HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

Abstract

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

Increased NKG2A found in cytotoxic natural killer subset in HIV-1 patients with advanced clinical status

“…Bonaparte and coworkers have showed that NK cells lacking inhibitory receptors to HLA-C and HLA-E kill HIV-1 infected CD4 cells [14]. Martini and coworkers' study showed that NKG2A-CD94/HLA-E interaction might contribute to NK cell dysfunction in destroying the HIV infected CD4 cells [21]. It is known that NKG2A/CD94 is one of the key inhibitory receptors for HLA-E on NK cells and the interaction between them delivers inhibitory signals to and thereby disarms NK cells.…”

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

“…Peptides derived from a variety of viruses, including EBV, HIV, and CMV, are known to bind to HLA-E (24-26). The HIV p24 peptide residues 14-22 (HIVp24 [14][15][16][17][18][19][20][21][22] , AISPRTLNA) was identified by a motif-based approach, and in chronic HIV infection the up-regulation of HLA-E on CD4 + T cells results in increased inhibition of NKG2A + NK cells (25,30). The peptide SQAPLPCVL from EBV BZLF-1 protein residues 39-47 (EBVbzlf [39][40][41][42][43][44][45][46][47] ) also has been shown to bind to HLA-E (24).…”

NK Cell Lysis of HIV-1-Infected Autologous CD4 Primary T Cells: Requirement for IFN-Mediated NK Activation by Plasmacytoid Dendritic Cells

“…In contrast, previous research indicates that autologous CD4 ϩ primary T cells infected with HIV-1 (aHIV ϩ CD4) are resistant to NK lysis unless KIR-expressing NK cells are removed from the NK pool (32,33). The selective downregulation of HLA-A and HLA-B by HIV-1 negative factor (34) in conjunction with an up-regulation of HLA-E on HIV-1-infected CD4 ϩ T cells (35,36) have been postulated to protect HIV-1-infected cells from NK surveillance. We now show that stimulation of NK cells by CpG ODN 2216-activated PDC triggers NK lysis of aHIV ϩ CD4 via a mechanism dependent on type 1 IFN.…”