Background:  NK cells are important mediators of the innate immune response, capable of killing virally infected cells. NK cells have been implicated in the control of HIV in groups of exposed uninfected individuals who showed higher levels of cytotoxicity than control individuals. We investigated the role of NK cells in the control of HIV in long-term non-progressors (LTNP).

Method:  NK cell cytotoxicity of 8 control, 6 HIV-infected, and 10 HIV LTNP (as defined by viral load or CD4⁺ count) individuals was measured using a standard 4-hour ⁵¹Cr-release assay. NK cell subsets were identified by staining PBMC with anti-CD16, anti-CD56, and anti-CD3 antibodies. Expression of NK cell receptors KIR3DL1, KIR2DL1, KIR2DL3, NKG2A, CD94, NKp30, NKp44, NKP46, and CD69 was examined by flow cytometry.

Results:  NK cell natural cytotoxicity was decreased in HIV patients relative to controls in agreement with previous reports. Cytotoxicity was increased in HIV LTNP patients relative to HIV (p = 0.01), although it did not reach control group levels. While the percentage of NK cells (CD56⁺ or CD16⁺ lymphocytes) was similar in all groups, expansion of CD16⁺CD56^–, a subset that shows poor cytotoxicity, was increased in both HIV and HIV LTNP. Cell surface expression of the triggering receptors NKp30 and NKp46 was decreased in HIV (previously reported), and this decrease was also found in the HIV LTNP group. The percentage of NK cells expressing KIR receptors was decreased in HIV infection; levels on NK cells of HIV LTNP patients were similar to control values. Expression of the HLA-specific inhibitory NKG2A receptor on NK cells, but not T cells, was decreased in HIV LTNP relative to control and HIV patients. NK cells from both HIV and HIV LTNP patients displayed an incomplete activated phenotype (CD69⁺ NKp44^–) as has been reported for NK cells from HIV patients. KIR expression on T cells was increased in HIV patients relative to controls. This increase was more pronounced in HIV LTNP group, possibly reflecting a chronic activation of a subset of T cells in HIV and HIV LTNP.

Conclusions:  The decrease in NK cell cytotoxicity seen in HIV infection is reduced in HIV LTNP, a group that maintain control of viral replication, suggesting a possible role for NK cells in control of HIV. A number of phenotypic changes in the expression of NK cell receptors were found in both HIV patient groups that may contribute to clinical outcome.

Keywords: NK cells.; innate immunity; HIV long-term non-progression