Clinical Studies of HIV Drug Resistance

The Clinical Retrovirology Section develops and implements clinical protocols to elucidate mechanisms underlying the emergence of HIV drug resistance in vivo, the dynamics of infection under treatment, and the role of resistance mutations in the efficacy and failure of subsequent treatments.

In the first of three projects conducted by the Clinical Retrovirology Section, our goal is to determine the dynamics of viral replication in HIV-infected patients on suppressive antiretroviral therapy (ART).  These studies are being extended in clinical trials performed at NIH and elsewhere to determine the levels of viremia when treatment regimens are either simplified or intensified.  We are also exploring new strategies to decrease reservoirs of HIV-1 in infected individuals.

In a second research project, we are investigating the genetic structure of HIV populations in infected individuals.  We are using the single-genome sequencing technology developed by the Translational Research Section to analyze and understand the accumulation of genetic variation in the gag/pol and env genes of HIV-1 in a number of different patient groups, including chronically infected patients, both naive and on therapy, as well as in primary and early HIV-1 infection.  We are complementing existing single-genome sequencing and allele-specific PCR assays with next-generation sequencing and new single-cell assays for cell-associated HIV RNA and DNA.  We are determining precise estimates of the roles of population size, genetic drift, selection, and recombination in shaping HIV populations.  The goal of this study is to understand the nature of the forces (mutation, selection, drift, recombination) that mold the genetic diversity of virus populations before and after ART is introduced.

The third project is focused on elucidating the mechanisms of persistent viremia in vivo.  We are conducting clinical trials of targeted interventions to characterize HIV reservoirs in individuals suppressed on ART.  We are determining the role of generalized immune activation and gut-associated lymphoid tissue (GALT) on persistence using nonabsorbable antibiotics to specifically reduce gut bacteria, and studying the effects of specific antigenic activation on HIV using immunization and sampling protocols.  We are also investigating the role of target cell number on HIV reservoirs by studying the effects of cytotoxic chemotherapeutics on HIV viremia, and we are investigating the role of innate immunity in HIV persistence by studying the effects of the innate immune modulator interferon alpha 2b.