduction in HIV acquisition in people who received acyclovir to prevent recurrences of HSV-2 disease.^[27] Randomised trials of treatment for bacterial STIs also did not show a reduction in HIV transmission.^[28] There is no convincing evidence to date that treatment of STIs results in prevention of HIV infection at the population level.^[29] Further studies are awaited to determine if the treatment of STIs will have any real impact on HIV transmission.

The role of circumcision

Male circumcision has a profound effect on the risk of acquiring HIV infection in heterosexual couples. Several large randomised prospective studies performed in Africa have shown a 70% reduction in the risk of HIV acquisition following circumcision. ^[30] [31] However, the role of male circumcision in prevention of HIV infection in men who have sex with men (MSM) remains to be determined. Although male circumcision clearly reduces STIs among heterosexual men, its effects among MSM are unclear. Observational studies of MSM have reported conflicting levels of association with HIV acquisition. A meta-analysis incorporating more than 50,000 MSM did not find an association between HIV status and being circumcised (OR 0.95, 95% CI 0.81-1.11) ^[32]