New research published in the Journal of Virology and led by Khlood Alsulami and Dr. Nicole Bernard reveals the link between NKG2C genotype status and susceptibility to HIV infection.
The NKG2C receptor is among one of the various activation receptors expressed by NK cells. Recognition of HLA-E on the surface of virally infected cells promotes NKG2C+ NK cell activation. Furthermore, while NK cells are known for their innate effector functions, NK cells can also undergo clonal expansion during CMV infection. This results in an expanded population of adaptive NKG2C+ NK cells which are distinguished from conventional NK cells by epigenetic modifications.
While HIV and CMV coinfection has been previously suggested to drive greater expansion of NKG2C+ NK cells than in CMV mono-infected individuals, it is unclear whether NKG2C+ NK cells directly contribute to control of HIV infection. Furthermore, some individuals do not express NKG2C on the NK cell surface due to homozygous deletion of the nkg2c gene. Few studies have examined how a lack of NKG2C may impact susceptibility and early control of HIV viral load.
To investigate the role of NKG2C in protection against HIV infection, Alsulami et al. analyzed the NKG2C genotype distributions in people living with HIV compared to uninfected individuals with multiple HIV exposures. The NKG2C-/- genotype was more frequently observed in people living with HIV, while none of the HIV-exposed seronegative individuals were NKG2C-/-, suggesting a role for NKG2C in protection against HIV infection. When comparing exposure through injection drug use vs sexual exposure, they found that carriage of the NKG2C-/- genotype was significantly associated with higher HIV susceptibility in injection drug users, but not in individuals with sexual exposure to HIV. These results suggest that NKG2C+ NK cells may play a role in protection against HIV infection when HIV is transmitted by injection (parental exposure), but not during mucosal exposure.
While these results indicated a role for NKG2C in susceptibility to HIV infection, its role in control of HIV viral load following infection remained unclear. In this cohort of individuals living with HIV, pre-treatment plasma viral load was calculated for comparison between NKG2C genotypes. However, the authors did not find any significant differences between NKG2C genotype, frequency or intensity of NKG2C expression in NK cells, and the viral load set point. Thus, although NKG2C+ NK cells may contribute to early protection against establishment of a productive HIV infection, they do not appear to play a role in viral control in the post-acute phase of HIV infection, before beginning treatment.
Overall, Alsulami et al. demonstrate that carriers of the NKG2C-/- genotype exhibit increased susceptibility to HIV infection, particularly through parental exposure. These results provide essential insight into the immunological mechanisms of early protection against HIV infection. Further research is needed to understand why the route of HIV infection alters the ability for NKG2C+ NK cells to protect against infection.