CD4-HIV-NK

CD4-HIV-NK - Lysis of Endogenously Infected CD4+ T Cell...

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Lysis of Endogenously Infected CD4 + T Cell Blasts by rIL-2 Activated Autologous Natural Killer Cells from HIV- Infected Viremic Individuals Manuela Fogli 1 . , Domenico Mavilio 1,2 . * , Enrico Brunetta 1,2 , Stefania Varchetta 1,2,3 , Khaled Ata 1 , Gregg Roby 1 , Colin Kovacs 4 , Dean Follmann 5 , Daniela Pende 6 , Jeffrey Ward 7 , Edward Barker 8 , Emanuela Marcenaro 9 , Alessandro Moretta 9 , Anthony S. Fauci 1 1 Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Laboratory of Experimental Immunology, Istituto Clinico Humanitas, Rozzano, Milano, Italy, 3 Centre for Hepatology and Infectious Diseases, Policlinico San Matteo and University of Pavia, Italy, 4 Department of Medicine, University of Toronto, Toronto, Ontario, Canada, 5 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 6 Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy, 7 Department of Microbiology and Immunology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America, 8 Department of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America, 9 Dipartimento di Medicina Sperimentale, University of Genova, Genova, Italy Abstract Understanding the cellular mechanisms that ensure an appropriate innate immune response against viral pathogens is an important challenge of biomedical research. In vitro studies have shown that natural killer (NK) cells purified from healthy donors can kill heterologous cell lines or autologous CD4 + T cell blasts exogenously infected with several strains of HIV-1. However, it is not known whether the deleterious effects of high HIV-1 viremia interferes with the NK cell-mediated cytolysis of autologous, endogenously HIV-1-infected CD4 + T cells. Here, we stimulate primary CD4 + T cells, purified ex vivo from HIV- 1-infected viremic patients, with PHA and rIL2 (with or without rIL-7). This experimental procedure allows for the significant expansion and isolation of endogenously infected CD4 + T cell blasts detected by intracellular staining of p24 HIV-1 core antigen. We show that, subsequent to the selective down-modulation of MHC class-I (MHC-I) molecules, HIV-1-infected p24 pos blasts become partially susceptible to lysis by rIL-2-activated NK cells, while uninfected p24 neg blasts are spared from killing. This NK cell-mediated killing occurs mainly through the NKG2D activation pathway. However, the degree of NK cell cytolytic activity against autologous, endogenously HIV-1-infected CD4 + T cell blasts that down-modulate HLA-A and –B alleles and against heterologous MHC-I neg cell lines is particularly low. This phenomenon is associated with the defective surface expression and engagement of natural cytotoxicity receptors (NCRs) and with the high frequency of the anergic CD56 neg /CD16 pos subsets of highly dysfunctional NK cells from HIV-1-infected viremic patients. Collectively, our data
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CD4-HIV-NK - Lysis of Endogenously Infected CD4+ T Cell...

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