Delayed Reconstitution of CD4+ iNKT Cells after Effective HIV Type 1 Therapy

Abstract

CD1d-restricted natural killer T (iNKT) cells are increasingly recognized as key immunoregulatory cells linking innate and adaptive immunity. These fall into functionally distinct CD4⁺ versus CD4⁻ subsets that are believed to steer cellular immunity toward tolerigenic/atopic versus proinflammatory phenotypes, respectively. Preferential depletion of the CD4⁺ subset has been observed in HIV-1 infection, but the repletion of these cells after antiretroviral therapy has not been examined in detail. T lymphocytes, CD8⁺ lymphocyte activation, viremia, and iNKT cell subsets in peripheral blood were compared between 18 HIV-1-uninfected (Control) and 18 seropositive (SP) men initially not on suppressive antiretroviral therapy. Compared to the Control group, the SP group demonstrated reduction of CD4⁺ and lesser reduction of CD4⁻ iNKT cells at baseline. After initiation of suppressive antiretroviral treatment, the SP CD4⁺ iNKT cell levels remained unchanged after a year and increased by 2 years, while CD4⁺ iNKT cells showed a gradual increase notable after the first year. Over the first year of treatment, there was a significant correlation between changes in total CD4⁺ T lymphocyte and changes in CD4⁺ iNKT cell levels, and a significant inverse correlation between changes in CD8⁺ T lymphocyte activation and changes in CD4⁻ iNKT cell levels. These results confirm preferential depletion of tolerigenic/atopic CD4⁺ iNKT cells by HIV-1, and suggest that disproportionate persistence of proinflammatory CD4⁻ iNKT cells could contribute to the inappropriate immune activation believed to cause immunodeficiency in HIV-1 infection.