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.
Highlights
Natural killer (NK) cells are important effectors of innate immune responses and are capable of providing cellular immunity against tumor-transformed and virally-infected cells, without prior antigen sensitization [1,2]
Subsequent to the selective down-modulation of MHC class-I (MHC-I) molecules, HIV-1-infected p24pos blasts become partially susceptible to lysis by recombinant IL-2 (rIL-2)-activated NK cells, while uninfected p24neg blasts are spared from killing
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
Summary
Natural killer (NK) cells are important effectors of innate immune responses and are capable of providing cellular immunity against tumor-transformed and virally-infected cells, without prior antigen sensitization [1,2]. NK cell cytolytic machinery is modulated by a delicate balance between opposing signals delivered by two heterogeneous families of inhibitory and activating NK cell receptors. Cytotoxicity against normal autologous cells is blocked by the specific recognition of different MHC class – I (MHC-I) molecules by inhibitory NK cell receptors (iNKRs). Diminution or absence of expression of HLA-I alleles on a cell surface following viral infection or tumor transformation results in the reduced engagement of iNKRs and allows activating NK receptors and co-receptors to trigger NK cell-mediated cytolysis [5]
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