Natural killer (NK) cells as major effector cells of the innate immune system can contribute significantly to human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) control. However, a specific role for NK cells in blocking lentivirus transmission remains incompletely clear.

People with HIV (PWH) on combined antiretroviral therapy (cART) are living longer lives due to modern cART advances and increased routine medical care. The full landscape of aging with HIV is unclear; given that HIV emerged relatively recently in human history and initially had a high mortality rate, there has not been a substantially aged population to evaluate. In the present study, we set out to perform high throughput plasma analyte profiling by multiplex analysis, focusing on various T helper (Th)-related cytokines, chemokines, and pro- and anti-inflammatory cytokines. The primary goals being to provide reference ranges of these analytes for aging PWH cohorts, as well as testing the utility of high throughput multiplex plasma assays. The cohort used in this study was comprised of age-matched healthy donors (aged 32.6-73.5), PWH on cART (aged 26.7-60.2), and viremic PWH (aged 27.5-59.4). The patients in each group were then stratified across the age span to examine age-related impacts of these plasma biomarkers. Our results largely indicate feasibility of plasma analyte monitoring by multiplex and demonstrate a high degree of person-to-person variability regardless of age and HIV status. Nonetheless, we find multiple associations with age, duration of known infection, and viral load, all of which appear to be driven by either prolonged HIV disease progression or long-term use of cART.

Natural killer (NK) cells play a critical role in virus control. However, it has remained largely unclear whether NK cell mobilization in SARS-CoV-2 infections is beneficial or pathologic. To address this deficit, we employed a validated experimental NK cell depletion non-human primate (NHP) model with SARS-CoV-2 Delta variant B.1.617.2 challenge. Viral loads (VL), NK cell numbers, activation, proliferation, and functional measures were evaluated in blood and tissues. In non-depleted (control) animals, infection rapidly induced NK cell expansion, activation, and increased tissue trafficking associated with VL. Strikingly, we report that experimental NK cell depletion leads to higher VL, longer duration of viremia, significantly increased levels of pro-inflammatory cytokines in the lungs, and overt lung damage. Overall, we find the first significant and conclusive evidence for NK cell-mediated control of SARS-CoV-2 virus replication and disease pathology. These data indicate that adjunct therapies for infection could largely benefit from NK cell-targeted approaches.

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