CD32 is expressed on cells with transcriptionally active HIV but does not enrich for HIV DNA in resting T cells

Abstract

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 m ark 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 H IV 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.

Targeting the DNA-PK complex: Its rationale use in cancer and HIV-1 infection

“…Indeed, apart from CD32a, a low affinity receptor for immunoglobulin G Fc fragment recently described as a specific biomarker for CD4+ T cell HIV-reservoir [102], there is a crucial lack of specific biomarkers for latently infected cells. Indeed, even the CD32a marker is a matter of controversy with several papers challenging with their finding [103,104]. However, a recent communication at the 2018 Frontier of Retrovirology congress corroborated the results of the group of Benkirane by showing with another approach that indeed CD32+CD4+ T cells are enriched in HIV-1 DNA [105].…”

Despite early antiretroviral therapy effector memory and follicular helper CD4 T cells are major reservoirs in visceral lymphoid tissues of SIV-infected macaques

“…38 It has been also proposed that HIV reservoirs persist in long-lived stem cell memory CD4 + T cells 39 and in CD4 T cells expressing CD32, 40 although these results are controversial. 41,42 Consistent with the fact that HIV targets lymphoid organs, follicular helper (TFH) cells, a subset of memory CD4 T cells, which are mainly localized in germinal centers, have been known to be infected by both HIV and simian immunodeficiency virus (SIV). [43][44][45][46][47][48][49] Recently, analyses of viral sequences in the plasma of viremic controllers have indicated that viral sequences are closer to HIV DNA sequences observed in TFH cells from peripheral LNs, than those observed in CD4 T cells derived from peripheral blood.…”

CD32 expressing doublets in HIV-infected gut-associated lymphoid tissue are associated with a T follicular helper cell phenotype

“…Recent work suggesting that CD32a (a low-affinity IgG receptor not generally expressed on T cells 10 ) was a specific marker for latent HIV infection 11 was initially supported by studies showing that CD32 may be found on cells that are transcriptionally active, and was associated with HIV DNA levels in some patients. [12][13][14][15][16][17][18][19] However, the finding that CD32 co-expression with CD4 is predominantly due to T-cell-B-cell doublets 17 likely undermines the argument that CD32 is a definitive marker of latency.…”