An early functional adaptive NK cell signature drives optimal CD8+ T-cell activation and predicts sustained HIV-1 viral control.

Alrubayyi, A.; Hassan, A.; Hare, J.; Hsieh, A.; Gilmour, J.; Price, M. A.; Kilembe, W.; Karita, E.; Ruzagira, E.; Esbjornsson, J.; Sanders, E. J.; Peppa, D.; Rowland-Jones, S.

doi:10.1101/2025.03.17.643703

bioRxiv · 10.1101/2025.03.17.643703

An early functional adaptive NK cell signature drives optimal CD8+ T-cell activation and predicts sustained HIV-1 viral control.

Alrubayyi, A.·Hassan, A.·Hare, J.·Hsieh, A.·Gilmour, J.·Price, M. A.·Kilembe, W.·Karita, E.·Ruzagira, E.·Esbjornsson, J.·Sanders, E. J.·Peppa, D.·Rowland-Jones, S.

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Abstract

A better understanding of the immune responses associated with future viral control in humans during acute HIV-1 infection (AHI) is critical to inform vaccines and immune-based therapeutics. Natural killer (NK) cells and CD8+ T-cells are pivotal in antiviral defence, yet the dynamics and complementary roles of these effector subsets during AHI with different HIV-1 subtypes remain poorly understood. Access to a unique patient cohort recruited during and post-peak HIV-1 viral load with different HIV-1 subtypes and followed up longitudinally in the absence of antiretroviral therapy up to six years post estimated date of infection (EDI) provided a rare opportunity to fill this knowledge gap. Our data show an early expansion of Fc{varepsilon}R{gamma}-CD57+ NK cells with classical adaptive traits concomitant with an enhanced capacity for antibody-dependent cellular cytotoxicity (ADCC) and reactivity against HIV-1 antigens. This distinctive NK cell profile was more abundant in donors with subtype A infection compared to non-subtype A, partially driven by elevated pro-inflammatory cytokine levels and changes in the epigenetic landscape. The accumulation of adaptive NK cells during the first month of infection contributed to the optimal activation of CD8+ T-cells, promoting virus-specific responses. Notably, individuals with higher levels of Fc{varepsilon}R{gamma}-CD57+ adaptive NK cells during the first month of infection were more likely to exhibit long-term viral control in the absence of ART. These findings underscore the critical role of early, high-magnitude adaptive NK cell responses in CD8+ T-cell activation and subsequent immune control. This work provides novel insights into the correlates of protective immunity against HIV-1 infection, with implications for preventative or therapeutic vaccine strategies aimed at promoting adaptive NK cell responses. One Sentence SummaryEarly expansion of adaptive NK cells during acute HIV-1 infection promotes long-term viral control.

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Alrubayyi, A., Hassan, A., Hare, J., Hsieh, A., Gilmour, J., Price, M. A., Kilembe, W., Karita, E., Ruzagira, E., Esbjornsson, J., Sanders, E. J., Peppa, D., Rowland-Jones, S.. 2025-03-19. An early functional adaptive NK cell signature drives optimal CD8+ T-cell activation and predicts sustained HIV-1 viral control.. https://doi.org/10.1101/2025.03.17.643703

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