Selective loss of innate CD4⁺ Vα24 natural killer T cells in human immunodeficiency virus infection

Vα24 natural killer T (NKT) cells are innate immune cells involved in regulation of immune tolerance, autoimmunity, and tumor immunity. However, the effect of human immunodeficiency virus type 1 (HIV-1) infection on these cells is unknown. Here, we report that the Vα24 NKT cells can be subdivided into CD4⁺ or CD4^- subsets that differ in their expression of the homing receptors CD62L and CD11a. Furthermore, both CD4⁺ and CD4^- NKT cells frequently express both CXCR4 and CCR5 HIV coreceptors. We find that the numbers of NKT cells are reduced in HIV-infected subjects with uncontrolled viremia and marked CD4⁺ T-cell depletion. The number of CD4⁺ NKT cells is inversely correlated with HIV load, indicating depletion of this subset. In contrast, CD4^- NKT-cell numbers are unaffected in subjects with high viral loads. HIV infection experiments in vitro show preferential depletion of CD4⁺ NKT cells relative to regular CD4⁺ T cells, in particular with virus that uses the CCR5 coreceptor. Thus, HIV infection causes a selective loss of CD4⁺ lymph node homing (CD62L⁺) NKT cells, with consequent skewing of the NKT-cell compartment to a predominantly CD4^- CD62L^- phenotype. These data indicate that the key immunoregulatory NKT-cell compartment is compromised in HIV-1-infected patients.