Epigenetic mechanisms of retroviral regulation: a comparative review

Major pharmacologic advances the past few decades have transformed infection with Human Immunodeficiency Virus (HIV) from a fatal disease into a chronic, manageable condition for people with access to antiretroviral therapy (ART). However, a cure remains elusive because HIV persists in a latent state throughout the body, evading immune clearance after ART suppression. Our understanding of HIV latency has made tremendous strides the past few decades, but the specific epigenetic mechanisms underlying latency are still being elucidated. Insights might be gained from simpler retroviruses capable of endogenization, such as the gammaretrovirus Murine Leukemia Virus (MLV). Most vertebrates, including humans, exhibit evidence for ancient retroviral infections that have been epigenetically silenced during early embryogenesis, offering natural modes of viral repression. This review summarizes our current understanding of epigenetic and epitranscriptomic silencing of HIV-1, highlighting parallels and contrasts with MLV and other retroviruses throughout the animal kingdom. We also discuss epigenetic mechanisms of pre-integration latency and T cell-mediated control, made possible through comparative studies of retroviral infections in other species. Finally, we propose how insights from other retroviruses might inform strategies for durable HIV-1 suppression.