Background
Natural Killer (NK) cells are underappreciated regulators of the antibody response to infection. In mice, NK cells can kill T follicular helper cells which decreases somatic hypermutation and vaccine response. In the context of HIV, dysfunctional NK cells are associated with broadly neutralizing antibodies. Understanding the temporal immune factors that influence breadth is an important component of developing a successful HIV vaccine.
Methods
For this project, we profiled subjects from a longitudinal cohort of HIV positive women in Mombasa, Kenya. This cohort was initiated in 1993 and HIV negative who enrolled were followed for seroconversion. Antiretroviral therapy was not available in Kenya at this time which gives us unique longitudinal samples of untreated HIV infection to understand factors that contribute to breadth development over the course of infection. We profiled 22 subjects with a range of neutralization breadth by scRNAseq and mass cytometry by time of flight (CyTOF).
Results
In our cohort, gene modules related to NK cell cytotoxicity were enriched in broad neutralizers in early infection, but enriched in narrow neutralizers in late infection. This indicates that although NK cell cytotoxicity may be associated with favorable immune responses in acute HIV infection, when antibody responses are forming and breadth is developing NK cell activity may be detrimental. This was validated by cyTOF data where, in early infection, broad neutralizers expressed higher levels of HLA-DR at baseline and IFNγ upon stimulation indicating early activation. In late infection NK cells from narrow neutralizers expressed higher levels of CCR7, CXCR3, CXCR5, CD107a and TRAIL, indicating NK trafficking to lymphoid tissue where they could limit antibody responses as well as cytotoxic potential.
Conclusions
Here we find that NK cells have differential phenotypes in broad and narrow neutralizers. In early infection NK cells from broad neutralizers are more activated, but by late infection timepoints, NK cells from narrow neutralizers show greater activation. This flip-flop in NK cell function during the course of HIV infection could indicate that NK cell responses may be favorable in the context of early untreated infection for their natural antiviral activity. However, as infection progresses, NK cell activity may be detrimental when it comes to antibody development, which could similarly affect vaccine responses.