Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation

The persistence of latent HIV proviruses in long-lived CD4(+) T cells despite antiretroviral therapy (ART)(1–3) is a major obstacle to viral eradication(4–6). Because current candidate latency-reversing agents (LRAs) induce HIV transcription but fail to clear these cellular reservoirs,(7–8) new approaches for killing these reactivated latent HIV reservoir cells are urgently needed. HIV latency depends upon transcriptional quiescence of the integrated provirus and circumvention of immune defense mechanisms(4–6,9). These defenses include cell-intrinsic innate responses that use pattern-recognition receptors (PRR) to detect viral pathogens and subsequently induce apoptosis of the infected cell(10). Retinoic acid-inducible gene I (RIG-I) forms one class of pattern-recognition receptors that mediates apoptosis and elimination of infected cells after recognition of viral RNA(11–14). Here we show that acitretin, an FDA-approved retinoic-acid derivative, enhances RIG-I signaling ex vivo, increases HIV transcription, and induces preferential apoptosis of HIV-infected cells. These effects are abrogated by RIG-I knockdown. Acitretin also decreases proviral DNA levels in CD4+ T cells from HIV-infected subjects on suppressive ART, an effect amplified by combination with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor. Pharmacologic enhancement of an innate cellular defense network could provide a means to eliminate reactivated cells in the latent HIV reservoir