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.


METHODS
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-γ (IFNγ) 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 IFNγ responses to human leukocyte antigen-deficient 721.221 cells than controls (median %IFNγposNK 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 IFNγ responses to in-vitro HIV-infected autologous T cells than controls even after adjusting for responses to uninfected blasts (median %IFNγposNK-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). IFNγ 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).


CONCLUSIONS
At the time of exposure to HIV, women with impaired NK cell IFNγ 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.
Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.
Vivek
V
Naranbhai
Marcus
M
Altfeld
Quarraisha
Q
Abdool Karim
Thumbi
T
Ndung'u
Salim S
SS
Abdool Karim
William H
WH
Carr
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000287:Administration, Topical; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D004198:Disease Susceptibility; D005260:Female; D005434:Flow Cytometry; D006679:HIV Seropositivity / Q000188:drug therapy / Q000276:immunology* / Q000635:transmission; D015497:HIV-1 / Q000276:immunology*; D006558:Herpes Genitalis / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage*; D018570:Risk Assessment; D012725:Sexual Behavior / Q000706:statistics & numerical data; D013019:South Africa / Q000453:epidemiology; D000068698:Tenofovir; D014622:Vaginal Creams, Foams, and Jellies
D019380:Anti-HIV Agents; D007376:Interleukin-2; D063065:Organophosphonates; D014622:Vaginal Creams, Foams, and Jellies; D007371:Interferon-gamma; D000068698:Tenofovir; D000225:Adenine