Purpose of Review <p>Cytotoxic CD4 T cells (CD4 CTL) have long been recognized for their potentially protective role in people with HIV, but only recently have their contributions in HIV-1 pathogenesis and viral persistence been appreciated. This review summarizes evidence highlighting their critical role in HIV-1-mediated CD4 T cell depletion and in maintaining the viral reservoir, with special consideration for their abundance and development in the gut.</p> Recent Findings <p>CD4 CTL are increased in frequency in people with HIV (PWH). Granzyme B activity in CD4 CTL promotes HIV-1 mediated death of gut CD4 T cells. CD4 CTL that express survival markers such as BCL-2, TNFR2/CD120b, and OX40 appear to resist HIV-1 mediated cell death, potentially contributing to the viral reservoir. Multiple cytokine (IL-2, IL-15) and transcriptional (BACH2, EOMES) pathways were implicated in CD4 CTL differentiation and maintenance. In the gut, CD4 CTL activity appears to be intricately linked to the microbiome, as cytotoxic protein expression can develop in response to bacterial exposure. CD4 CTL from the gut, induced by the presence of bacteria in vitro, are highly infectable by HIV-1.</p> Summary <p>CD4 CTL may act as dual agents in HIV-1 infection, amplifying tissue damage and serving as resilient cellular reservoirs. Understanding the mechanisms regulating their differentiation, cytotoxicity, and survival could inform new therapeutic strategies aimed at restoring gut mucosal integrity, resolving chronic inflammation, and targeting the persistent HIV-1 reservoir.</p>