Role of HLA-E antigen presentation on NK control of HIV infection

Background: MHC-E restricted T-cell responses have been observed in SIV-vaccine strategies using CMV-based vectors but their contribution to virus control is unclear. HLA-E was originally identified as a ligand of some NKG2 family receptors expressed by NK cells. Two highly frequent, functional, HLA-E alleles (*01:01 and *01:03) have been defined and T-cell responses to bacterial and viral pathogens restricted by these molecules have been described. Methods: In order to evaluate the interaction of HLA-E-presented viral epitopes with NK- and T-cell receptors, we modeled the structural interaction of HLA-E presenting canonical (VL9) and non-canonical (HIV-derived RL9 and PM9) epitopes with NKG2A/2C or TCR. We determined the ability of 14 peptides (including VL9, 1 CMV-, 1 EBV-and 11 HIV-derived) to stabilize HLA-E *01:01 and *01:03 and how this modified NK degranulation and cytotoxic activity. In vitro inhibition of viral replication by NK cells was assessed in autologous HIV infected CD4+ T-cells from HIV-seronegative individuals (N = 12). HLA-E expression on these target cells was assessed by RT-PCR and flow cytometry. The relationship of HLA-E expression with in-vivo HIV control was tested by measuring HLA-E expression in HIV-controllers (N = 31) and non-controllers (N = 16) by RT-PCR. Results: Our structural models evidenced that TCR have less affinity for HLA-E than NKG2 receptors. Interestingly, HIV peptides RL9 or PM9 presented by HLA-E*01:01 or HLA-E*01:03 showed a predicted increase in affinity to NKG2A and NKG2C, respectively. In vitro experiments indicated that HLA-E*01:01 was generally less stable on the cell surface, but none of HIV-derived peptides stabilized HLA-E. HIV KG9-HLA-E*01*03 and RL9/TP9/VI9/YG9-HLA-E*01*01 decreased NK cytokine secretion. RL9/MD9-HLA-E*01:01 resulted in increased lysis of peptide pulsed target cells. NK-mediated inhibition of viral replication correlated positively with HLA-E expression. Conversely, in HIV-infected individuals, HLA-E expression on total PBMC was significantly higher in non-controller individuals. Conclusions: The elevated expression of HLA-E in uncontrolled HIV infection and its potential differential interaction with NKG2 molecules depending on peptide binding indicates a pivotal role in NK during HIV infection. As such, HLA-E presenting HIV-derived epitopes may sensitize target cells for NK lysis in early infection whereas prolonged, elevated expression of HLA-E may lead to NK reduced viral control.
OA05.01 L. Romero-Martin (1); C. Duran-Castells (1); M. Olivella (2); M. Rosas-Umbert (1); M. Ruiz-Riol (1); A. Olvera (1) and C. Brander (1) (1) Institut de Recerca de la Sida [...]