Human NK cells confer protection against HIV-1 infection in humanized mice

• Published in: The Journal of clinical investigation Vol. 132; no. 24; pp. 1 - 11
• Main Authors: Sungur, Can M, Wang, Qiankun, Ozantürk, Ayşe N, Gao, Hongbo, Schmitz, Aaron J, Cella, Marina, Yokoyama, Wayne M, Shan, Liang
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15-12-2022
• Subjects: Animal models; Animals; Antibodies; Antibody-Dependent Cell Cytotoxicity; Antiretroviral therapy; Antiviral agents; Biomedical research; Care and treatment; Cytokines; Cytotoxicity; Degranulation; Development and progression; Drug therapy; Health aspects; HIV; HIV infection; HIV Infections; HIV-1; Host-virus relationships; Human immunodeficiency virus; Humans; Immune response; Immunology; Infections; Inflammation; Killer cells; Killer Cells, Natural; Ligands; Lymphocytes; Mice; Monoclonal antibodies; Natural killer cells; Observations; Viral Load; United States; NK cells; Immunology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI162694

The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound after analytic treatment interruption. Moreover, a broadly neutralizing antibody, PGT121, enhanced NK cell function in vivo, consistent with antibody-dependent cellular cytotoxicity. Monoclonal antibody depletion of NK cells resulted in higher viral loads in multiple nonlymphoid organs. Overall, our results in humanized MISTRG-6-15 mice demonstrated that NK cells provided direct anti-HIV-1 responses in vivo but were limited in their responses in lymphoid organs.