Background:  The objective of this study was to assess the kinetics of CD4⁺ T-cell repopulation and to evaluate antigen-specific cytokine production in jejunal lamina propria following antiretroviral therapy(ART).

Methods:  Two cohorts, including 3 subjects who began ART during primary HIV-1 infection and 8 who began during chronic infection, are being longitudinally assessed for restoration of CD4⁺ T cells and HIV-specific T-cell responses in peripheral blood and gastrointestinal mucosa. Two long-term non-progressors (LTNP) and 2 HIV-negative individuals were also included. Jejunal biopsies and blood samples were collected at baseline, 3 months, 6 months, 1 year, 2.5 years, and 5 years. CD4⁺ and CD8⁺ percentages from PBMC and lamina propria lymphocytes (LPL) were evaluated by flow cytometry at all time points. Antigen-specific T-cell responses interferon-γ and interleukin-2 (IFN-γ and IL-2) production to HIV-1 Gag, CMV, and SEB were evaluated by cytokine flow cytometry at 1, 2.5, or 5 years post-initiation of ART. Plasma and tissue viral loads were measured by real-time polymerase chain reaction.

Results:  Initiation of ART during early HIV-1 infection was more effective at restoring or maintaining CD4⁺ T-cell numbers in the intestinal mucosa than initiation during chronic infection. Incomplete and delayed restoration of CD4⁺ T-cell numbers was observed in subjects who initiated ART during chronic infection. Nearly complete restoration of CD4⁺ T-cell numbers was observed in LPL of 2 subjects after 5 to 6 years of ART. Following 1 to 5 years of ART, most subjects showed weak HIV Gag-specific CD4⁺ and CD8⁺ T-cell responses in blood (<0.5%). However, 5 subjects had strong Gag-specific IL-2 responses (>1% of CD4⁺ T-cells) in LPL. The magnitude of Gag-specific responses did not correlate with the time of initiation of therapy (early vs chronic infection). Both LTNP had strong Gag-specific CD8⁺ responses in LPL, and 1 also had a strong Gag-specific CD4⁺ response in LPL.

Conclusions:  Early initiation of ART was more effective at restoring or maintaining mucosal CD4⁺ T-cell numbers than initiation during chronic infection. However, a delay in restoration of mucosal CD4⁺ T cells was observed in both groups. Although weak HIV-specific CD8⁺ T-cell responses were observed in peripheral blood mononuclear cells of patients on ART, strong HIV-specific CD4⁺ T-cell responses were detected in jejunal LPL of individuals following 1 to 5 years of ART. This finding suggests that long-term ART can restore HIV-specific CD4⁺ T-cell function in the gastrointestinal mucosa.

Keywords: HAART; Intestinal Mucosa; Immune Restoration