Early Combination Antiretroviral Therapy Initiation During Primary HIV Infection Restricts HIV Reservoirs and Gut-Driven Inflammation but Fails to Rewire the Systemic Cytokine Landscape.

Background: HIV reservoirs, dysregulated cytokine profile, and gut barrier damage persist despite suppressive combination antiretroviral therapy (cART). Whether initiating cART during primary HIV infection (PHI) mitigates these pathological processes remains unclear. Methods: We studied 55 individuals with PHI at baseline (T0), after 12 (T12), and 48 weeks (T48) of cART, 18 individuals with chronic HIV infection (CHI) and 10 sex-matched people without HIV (PWOH). Total HIV DNA was measured in peripheral blood mononuclear cells (PBMCs) using ddPCR, while cytokines profiles (IL-2, IL-4, TNF-α, IFN-γ) were measured in plasma by Luminex and antigen-specific T-cell responses were assessed in PBMCs of a subset of participants by intracellular cytokine staining. Microbial translocation markers (EndoCab, 1,3-β-D-glucan, lipopolysaccharide-binding protein [LBP], soluble CD14 [sCD14]) and gut barrier integrity markers (E-cadherin, I-FABP) were measured in plasma by ELISA, at each corresponding time point. Statistical analyses included Friedman tests with Dunn's multiple comparisons, Wilcoxon paired tests, and Mann-Whitney tests, as appropriate. Results: At baseline, both groups displayed a cytokine profile characterized by elevated IL-4 levels compared with PWOH, with individuals with PHI showing significantly higher IL-2 levels and comparable IFN-γ and TNF-α levels to individuals with CHI. Over 48 weeks of cART, IL-4 and IL-2 declined only in individuals with PHI, yet, remained elevated compared with PWOH, whereas cytokine levels remained largely stable in individuals with CHI. Conversely, antigen-specific CD4⁺ T-cell responses remained mainly Th1-skewed, with minimal IL-4 production. Individuals with PHI showed lower baseline sCD14, comparable to PWOH, which further declined during cART, whereas sCD14 remained elevated in individuals with CHI compared with PWOH. Markers of microbial translocation (LBP, 1,3-β-D-glucan) remained stable in individuals treated in PHI and comparable to PWOH but increased in individuals treated in CHI over time. E-cadherin levels were consistently lower in individuals with PHI, similar to PWOH. In contrast, I-FABP showed a non-significant decline over time only in individuals with PHI, while remaining higher in both individuals with PHI and CHI compared with PWOH. Conclusions: Early cART initiation in individuals with PHI reduces viral reservoirs and limits gut barrier disruption and microbial translocation but fails to restore the systemic cytokine landscape compared with PWOH. These findings support the benefits of prompt treatment initiation during acute infection to limit HIV reservoir size and preserve mucosal integrity.