NK Cells in HIV Disease

Abstract

Natural killer (NK) cells play a critical role in viral immunity. In the setting of HIV infection, epidemiologic and functional evidence support a role for NK cells in both protection from new infection and in viral control. Specifically, NK cells directly mediate immune pressure leading to virus evolution, and NK cell receptor genotypic profiles, clonal repertoires, and functional capacity have all been implicated in virus containment. In addition, indirect NK cell-mediated antibody-dependent cellular cytotoxicity has been linked to vaccine-induced protective immunity against HIV infection. With recent advances in our understanding of NK cell deficiency, development, memory-like responses, and editing of the adaptive immune system, the opportunities to direct and exploit NK cell antiviral immunity to target HIV have exponentially grown. In this review, we seek to highlight the intersections between discoveries in basic NK cell biology and the challenges of HIV chronic infection, vaccine development, and cure/eradication strategies.

Keywords: Antibody-dependent cellular cytotoxicity; HIV; HIV pathogenesis; Innate immunity; NK cell; NK cell memory; Natural killer (NK); Review; Viral immunity.

Fig. 1

Multiple facets of NK cell biology can be harnessed towards the goal of HIV prevention and eradication. (Right panel) NK cells can directly recognize HIV-infected targets through expression of stress ligands on infected cells or potentially through antigen-specific responses as has been demonstrated in the SIV infection in rhesus macaques. This recognition may lead to degranulation and target cell cytolysis. In addition, secretion of chemokines such as MIP-1β can block new rounds of infection and effectors such as IFNγ can activate antiviral programs. (Bottom panel) NK cells can also be indirectly recruited to HIV-infected cells through CD16 engagement of the Fc receptor of antibodies bound to HIV epitopes. Optimization of these antibodies through subtypes with multiple coordinated activities and glycan patterns that direct maximal responses can enhance NK effector function. (Left panel) NK cell cross-talk with the adaptive immune system also affords opportunities for modulating responses. NK cells edit T follicular helper (T_FH) cells altering germinal center formation and antibody development through cross-talk with B cells. T_FH cells are also a reservoir of HIV infection, and could potentially be targeted by NK cells in early infection or during curative interventions. NK cell editing of CD4⁺ T cell responses also contributes to immune exhaustion in chronic viral infection models, and limits immunopathology in acute infections that are cleared. There is the potential for bidirectional effects with NK cell limiting or enhancing CD4 function, and CD4 T cell cytokine production supporting improved NK cell effector capacity. In sum, there are multiple avenues through which NK cell function can be leveraged to optimize immune responses to HIV