Activation of NK Cells Induces CD4 Expression and Allows HIV−1 Infection.

Natural killer (NK) cells play critical roles in immune surveillance without deliberate prior sensitization and restriction by major histocompatibility complex (MHC). Although function and cell number of NK cells are influenced in AIDS patients, direct interaction between HIV and NK cells is still controversial. Because steady-state NK cells are negative for CD4 which is a key molecule for HIV infection. In this study, we established a condition inducing CD4 expression and HIV-1 infection of NK cells in vitro.

CD4 was expressed on NK cells co-cultured with HFWT cells (NK cell-selective stimulating feeder cells) and IL-2. There were no differences in expression level of NK receptors, adhesion molecules and cytotoxicity between CD4⁺ and CD4^- NK cell subpopulations. However, expression of activation markers, CD25 and HLA-DR, and size/granularity of the CD4⁺ NK cells were higher than CD4^- NK cells. CD4⁺ NK cells expressed co-receptors for HIV-1, CCR5 and CXCR4. Thus, CD4 is induced on NK cells by activation, and the CD4⁺ NK cells are the possible target for HIV.

Next, we exposed HIV-1 clone (JR-FL) to the HFWT-activated NK cells, however, direct HIV infection to the NK cells was not observed. While, co-culture of activated NK cells with HIV infected T cells allowed HIV infection of NK cells. Because NK cell-specific marker, NKp46, was detected on p24⁺CD3^-CD56⁺ cells but not on CD3⁺ cells, p24⁺CD3^-CD56⁺ cells were certainly NK cells. These results demonstrate that NK cells are the targets of HIV.

Altogether, our data suggest that CD4⁺ T cells transfer HIV to NK cells during this cell-to-cell contact, which cause the NK cells to be the long-living viral reservoirs or modify the function of NK cells in HIV-infected patients. Our novel co-culture system using activated NK cells and HIV-infected T cells is the powerful tool to study the function of NK cells on HIV infection.