HIV-1 infection persists in humans due to a latent reservoir of CD4+ T cells containing integrated HIV-1 DNA, forming a stable provirus. In this group of cells, the provirus remains latent and shielded from immune responses, making treatment difficult. In this study, Armani-Tourret et al. undertook a randomized controlled clinical trial where 17 individuals positive for HIV-1 undergoing suppressive antiretroviral therapy were treated with either panobinostat (a histone deacetylase inhibitor), pegylated interferon-α2a (an innate immune modulator that can reverse viral latency) or a combination of both. The combination not only increased proviral transcriptional activity and lowered the frequency of intact proviruses, but also induced substantial structural and compositional changes in the HIV-1 reservoir. HIV-1 proviruses integrated in zinc-finger genes and in chromatin regions with reduced histone H3 lysine 27 acetylation (H3K27ac) epigenetic marks were highly over-represented. Furthermore, the combination therapy eliminated proviruses integrated in chromatin regions with H3K27ac modifications, which is the primary target site of panobinostat.

In sum, histone deacetylase inhibitors in combination with innate immune modulators can transform the HIV-1 reservoir landscape.