NK cells acquire CCR5 and CXCR4 by trogocytosis in people living with HIV-1

Abstract NK cells play a major role in the antiviral immune response, including against HIV-1. HIV patients have impaired NK cell activity with decrease in CD56 dim NK cells and increase in CD56 − CD16 + subset and recently it has been proposed that a population of CD56 + NKG2C + KIR + CD57 + cells represents antiviral memory NK cells. Antiretroviral therapy (ART) partly restores the functional activity of this lymphocyte lineage. NK cells when interacting with their targets can gain antigens from them by the process of trogocytosis. Here we show that NK cells can obtain CCR5 and CXCR4, but barely CD4, from T cell lines by trogocytosis in vitro . By UMAP (Uniform Manifold Approximation and Projection), we show that aviremic HIV patients have unique NK cell clusters that encompass for cells expressing CCR5, NKG2C and KIRs, but lack CD57 expression. Viremic patients have a larger proportion of CXCR4 + and CCR5 + NK cells than healthy donors (HD) and this is largely increased in CD107 + cells, suggesting a link between degranulation and trogocytosis. In agreement, UMAP identified a specific NK cell cluster in viremic HIV patients, which contains most of the CD107a + , CCR5 + and CXCR4 + cells. However, this cluster lacks NKG2C expression. Therefore, NK cells can gain CCR5 and CXCR4 by trogocytosis, which depends on degranulation. Author Summary NK cells play a major role in the antiviral immune response, including against HIV-1. HIV-1 infection largely impacts NK cell lineage. However, identification of the NK cells fighting the virus and eliminating infected cells has remained elusive. By using FACs analysis and analyzing T cell markers, we identify specific NK cell subsets that have gained T cell antigen markers by trogocytosis. We show a strong association of degranulation and trogocytosis ex vivo suggesting that NK cells are eliminating or trying to eliminate HIV-1 infected cells. Moreover, we show that NK cells can obtain the HIV-1 coreceptors CCR5 and CXCR4, but barely CD4, from T cells. Therefore, by uncovering that NK cells gain CCR5 and CXCR4 by trogocytosis we show that NK cells are actively fighting against HIV-1 infection in viremic and aviremic patients. This should help to identify why certain patients better control the virus, to develop new anti-HIV-1, NK cell-based, immunotherapies and to understand if NK cells can be a new HIV-1 reservoir.