Irreversible Loss of HIV-1 Proviral Competence in Myeloid Cells upon Suppression of NF-κB Activity.

Although antiretroviral therapy (ART) sustains potent suppression of plasma viremia in people with HIV-1 infection (PWH), reservoirs of viral persistence rekindle viral replication and viremia if ART is halted. Understanding the nature of viral reservoirs and their persistence mechanisms remains fundamental to further research aiming to eliminate them and achieve ART-free viral remission or virological cure. CD4+ T-cell models have helped to define the mechanisms that regulate HIV-1 latency as well as to identify potential latency manipulators, and we similarly hoped to extend this understanding to macrophages given the increasing evidence of a role for myeloid cells in HIV-1 persistence under ART (T. Igarashi, C. R. Brown, Y. Endo, A. Buckler-White, et al., Proc Natl Acad Sci U S A 98:658-663, 2001, https://doi.org/10.1073/pnas.98.2.658; J. M. Orenstein, C. Fox, and S. M. Wahl, Science 276:1857-1861, 1997, https://doi.org/10.1126/science.276.5320.1857). In the pursuit of a primary cell model of macrophage latency using monocyte-derived macrophages (MDMs), we observed that NF-κB inhibition, originally intended to promote synchronous entry into a latent state, led to an irreversible loss of proviral competence. Proviruses were refractory to latency reversal agents (LRAs), yet host cell functions such as phagocytic capacity and cytokine production remained intact. Even after NF-κB inhibition was relieved and NF-κB action was restored, proviruses remained refractory to reactivation. Agents that interfere with the NF-κB-HIV-1 axis in myeloid cells may provide an approach with which to render myeloid cell reservoirs inert. IMPORTANCE Although HIV-1 infection can be suppressed using antiretroviral therapy, it cannot yet be cured. This is because HIV-1 integrates itself into host cells and may become dormant but also remains ready to emerge from such reservoirs when antiretroviral therapy stops. The CD4+ T cell has been the most actively investigated cell type in reservoir research due to its prominent role in hosting HIV-1; however, HIV-1 can infect and fall latent in myeloid cells, and therefore, their role must also be assessed in pursuit of a cure. Here, we show that caffeic acid and resveratrol, two nontoxic chemicals, both of which interfere with the same set of host mechanisms, can each prevent HIV-1 reactivation from latency in myeloid cells even after either chemical is removed and previous cell functionality is restored. Strategies to interfere with latency underlie the future of HIV-1 cure research, and our findings help to focus such strategies on an important but often neglected cell type.