Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8⁺ T cells

Background: Harnessing CD8⁺ T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8⁺ T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood. Methods: We analyzed the differentiation status and function of HIV-specific CD8⁺ T cells after long-term ART initiated in acute or chronic HIV infection ex vivo and upon in vitro recall. Findings: ART initiation in any stage of acute HIV infection promoted the persistence of long-lived HIV-specific CD8⁺ T cells with high expansion (P<0·0008) and cytotoxic capacity (P=0·02) after in vitro recall, albeit at low cell number (P=0·003). This superior expansion capacity correlated with stemness (r=0·90, P=0·006), measured by TCF-1 expression, similar to functional HIV-specific CD8⁺ T cells found in spontaneous controllers. Importanly, TCF-1 expression in these cells was associated with longer time to viral rebound ranging from 13 to 48 days after ART interruption (r =0·71, P=0·03). In contrast, ART initiation in chronic HIV infection led to more differentiated HIV-specific CD8⁺ T cells lacking stemness properties and exhibiting residual dysfunction upon recall, with reduced proliferation and cytolytic activity. Interpretation: ART initiation in acute HIV infection preserves functional HIV-specific CD8⁺ T cells, albeit at numbers too low to control viral rebound post-ART. HIV remission strategies may need to boost HIV-specific CD8⁺ T cell numbers and induce stem cell-like properties to reverse the residual dysfunction persisting on ART in people treated after acute infection prior to ART release. Funding: U.S. National Institutes of Health and U.S. Department of Defense.