Lysis of Endogenously Infected CD4+ T Cell Blasts by rIL-2 Activated Autologous Natural Killer Cells from HIV-Infected Viremic Individuals

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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 p24pos blasts become partially susceptible to lysis by rIL-2-activated NK cells, while uninfected p24neg 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-Ineg 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 CD56neg/CD16pos subsets of highly dysfunctional NK cells from HIV-1-infected viremic patients. Collectively, our data demonstrate that the chronic viral replication of HIV-1 in infected individuals results in several phenotypic and functional aberrancies that interfere with the NK cell-mediated killing of autologous p24pos blasts derived from primary T cells. Natural killer (NK) cells represent an important line of defense against viral infections. In vitro studies with exogenously infected CD4+ T cell blasts from healthy donors have demonstrated that NK cells can kill autologous HIV-1-infected target cells. However, the ability of NK cells from HIV-1-infected viremic patients to kill autologous, endogenously infected CD4+ T cells had never been examined and remains uncertain. Given the reported abnormalities in phenotype and functions of NK cells from HIV-infected viremic individuals, we determined the function of NK cells in killing HIV-1-infected target cells under conditions that more closely mimic the in vivo environment in HIV-infected individuals. We show that NK cells from HIV-1-infected viremic patients display a variable although generally low ability to selectively eliminate autologous and endogenously HIV-1-infected CD4+ T cell blasts expanded ex vivo from peripheral blood. Various factors, including the markedly defective engagement of important NK cell activation pathways and high frequencies of the pathologic CD56neg/CD16pos NK cell subset in HIV-1-infected viremic patients, influenced NK cell–mediated cytolysis of endogenously infected CD4+ T cell blasts.

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