IL-7 is a potent and proviral strain–specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART

Abstract

The persistence of HIV-1 in virally suppressed infected individuals on highly active antiretroviral therapy (HAART) remains a major therapeutic problem. The use of cytokines has been envisioned as an additional therapeutic strategy to stimulate latent proviruses in these individuals. Immune activation therapy using IL-2 has shown some promise. In the present study, we found that IL-7 was significantly more effective at enhancing HIV-1 proviral reactivation than either IL-2 alone or IL-2 combined with phytohemagglutinin (PHA) in CD8-depleted PBMCs. IL-7 also showed a positive trend for inducing proviral reactivation from resting CD4 + T lymphocytes from HIV-1-infected patients on suppressive HAART. Moreover, the phylogenetic analyses of viral envelope gp120 genes from induced viruses indicated that distinct proviral quasispecies had been activated by IL-7, as compared with those activated by the PHA/IL-2 treatment. These studies thus demonstrate that different activators of proviral latency may perturb and potentially deplete only selected, specific portions of the proviral archive in virally suppressed individuals. The known immunomodulatory effects of IL-7 could be combined with its ability to stimulate HIV-1 replication from resting CD4 + T lymphocytes, in addition to other moieties, to potentially deplete HIV-1 reservoirs and lead to the rational design of immuneantiretroviral approaches.

Mechanisms of HIV Latency: an Emerging Picture of Complexity

“…IL-7, a cytokine essential for maintenance of T-cell homeostasis, can induce HIV expression from quiescent resting cells without global T-cell activation, via the JAK/ STAT5 signaling pathway. This cytokine has recently been studied for use in HIV-infected patients and thus might be tested for its ability to purge quiescent HIV genomes [37][38][39]. However, the findings of Chomont et al [31••] raise the concern that IL-7 exposure could induce the homeostatic proliferation of latently infected resting memory cells.…”

Recurrent HIV‐1 Integration at theBACH2Locus in Resting CD4+T Cell Populations during Effective Highly Active Antiretroviral Therapy

“…Resting CD4 + T cells were purified by use of a method described elsewhere [24]. Briefly, CD4 + T cells in PBMCs from a healthy donor or patient 1 were isolated by negative selection, as described above.…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…gov/clinical-trials/search/b/0/reservoirs and http:// aidsinfo.nih.gov/clinical-trials/search/b/0/vorinostat), using pharmacological drugs or cytokines that directly and/or indirectly induce activation of HIV provirus through a variety of cellular pathways [28][29][30] . However, while viral transcripts from apparently latently infected cells have been detected, no significant change or reduction in the size of the latent reservoir-proviral integrated DNAhas been observed [30,31] .…”