CD133+ Hematopoietic Progenitor Cells Harbor HIV Genomes in a Subset of Optimally Treated People With Long-Term Viral Suppression

(See the editorial commentary by Pace and O'Doherty on pages 1790–2.) Latent human immunodeficiency virus (HIV) infection represents a major barrier to curing HIV [1, 2]. When HIV establishes a latent infection within a cell, the DNA provirus integrates into the host cell's genome, but viral genes are not transcribed [3]. The latently infected cell is thus indistinguishable from an uninfected cell and cannot be targeted by the immune system or current antiretroviral therapies. The HIV provirus can persist in this state for the lifetime of the cell; however, it can also be reactivated if cellular conditions change, leading to the production of new virions and potentially new infection events [4]. Thus, HIV replication will resume if antiretroviral therapy is discontinued, unless all latent reservoirs of virus are eliminated. Although resting memory CD4+ T cells are a well-studied reservoir for latent HIV, not all HIV sequences in the plasma of many successfully treated HIV-positive donors can be matched to sequences in peripheral blood CD4+ T cells [5–7]. These data may suggest that additional reservoirs of virus exist and contribute to residual viremia during treatment, as well as to viral rebound upon treatment interruption [7]. Recently, we proposed that hematopoietic progenitor cells (HPCs) in the bone marrow serve as a reservoir for latent HIV. We assessed HIV type 1 (HIV-1) infection in CD34+ HPCs from 9 HIV-infected donors receiving highly active antiretroviral therapy (HAART) in whom viral loads had been undetectable for at least 6 months [8]. In 4 of 9 donors, we detected HIV-1 proviral genomes in CD34-sorted cells at a frequency of 3-40 genomes per 10 000 cells [8], suggesting that HPCs might serve as a reservoir of virus. Comparable amounts of HIV DNA were not observed in bone marrow cells immunodepleted for CD34 [8]. However, subsequent studies have not detected HIV genomes in CD34+ HPCs from donors with undetectable viral loads [9, 10] and have suggested that HIV genomes in CD34+ samples may be due to contaminating CD3+ T cells [9]. In addition to detecting HIV genomes in CD34+ cells ex vivo, we have shown that CD34+ cells can be infected by CCR5- and CXCR4-tropic HIV in vitro [8]. We also demonstrated that HPCs expressing CD133, a marker for an immature subset of CD34+ HPCs, are only infected by CXCR4-using HIV-1 in vitro [11]. However, HIV infection of CD133+ cells in vivo has not been assessed. To investigate whether CD133+ HPCs harbor HIV-1 in vivo, we quantified HIV proviral genomes in CD133+ HPCs from 11 HIV-positive donors in whom plasma viral loads had been <48 copies/mL for at least 6 months. We furthermore analyzed the frequency of CD3+ T cells in each sample to assess whether HIV genomes could arise from contamination with CD3+ T cells.