Transcriptional Reprogramming during Effector-to-Memory Transition Renders CD4+ T Cells Permissive for Latent HIV-1 Infection

Abstract

SUMMARY The latent reservoir for HIV-1 in resting memory CD4+ T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4+ T cells undergoing effector-to-memory transition including temporary upregulation of CCR5 expression and rapid downregulation of cellular gene transcription. These cells allowed completion of steps in the HIV-1 life cycle through integration but suppressed HIV-1 gene transcription, thus allowing the establishment of latency. CD4+ T cells in this stage were substantially more permissive for HIV-1 latent infection than other CD4+ T cells. Establishment of latent HIV-1 infection in CD4+ T could be inhibited by viral-specific CD8+ T cells, a result with implications for elimination of latent HIV-1 infection by T cell-based vaccines.

Single cell analysis of quiescent HIV infection reveals host transcriptional profiles that regulate proviral latency

“…These results suggest a role for T cell subset identity and intracellular environment in regulating the outcome of infection. Consistent with this notion, it has recently been demonstrated that HIV preferentially enters latency if infection occurs during a period of global cellular transcriptional downregulation as cells return to rest from activation (Shan et al, 2017). It is unlikely that the preferential silencing we observe in Tn and Tcm in our primary cell model is related to differential mutagenesis of the provirus, since almost 90% of sorted latent (GFP-) primary cells in our model re-expressed GFP upon TCR stimulation.…”

Single-Cell Analysis of Quiescent HIV Infection Reveals Host Transcriptional Profiles that Regulate Proviral Latency

“…These results thus suggest a role for T cell subset identity and intracellular environment in regulating the outcome of infection. Consistent with this notion, it has recently been demonstrated that HIV preferentially enters latency if infection occurs during a period of global cellular transcriptional downregulation as cells return to rest from activation (Shan et al, 2017). It is unlikely that the preferential downregulation we observe in Tn and Tcm in our primary cell model is related to differential mutagenesis of the provirus, because almost 90% of sorted latent (GFP − ) primary cells in our model re-expressed GFP upon TCR stimulation.…”

Targeting the Latent Reservoir for HIV-1

“…However, infection of activated CD4 + T cells that are reverting to a resting memory state , or effector-to-memory transitioning (EMT) cells, provides the best conditions for the establishment of latency due to high CCR5 expression, adequate dNTP pools for reverse transcription, and reduced viral gene expression due to the sequestration of activation-dependent host transcription factors (i.e. NFκB and NFAT) (Shan et al 2017). For cells in this state, steps in the viral life cycle from entry to integration can proceed, but gene expression from the integrated provirus is minimal and transient (Figure 2).…”

“…Even in the uninfected state, very few activated CD4 + T cells progress to a memory state, with most cells dying during the contraction phase of the immune response. With HIV-1 infection, even fewer activated CD4 + T cells may escape viral cytopathic effects and host immune targeting to revert to a memory phenotype, and only rare infection of EMT cells provides the synergistic conditions that allow for the establishment of latency (Shan et al 2017). As determined by the limiting dilution quantitative virus outgrowth assay (Q-VOA), the frequency of latently infected cells in HIV + individuals is .03–3 infectious units per million (IUPM) resting CD4 + T cells (Siliciano et al 2003).…”