Lithium attenuates HIV-1 latency reversal in an autophagy-independent way

The major barrier to eradicate HIV-1 is its persistence in latently infected cells. Inducing deep latency to prevent HIV-1 reactivation in the absence of combined antiretroviral therapy (cART) remains a primary goal. Here, we evaluated the repurposing of lithium as an HIV-1 latency-promoting drug (LPA). We demonstrated that lithium attenuates virus reactivation in three cell models for HIV-1 latency. Lithium induced autophagy in CD4⁺ T cells via an mTOR-independent pathway and found that autophagy is not absolutely required to attenuate HIV-1 reactivation. Latently infected CD4⁺ T_CM cells expressing a dual fluorescent HIV-1 reporter and treated with lithium increased productively infected cells but rendered them resistant to reactivation. A similar trend was observed in primary infected CD4⁺ T_CM cells. These findings demonstrate that lithium elicits two independent effects, highlighting the potential of lithium as a latency-promoting agent to control HIV-1 expression.