While there is a great deal that we do not understand about the biology of HIV transmission, we do know biological factors are critical determinants of exposure outcome.21,22 The most important determinants of transmission are (i) the HIV level in the blood and genital/rectal secretions of the HIV-infected partner and (ii) the number and density

of HIV-susceptible target cells to which the virus can gain access at the site of exposure (usually the mucosal lining of the penis, rectum or female genital tract) in the HIV-uninfected partner.23,24 As will be discussed, these two critical determinants are affected by numerous, overlapping biological factors: we hypothesize that this biology, in addition to any sociocultural and economic factors, has played and continues to play an important role in the racial imbalance that characterizes the global HIV pandemic. Important biological factors and the potential interactions of these factors with race Nivolumab and geography are now reviewed under the broad headings of viral factors, host genetic factors, co-infections and host immunology. HIV-1 group M viruses are subdivided into several subtypes or clades based on genetic heterogeneity: these clades have strong geographical associations,25

and considerable research has examined the potential associations of clade with HIV transmission. Clade C predominates globally and is responsible for most HIV infections in southern Africa and India, while clade B predominates in North America, Europe and Australia. East Africa is dominated Erlotinib by clade A and to a lesser extent D, while the recombinant virus designated CRF01_AE (previously clade L-gulonolactone oxidase E) is most common in Thailand. Early studies suggested that clade C and CRF01_AE were more easily transmitted through heterosexual sex,26 potentially because they bound preferentially to Langerhans cells in the vaginal mucosa and penis.27 Research continues in this area, and more recent work has found that HIV clade C shows enhanced replication (compared to clade A) in a dual virus culture system, as well as in an ex vivo cervical explant model;28

in addition, observational studies demonstrate that clade A may be transmitted more easily than clade D.29 While these data are interesting, it is probably fair to say that it remains unclear what effect, if any, virus clade has on patterns of HIV epidemic spread in the real world. Certainly, virus subtype cannot explain racial differences in HIV prevalence that are apparent in multiple regions and across different virus clades. The clearest association of viral factors with HIV transmission is the plasma HIV RNA viral load, with higher plasma levels being associated with stepwise increases in the probability of transmission30 and in virus levels within genital secretions.21 There are a few data to suggest that plasma viral load varies substantially with viral clade, geography or race per se.