HIV-1 Genetic Variation in Infected Individuals

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

My group continued a long term collaboration with S. Kassaye's group at Georgetown to continue analysis of HIV spread in Washington D.C. In initial studies we demonstrated high and longstanding rates of resistance to antiretrovirals in Washington D.C. including in female PWH[21]. With Kassaye and Crandall we further characterized dynamics of HIV spread [17]. Identifying factors associated of transmission the prevalence of HIV in the jurisdiction of Washington DC (c. 1.8%) is complicated by ongoing transmission occurring in multiple counties surrounding DC, data that are not centrally tabulated. To overcome this limitation, we coordinated HIV sequence information with zip code information across the entire DC metro area, facilitating geospatial analyses. We found transmission clusters were common, more frequent among male PWH, but not localized by geographic location with bridging across HIV risk factors. Public health implications for eradication efforts are clear; broader outreach to several key populations, especially males and females engaging in condomless sex is essential. Our studies highlight the scalable power of molecular epidemiology, which has now been implemented as a key strategy identified by DC government in their public health approach to eliminate HIV. The development of high-level resistance to dolutegravir, in INSTI-experienced individuals is not well understood. We previously collaborated with Alice Pau (NIAID), in a study of INSTI-experienced individuals undergoing salvage therapy (Protocol 14-I-009, Maldarelli, co-investigator) and analyzed samples from individuals with primary integrase strand transfer inhibitors (INSTI) mutations at positions 140 and 148 in integrase (IN) confer variable resistance to raltegravir:in some circumstances, variants retain relative sensitivity to dolutegravir, while in combination with other mutations, may result in high level resistance. My group performed an in-depth population genetics analysis and determined that the addition of T97A resistance mutation emerged on a background of IN with G140S and Q148H in 4 distinct lineages from a relatively large (>105 ) replicating population over the course of a short (four week) period and conferred an additional 10-fold resistance to dolutegravir. We are interested in understanding forces driving drug resistance in anatomic compartments, and we characterized the dynamics of appearance of drug resistant HIV in blood and CSF in the setting of IRIS[29]. Drug resistance mutants (DRM) were documented in CSF and plasma at the time of rebound viremia, though not in cell associated DNA in cells . We hypothesized that analysis of DNA would not be sufficiently sensitive for DRM detection because of the high background of defective proviruses persisting on therapy, only a small minority of which contain proviruses from the recent drug resistant HIV. We investigated cell associated RNA instead and readily identified DRM 8 weeks prior to detectable increases in HIV RNA in blood or CSF. These data demonstrate HIV RNA in PBMC may be a more sensitive source of material to detect low level HIV drug resistance mutations This approach to detect low level resistance prior to emergence of viremia is under EIR submission. We have initiated collaborations with Drs. W-S. Hu and O. Nicolaitchik to understand transcriptional patterns of HIV infection in peripheral blood cells from HIV infected individuals, which we provide new insights on the populations of expressed HIV in vivo. The dynamics of HIV-1 populations in patients undergoing ART remain uncertain, and we are conducting an extensive genetic analysis of HIV-1 before and after initiation of ART (completed Protocol 97-I-0082, currently Protocol 08-I-0221). These results (Nicolaitchik et al., 2024) have yielded new information regarding the nature and timing of genetic bottlenecks occurring during ART. We are also investigating determinants of emergence of drug resistance in vivo by studying clinical factors associated with rebound viremia on therapy. In collaboration with investigators at the University of Indonesia (Nawang Wulan and Dr. Pritiwi Sudarmono), we have used our expertise in identifying early infection and in characterizing spread to develop the first empiric estimates of HIV incidence in Indonsia. In these studies (Wulan et al., iScience, 2023), we have found 12.5% of all newly diagnosed individuals are likely to have been infected in the year prior to diagnosis. We are currently completing a new analysis of spread of HIV in Indonesia from earliest introduction in the 1980's; current patterns of spread indicate substantial bridging across risk groups, demonstrating that a broad approach to prevention will be essential to public health efforts to reduce and eliminate HIV infection. Critically we have identified spread of HIV that links adults with the HIV risk factor men who have condomless sex with men to vertical transmission of HIV. These HIV risk factors These studies have shed new light on the spread of HIV in populations and inform the public health efforts to eradicate HIV worldwide.