Human NK cells confer protection against HIV-1 infection in humanized mice
Can M. Sungur, … , Wayne M. Yokoyama, Liang Shan
Can M. Sungur, … , Wayne M. Yokoyama, Liang Shan
Published October 25, 2022
Citation Information: J Clin Invest. 2022;132(24):e162694. https://doi.org/10.1172/JCI162694.
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Human NK cells confer protection against HIV-1 infection in humanized mice

Abstract

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.

Authors

Can M. Sungur, Qiankun Wang, Ayşe N. Ozantürk, Hongbo Gao, Aaron J. Schmitz, Marina Cella, Wayne M. Yokoyama, Liang Shan

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Figure 4

NK cell expansion and increased functionality during the course of HIV-1 infection wanes with time.

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NK cell expansion and increased functionality during the course of HIV-1...
MISTRG-6-15 mice were infected with HIV-1BAL. On days 0, 10, 21, 42, 56, 112, and 168 after infection, 4–6 mice at each time point were euthanized for blood and tissue collection. (A) Plasma HIV-1 RNA levels; red line illustrates the average. (B) Number of human NK cells (huCD45+CD3–CD56+) throughout the course of infection in spleen, liver, lung, and LN. (C–F) Ki67, CD107a, IFN-γ, and GZMB expression by NK cells in blood, spleen, liver, lung, and LN. NK cells purified from tissues were stimulated with PMA/ionomycin ex vivo for 4 hours before flow cytometry analysis. Data displayed as mean ± SEM.