Investigating the HIV Reservoir in Hematopoietic Stem and Progenitor Cells

Abstract

Current antiretroviral therapies are not curative because they do not eradicate long-lived cells harboring HIV proviral DNA and thus, if a patient stops therapy, circulating virus will rebound. A subset of hematopoietic stem and progenitor cells (HSPCs) express HIV receptors (CD4 and CCR5 or CXCR4) that enable both active and latent infection. Thus, HSPCs have been implicated as a source of persistent virus in vivo. In this dissertation, we first show that HIV genomes can be detected in CD133-sorted HSPCs from a subset of donors with long- term viral suppression and in most cases cannot be explained by contamination with CD3+ T cells. In an analysis of a larger cohort of optimally treated HIV-infected donors, we wished to determine the tropism of virus in HSPCs and delineate which progenitor subsets are infected in vivo. In contrast to HIVs that utilize CXCR4, we found that CCR5-tropic viruses are likely to not infect hematopoietic stem cells. Instead, CCR5-tropic viruses may infect non-stem cell progenitors that may actually be long-lived in vivo as implicated by other recent studies. Finally, we describe a distinct CD4high HSPC subpopulation that is enriched in multipotent cells and preferentially infected by HIVs of both tropisms. In sum, these results provide evidence that HIV-infected HSPCs do persist in vivo and may be a relevant reservoir of the virus in HIV+ people on therapy.