Phenotyping Viral Reservoirs to Reveal HIV-1 Hiding Places

Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist in various cell types and tissues and reignite active replication if therapy is stopped. Persistence of the viral reservoirs in people with HIV-1 (PWH) is the main obstacle to achieving a cure. Identification and characterization of cellular and tissue HIV-1 reservoirs is thus central to the cure research. Here, we discuss emerging insights into the phenotype of HIV-1 reservoir cells.

HIV-1 persists in multiple tissues, anatomic locations, and cell types. Although contributions of different CD4 + T-cell subsets to the HIV-1 reservoir are not equal, all subsets harbor a part of the viral reservoir. A number of putative cellular markers of the HIV-1 reservoir have been proposed, such as immune checkpoint molecules, integrins, and pro-survival factors. CD32a expression was shown to be associated with a very prominent enrichment in HIV-1 DNA, although this finding has been challenged. Recent technological advances allow unbiased single-cell phenotypic analyses of cells harbouring total or intact HIV-1 proviruses. A number of phenotypic markers have been reported by several independent studies to be enriched on HIV-1 reservoir cells. Expression of some of these markers could be mechanistically linked to the reservoir persistence, as they could for instance shield the reservoir cells from the immune recognition or promote their survival. However, so far no single phenotypic marker, or combination of markers, can effectively distinguish HIV-infected from uninfected cells or identify all reservoir cells.