Understanding risk factors for HIV-1 infectiousness and transmission:prospective studies in HIV-1 serodiscordant couples

Abstract

The studies described in this dissertation focus on clinical and biologic factors associated with increased HIV-1 infectiousness among heterosexual HIV-1 serodiscordant couples. The specific aims include 1) evaluating whether specific characteristics of HIV-1 serodiscordant couples could be used to defined a higher-risk subgroup for targeted prevention research, 2) assessing the prevalence of unreported antiretroviral therapy (ART) in HIV-1 infected participants enrolling in an HIV-1 prevention trial, 3) determining whether HIV-1 subtype C is associated with increased HIV-1 transmission, and 4) assessing whether immune activation is associated with increased HIV-1 transmission. The identification of a composite set of predictors for HIV-1 transmission is applicable to the design of efficient prevention programs targeting high-risk subpopulations to maximize limited prevention resources. We developed a risk score for identifying a high-risk subpopulation of HIV-1 serodiscordant couples which will provide greater predictive ability in identifying HIV-1 transmission risk than individual risk predictors (i.e. viral load, unprotected sex). A well-developed and validated risk scoring tool, such as ours, is a valuable addition to HIV-1 prevention intervention research in order to reduce sample size, decrease cost of study and provide more efficient recruitment. Biologic factors, including both viral and host characteristics, may be associated with increased HIV-1 infectiousness. HIV-1 subtype, specifically subtype C, has been suggested as a factor in differential HIV-1 transmission between populations, although no epidemiologic evidence supports this conclusion. We compared HIV-1 subtype C and non-C subtypes and found no significant difference in risk of HIV-1 transmission in a multinational population in sub-Saharan Africa. In an analysis of cytokines as markers for immune activation, we found elevated IL-10 and IP-10 concentrations to be associated with increased HIV-1 transmission and acquisition, suggesting a potential biologic mechanism in both HIV-1 infected and susceptible partners. HIV-1 serodiscordant couples cohorts offer unique opportunities to assess correlates of HIV-1 infectiousness, as transmissions can be directly measured within partnerships. The application of our study findings will provide more efficient methods for identifying target populations and a better understanding of the virologic and immunologic mechanisms of HIV-1 infectiousness.