Preferential depletion of gut CD4-expressing iNKT cells contributes to systemic immune activation in HIV-1 infection

Chronic inappropriate immune activation is the central defect-driving loss of CD4 + T helper cells and progression to AIDS in persons with HIV-1 infection, but the mechanisms remain controversial. We examined key regulatory invariant receptor natural killer T (iNKT) cells in the gut, the largest reservoir of lymphocytes and a key arena of HIV-1 pathogenesis. In healthy control persons, the anti-inflammatory CD4 + iNKT-cell subset predominated over the pro-inflammatory CD4 − iNKT-cell subset in the gut, but not in the blood, compartment. HIV-1 infection resulted in a preferential loss of this anti-inflammatory CD4 + iNKT-cell subset within the gut. The degree of loss of the CD4 + iNKT-cell subset in the gut, but not in the blood, correlated to the systemic immune activation and exhaustion that have been linked to disease progression. These results suggest a potentially important contribution of gut iNKT-cell imbalance in determining the systemic immune activation that is the hallmark of HIV-1 pathogenesis.