HIV/AIDS is a global pandemic with nearly 33 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with sexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We previously reported the results of a randomized clinical trial of circumcision to prevent HIV acquisition among 4,996 men in Uganda. The estimated efficacy of circumcision was 51% after 2 years but has risen to nearly 75% three years later. In addition to the protective efficacy against HIV acquisition, circumcision also reduced the frequency of genital ulcer by 50%. Since herpes is the predominant cause of genital ulcers, we examined the effect of circumcision on acquisition to herpes simplex virus type 2 (HSV-2) within the context of this trial. The cumulative probability of HSV-2 seroconversion over two years was 7.8% in the circumcision group compared to 10.3% in the control group with an adjusted estimate of efficacy of 28% (p = 0.008). We also examined the effect of circumcision on human papillomavirus (HPV) in these men. Two years after circumcision, the prevalence of high-risk HPV genotypes was 18.0% in the circumcised men and 27.9% in the control group (adjusted risk ratio, 0.65;95% CI, 0.46 to 0.90;P=0.009). Thus, in addition to decreasing the incidence of HIV infection, male circumcision significantly reduces the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure. Previous observational studies have also reported an association between male circumcision and reduced risk of transmission to their female partners. We assessed whether circumcision in HIV-infected men would reduce transmission of the virus to female sexual partners among 922 HIV-infected men and their partners in a randomized controlled trial of circumcision in Rakai, Uganda. After two years of follow-up, circumcision of HIV-infected men did not reduce HIV transmission to female partners, and there were no significant differences between the two groups. However, if circumcised men resumed sex with their partners before complete wound healing there was an increased risk of transmission. Consequently condom use after male circumcision is essential for HIV prevention. In order to explore the biological mechanisms by which the removal of foreskin decreases susceptibility to HIV, we assessed foreskin inflammation associated with HIV and herpes simplex virus type. Foreskin inflammation with infiltration of dendritic cells, CD4 and CD8 T-cells was markedly increased among men with serologic evidence for HSV-2, HIV infection, and significantly increased among those dually infected with HIV and HSV-2. Stromal inflammation was present in 14% of uninfected men compared to 29.7% in men with HSV-2 alone, 33% in men with HIV alone, and 61% in men with dual infection. In HIV-infected men, epithelial inflammation was also associated with higher HIV viral load. Epithelial inflammation was also more frequent among men reporting recent genital ulceration. In summary, foreskin inflammation is markedly increased among men with genital herpes and is associated with increased susceptibility to HIV infection as well as higher HIV viral load, and may have biological implications for HIV transmission and acquisition in uncircumcised men. Previous reports have suggested that microbial translocation is a cause of systemic immune activation and chronic HIV infection. We undertook a study to determine whether microbial translocation may play a significant role in disease progression among HIV-infected individuals in Africa. Multiple markers for microbial translocation including lipopolysaccharide, endotoxin antibody, and soluble CD14 were assessed among Africans prior to exposure to HIV infection and following infection. We could not document significant changes in the above markers for microbial translocation during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggested that microbial translocation and subsequent inflammatory immune response do not have a direct causal relationship with HIV disease progression in Africa. We also examined viral heterogeneity in relationship to disease progression. In Rakai, Uganda, subtype A, D and A/D recombinants predominate and have different disease characteristics and transmission potential. In one study we found that 89% of subtype D-infected individuals had clinical dementia compared to only 24% of those infected with subtype A. Similarly, those infected with subtype D had faster rates of progression whereas subtype A had significantly higher rates of HIV sexual transmission compared to subtype D. In a related study, we also documented that antiretroviral drug susceptibility also varied among ARV-nave individuals by subtype. For example, delaviridine hypersusceptibility was more frequent in subtype A than D and efavirenz hypersusceptibility was associated with substitution at codon 11 in HIV-RT in subtype D. Phenotyping may complement genotyping for analysis of ARV drug susceptibility in populations with non-subtype D HIV infection. We initiated a study to determine the frequency and transmission patterns of HIV-infected long-term non-progressors (LTNP) in Africa. A retrospective analysis of subjects in Uganda identified 4,813 HIV-infected individuals including 637 HIV seroconverters. Of all HIV-positive subjects, 4% were identified as LTNP defined as being infected for more than seven years with a CD4 cell count above 600 without ARVs. Of the HIV seroconverters, 9.1% were found to be LTNP and 1.4% were identified as HIV elite controllers, i.e., those who had no detectable viral load without ARV treatment. LTNP had significantly lower viral load setpoint than all other seroconverters (p <0.001). The transmission frequency of HIV from a LTNP to their sex partner was 8.2% (5/61) and three of the five partners progressed to AIDS. In comparison the frequency of HIV transmission in discordant partnerships where the prevalent partner was not an LTNP was 21.9% (159/726) with ten recipients ultimately becoming LTNP. None of the four HIV elite controllers identified in this study transmitted to their partners at any time during follow-up, suggesting that naturally suppressed viral load below detectable levels results in a very low probability of transmission. Thus, LTNP can transmit HIV to their partners although at a significantly lower frequency than that observed among non-LTNP. The finding that transmissions may occur from an LTNP and result in progressive AIDS in the recipient indicates that the host immune response is responsible for predicting those individuals that can either control their virus to undetectable levels or suppress it significantly to slow their progression rate and reduce transmission. These data have implications for the future design of therapeutic vaccines. The significance of these studies is that they provide important epidemiologic, clinical, virologic and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.
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