Ancient Viruses, Modern Immunity: Endogenous Retroviruses and KRAB Zinc Finger Proteins in Human Immunodeficiency Virus 1 Control
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Human immunodeficiency virus 1 (HIV-1) establishes lifelong infection by integrating into the host genome and persisting in long-lived cellular reservoirs. Despite advances in antiretroviral therapy, these reservoirs harbor proviruses that evade detection and clearance, acting as the central barrier to a cure. The “block and lock” approach aims to achieve permanent suppression by enforcing durable proviral silencing in infected cells. Understanding how host mechanisms regulate viral expression and latency is essential for developing these cure strategies. This dissertation examines how functional links between endogenous and exogenous retroviruses can illuminate key aspects of HIV-1 biology relevant to its durable control. Human endogenous retroviruses (HERVs) are genomic remnants of ancient germline infections that are controlled in large part by KRAB zinc finger proteins (KZFPs), providing a model for evolutionarily honed host-retrovirus regulatory dynamics. Through integrated computational and experimental analyses, this work shows that regulatory mechanisms forged for HERV domestication influence modern immunity against HIV. Analyses of CD4⁺ T cells from individuals who naturally control HIV-1 reveal increased expression of key antiviral genes, consistent with putative enhancer activity of proximal HERVs that is enabled by diminished KZFP-mediated repression. These findings expand our understanding of how retroelement regulation shapes human immunity and identify a novel aspect of host-driven HIV-1 control. Complementing this study, a comprehensive screen of human KZFPs identifies a subset capable of repressing HIV-1, each through a distinct mechanism. Their expression patterns in CD4⁺ T cells indicate that some may function as endogenous restriction factors, while low abundance repressors highlight the translational potential of exogenous introduction. Together, these studies reveal intriguing connections between HERV regulation and HIV-1 restriction, unified by KZFP-mediated control. By illustrating how host factors that evolved to repress ancient retroelements can also constrain a modern retrovirus through direct and indirect pathways, this work advances our understanding of host-mediated viral restriction and provides insights to inform future HIV treatment strategies.