Natural killer cell function in women at high risk for HIV acquisition: insights from a microbicide trial

Objective: To assess the role of natural killer (NK) cells in HIV acquisition. Design: We conducted a nested case-control substudy to the Center for the AIDS Programme of Research in South Africa (CAPRISA004) tenofovir gel trial. Methods: Thirty women who acquired HIV infection (cases) and 30 women with high-risk sexual activity who remained HIV-negative (controls) were selected. Proliferation, degranulation and interferon-gamma (IFN-gamma) secretion were measured by multiparametric flow cytometry after culture of recombinant human interleukin-2 (rhIL-2)-activated peripheral blood mononuclear cells with 721.221 cells or in-vitro HIV-infected, autologous CD4(+) T-cell blasts. Relationships between pre-acquisition NK cell responses and HIV acquisition were modeled with logistic regression models. Results: NK cells from cases had lower IFN gamma responses to human leukocyte antigen-deficient 721.221 cells than controls (median %IFN gamma posNK cells: 13.7 vs. 21.6%, P=0.03). rhIL-2-activated NK cells from cases had responses to autologous HIV-infected target cells distinct from controls: cases had fewer proliferating and more frequent degranulating NK cells. NK cells from cases had significantly lower IFN-gamma responses to in-vitro HIV-infected autologous T cells than controls even after adjusting for responses to uninfected blasts (median %IFN gamma posNK-cells: 0.53 vs. 2.09%, P=0.007). Responses to in-vitro HIV-infected autologous T cells were significantly lower in herpes simplex virus 2 (HSV-2)-infected women (P=0.003). IFN gamma NK cell responses to autologous HIV-infected cells were associated with lower risk of HIV acquisition (odds ratio adjusted for age, gel arm, HSV-2 and immune activation: 0.582, 95% confidence interval 0.347-0.977, P=0.04). Conclusion: At the time of exposure to HIV, women with impaired NK cell IFN gamma responses were more likely to acquire HIV infection. NK cells, as early responders to viral exposure, were associated with lower risk of HIV acquisition, independent of the intercalated effect of HSV-2 infection suppressing NK cell responses. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins