Natural Killer Cells Regulate Acute SIV Replication, Dissemination, and Inflammation, but Do Not Impact Independent Transmission Events

Woolley, Griffin; Mosher, Matthew; Kroll, Kyle; Jones, Rhianna; Hueber, Brady; Sugawara, Sho K.; Manickam, Cordelia; Terry, Karen; Varner, Valerie; Lifton, Michelle A.; Ram, Daniel R.; Fennessey, Christine M.; Keele, Brandon F.; Reeves, R. Keith

doi:10.1128/jvi.01519-22

Cited by 6 publications

(11 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The systemic-and tissuelevel NK cell depletion achieved by the anti-IL-15 mAb administration was highly successful (Fig. 1B) with little to no adverse or off-target impacts, similar to previous reports by our group and others 24,50 and providing a clean model to evaluate the impacts on virology and pathology. The VL in our study in the pharynx peaked at 3DPI (Fig.…”

Section: Groupsupporting

confidence: 87%

“…S2). Collectively these data indicated our NK cell depletion strategy (which has been well-defined by our group and others) 24,49,50 , was highly effective and NK cell-specific in this model. In control animals, longitudinal evaluation suggested significant NK cell mobilization in specific response to infection.…”

Section: T Cells (Supplementary Fig S1)supporting

confidence: 66%

“…To achieve this goal, we investigated the contribution of systemic NK cell mobilization to SARS-CoV-2 pathogenesis and clearance in cynomolgus macaque (CM) models using a welldescribed method of in vivo NK cell depletion specific for nonhuman primates. 24,[49][50][51] The results of this innovative study will contribute to our understanding of human immune responses against SARS-CoV-2 and provide the rationale to develop novel immunotherapeutic approaches which target specific NK cell subsets and could substantially strengthen ongoing and alternative efforts for the prevention and treatment of COVID-19.…”

Section: Introductionmentioning

confidence: 97%

“…23 Our group and others have also previously shown in simian immunodeficiency virus (SIV)-infected non-human primates (NHP) that depleting NK cells leads to increased systemic and tissue viremia, indicating that NK cells regulate replication, dissemination, and inflammation during viral infection. [24][25][26][27] There has been a plethora of studies in COVID-19 patients and non-human primate (NHP) models describing T and B cell responses during acute infection, immediate recovery, and extended convalescence, as well as post-vaccination. [28][29][30][31][32] However, less is known about NK cell responses to SARS-CoV-2 infection.…”

mentioning

confidence: 99%

See 3 more Smart Citations

NK cells are critical for in vivo control of SARS-CoV-2 replication and suppression of lung damage

Reeves

Balachandran

Kroll

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Groupsupporting

confidence: 87%

Section: T Cells (Supplementary Fig S1)supporting

confidence: 66%

Section: Introductionmentioning

confidence: 97%

mentioning

confidence: 99%

See 2 more Smart Citations

NK cells are critical for in vivo control of SARS-CoV-2 replication and suppression of lung damage

Reeves

Balachandran

Kroll

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Cohort studies of highly exposed seronegative (HESN) individuals have identified particular NK cell phenotypes and enhanced effector functions associated with resistance to HIV acquisition [26][27][28][29][30]. Furthermore, analysis of human samples prior to and then during acute HIV infection showed that increased NK cell activity was a correlate of future viremic control [31], and NK cell depletion in nonhuman primates (NHPs) enhanced acute viremia and inflammation [32], emphasizing the role of NK cells in control of early infection.…”

Section: Natural Killer Cell Contributions To Control Of Acute and Ch...mentioning

confidence: 99%

Harnessing immune cells to eliminate HIV reservoirs

Grasberger,

Sondrini,

Clayton

2024

Current Opinion in HIV and AIDS

View full text Add to dashboard Cite

Purpose of review Despite decades of insights about how CD8+ T cells and natural killer (NK) cells contribute to natural control of infection, additional hurdles (mutational escape from cellular immunity, sequence diversity, and hard-to-access tissue reservoirs) will need to be overcome to develop a cure. In this review, we highlight recent findings of novel mechanisms of antiviral cellular immunity and discuss current strategies for therapeutic deisgn. Recent findings Of note are the apparent converging roles of viral antigen-specific MHC-E-restricted CD8+ T cells and NK cells, interleukin (IL)-15 biologics to boost cytotoxicity, and broadly neutralizing antibodies in their native form or as anitbody fragments to neutralize virus and engage cellular immunity, respectively. Finally, renewed interest in myeloid cells as relevant viral reservoirs is an encouraging sign for designing inclusive therapeutic strategies. Summary Several studies have shown promise in many preclinical models of disease, including simian immunodeficiency virus (SIV)/SHIV infection in nonhuman primates and HIV infection in humanized mice. However, each model comes with its own limitations and may not fully predict human responses. We eagerly await the results of clinical trails assessing the efficacy of these strategies to achieve reductions in viral reservoirs, delay viral rebound, or ultimately elicit immune based control of infection without combination antiretroviral therapy (cART).

show abstract

Knockdowns of CD3zeta Chain in Primary NK Cells Illustrate Modulation of Antibody-Dependent Cellular Cytotoxicity Against Human Immunodeficiency Virus-1

Sugawara,

Lee,

Craemer

et al. 2024

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

Natural Killer Cells Regulate Acute SIV Replication, Dissemination, and Inflammation, but Do Not Impact Independent Transmission Events

Cited by 6 publications

References 52 publications

NK cells are critical for in vivo control of SARS-CoV-2 replication and suppression of lung damage

NK cells are critical for in vivo control of SARS-CoV-2 replication and suppression of lung damage

Harnessing immune cells to eliminate HIV reservoirs

Knockdowns of CD3zeta Chain in Primary NK Cells Illustrate Modulation of Antibody-Dependent Cellular Cytotoxicity Against Human Immunodeficiency Virus-1

Contact Info

Product

Resources

About