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CD32 is associated with highly activated T cells harboring HIV RNA transcripts and does not enrich for HIV DNA in resting T cells. Taking an active interest in HIV latency: HIV cure efforts have been thwarted by an inability to target the latent reservoir, which is thought to be largely composed of resting CD4+ T cells. A recent report suggested that the Fcγ receptor CD32 might be a marker of latently infected CD4+ T cells. Abdel-Mohsen et al. meticulously examined T cells from treated HIV patients across the world. They found that CD32+ HIV-infected T cells had an activated phenotype and HIV RNA, indicating active HIV transcription. In contrast, the majority of HIV DNA resided in CD32− cells. Their results suggest that targeting CD32+ cells is unlikely to hit the HIV latent reservoir. The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA–positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART. [ABSTRACT FROM AUTHOR]