Mechanism/predictors of genital/rectal HIV shedding during ART w/plasma <50c/mL

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In Peru antiretroviral therapy (ART) will be broadly available to HIV-1 infected individuals with <250 CD4 cells/uL. We hypothesize that: 1. A subset of Peruvian adults who initiate ART will have discordant suppression of viral replication in the blood and genital tract/rectum. 2. Continued shedding of virus from the genital tract or rectum will often be due to virus production following immune activation of latently infected cells, which will occur without the development of drug resistance; however, in some instances shedding will be due to continued viral replication, which will be associated with selection of drug-resistant virus. Discerning the relative frequency of genital/rectal shedding by these mechanisms is important for public health. While shedding without replication could place sexual partners at risk of infection, we suspect the infectiousness of these shedders will be low due to shedding of virus at low viral loads. In contrast, those that shed genital/rectal virus in association with viral replication will likely shed higher levels of virus, and have a higher risk of shedding drug-resistant virus. These latter individuals would present a higher public health risk, as they would be more likely to transmit virus due to higher genital/rectal viral loads and would be more likely to transmit drug-resistant virus, diminishing the benefits of ART within the community. By studies of blood and genital/rectal secretions and biopsies, including viral loads and genetics over time, this study aims to determine the rate of discordant shedding of virus in the blood plasma and genital tract/rectal; determine the epidemiological factors associated with discordant shedding; and provide further insight into the pathogenesis of expression of virus from activation of latent provirus versus full-cycles of replication with selection of drug-resistant virus. Lay language description of relevance to public health: Viral shedding from the rectum and genital tract allows transmission of HIV. Effective treatment that suppresses viral replication in the blood, does not curtail rectal and genital tract viral shedding from about one-third of treated individuals. By studying viral genetics we aim to discern the mechanisms that allow HIV to be shed from the genital tract and rectum when suppressed in the blood. A better understanding of this discordant genital tract and rectal shedding should allow us to develop better treatment strategies that should reduce HIV transmission.