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Despite advancements in antiretroviral therapy (ART), HIV-1 remains incurable due to latent viral reservoirs. These reservoirs are located in distinct areas, such as the central nervous system (CNS). The CNS reservoirs flourish inside unique cell types, including myeloid cells such as microglia, perivascular macrophages, and astrocytes. These reservoirs are established early in infection, evade immune detection, and pose a significant challenge to the delivery of therapeutic agents. Although current ARTs can suppress viral transcription, the latently infected CNS cells can produce low-level persistent neuroinflammation and contribute to HIV-associated neurocognitive disorders (HAND). Multiple molecular mechanisms underlie the establishment and maintenance of CNS HIV reservoirs, including epigenetic modifications, transcriptional repression, and limited penetration of antiretroviral drugs across the blood-brain barrier (BBB). Specifically, latency involves transcriptional silencing through histone deacetylation and histone methylation, as well as the recruitment of repressive transcriptional complexes. Therapeutically targeting these mechanisms is critical for latency reversal and reservoir eradication. Two strategies, "shock and kill" and "block and lock", take advantage of these mechanisms. The "shock and kill" method utilizes latency-reversing agents (LRAs) to stimulate transcriptional reactivation, exposing infected cells for immune clearance. Notably, several LRAs, including Vorinostat, JQ1, and Bryostatin-1, have been shown to penetrate the BBB and exhibit promising latency-reversal activity. However, their clinical efficacy is limited by incomplete reservoir reactivation and potential neurotoxicity. Emerging therapeutic targets, such as the transcription factor RUNX1, show significant promise for both potent HIV reactivation and lack of neurotoxicity. To enhance CNS reservoir targeting, novel strategies leveraging viral vectors or lipid nanoparticles are being explored. Overall, a comprehensive understanding of HIV-1 latency mechanisms in the CNS, coupled with the strategic development of BBB-penetrant, non-neurotoxic LRAs and adjunct immune therapies, is critical. Future therapeutic regimens will likely require a multifaceted approach to eradicate HIV-1 reservoirs safely and effectively within the CNS, ultimately progressing toward a functional cure.