Natural killer cell inhibition of HIV vaccine responses

Abstract

Abstract There is an increasing appreciation of the ability of natural killer (NK) cells to inhibit adaptive immunity. We previously found that NK cells inhibit antiviral T-cell responses and antibody production during acute virus infection in mice. NK cells also inhibit follicular helper (Tfh) T-cell and germinal center (GC) B-cell responses following immunization with alum-adjuvanted NP-KLH. Of note, NK-cells are linked to a reduced frequency of immunoglobulin heavy chain mutations and impaired affinity maturation of NP-specific GC B cells, indicating that NK cells are important modulators of both the magnitude and the quality of the humoral responses. As a successful HIV vaccine putatively requires more extensive and efficient affinity maturation of HIV-specific immunoglobulin sequences than has been achieved in vaccine efforts to date, we hypothesize that NK-cell suppression of Tfh and GC responses represents a promising target to enhance HIV-specific vaccine responses. To test this hypothesis, we administered a HIV envelope (Env)-expressing vaccinia virus (VACV-Env) to mice depleted or not of NK cells. The absence of NK cells was associated with increased frequencies of HIV-specific GC B cells and elevated production of Env-specific immunoglobulins. The enhancing effect of NK-cell depletion at both priming (VACV-Env) and boosting (Env protein) immunizations was robust. These results are consistent with recent demonstration of an association between NK-cell dysfunction and development of bnAbs in HIV-infected individuals. Thus, NK cells are important regulators of affinity maturation and of HIV-specific antibody responses, suggesting that interventions targeting this NK cell activity could enhance HIV vaccine efficacy.