Differentiation into an Effector Memory Phenotype Potentiates HIV-1 Latency Reversal in CD4⁺T Cells

Abstract

By performing phenotypic analysis of latency reversal in CD4+ T cells from virally suppressed individuals, we identify the TEM subset as the largest contributor to the inducible HIV reservoir. Differential responses of memory CD4+ T cell subsets to latency-reversing agents (LRAs) demonstrate that HIV gene expression is associated with heightened expression of transcriptional pathways associated with differentiation, acquisition of effector function, and cell cycle entry. In vitro modeling of the latent HIV reservoir in memory CD4+ T cell subsets identify LRAs that reverse latency with ranges of efficiency and specificity. We found that therapeutic induction of latency reversal is associated with upregulation of identical sets of TEM-associated genes and cell surface markers shown to be associated with latency reversal in our ex vivo and in vitro models. Together, these data support the idea that the effector memory phenotype supports HIV latency reversal in CD4+ T cells.

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

“…A final limitation is that this study did not examine proviruses from naive or memory CD4 + T cell subsets. Important studies have noted differences in the distribution of HIV-1 proviruses in different memory cell subsets (15,18,47,69,70). We have recently analyzed the distribution and inducibility of replication-competent HIV-1 proviruses in resting CD4 + T cells from the naive, central, transitional, and effector memory subsets and did not observe substantial and consistent differences in the frequency or inducibility of intact HIV-1 proviruses (71).…”

New Frontiers in Measuring and Characterizing the HIV Reservoir

“…On average, higher IUPM values were observed with the differentiated QVOA (dQVOA) compared to traditional QVOA assay methods (Wonderlich et al, 2019). This suggests that induction into the effector state prior to activation facilitates more efficient exit from latency (Kulpa et al, 2019).…”

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…Therefore, T-cell differentiation status may impact the action of LRAs. Indeed, Kulpa et al (2019) show in ex vivo and in vitro models that differentiated phenotype of T EM cells from that of quiescent T CM cells is associated with a potentiated response to LRAs and to a highest level of inducible HIV-1 reservoir. Additionally, the effects may also be cell type-specific.…”