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Human natural killer (NK) T cells are unique T lymphocytes that express an invariant T cell receptor (TCR) Vα24-Vβ11 and have been implicated to play a role in various diseases. A subset of NKT cells express CD4 and hence are potential targets for human immunodeficiency virus (HIV)-1 infection. We demonstrate that both resting and activated human Vα24⁺ T cells express high levels of the HIV-1 coreceptors CCR5 and Bonzo (CXCR6), but low levels of CCR7, as compared with conventional T cells. Remarkably NKT cells activated with α-galactosylceramide (α-GalCer)-pulsed dendritic cells were profoundly more susceptible to infection with R5-tropic, but not X4-tropic, strains of HIV-1, compared with conventional CD4⁺ T cells. Furthermore, resting CD4⁺ NKT cells were also more susceptible to infection. After initial infection, HIV-1 rapidly replicated and depleted the CD4⁺ subset of NKT cells. In addition …