Natural Killer Cell Receptor NKG2A/HLA-E Interaction Dependent Differential Thymopoiesis of Hematopoietic Progenitor Cells Influences the Outcome of HIV Infection.

HIV infection and its outcome is complex because there is great heterogeneity not only in clinical presentation, incomplete clinical information of markers of immunodeficiency and in measurements of viral loads. Also, there many gene variants that control not only viral replication but immune responses to the virus; it has been difficult to study the role of the many AIDS restricting genes (ARGs) because their influence vary depending on the ethnicity of the populations studies and because the cost to follow infected individuals for many years. Nevertheless, at least genes of the major histocompatibility locus (MHC) such as HLA alleles have been informative to classify infected individuals following HIV infection; progression to AIDS and long-term-non-progressors (LTNP). For example, progressors could be defined as up to 5 years, up to 11 years or as we describe in this report up to 15 years from infection, and LTNP could be individuals with normal CD4+ T cell counts for more than 15 years with or without high viral loads. In this review, we emphasized that in the studies of ARGs the HLA alleles are important in LTNP; HLA-B alleles influencing the advantage to pathogens to produce immune defense mediated by CD8+ T cells (cognate immunuity). Our main point we make in this report is that contrary to recent reports claiming that this dominant effect was unlikely due to differences in NK activation through ligands such as HLA-Bw4 motif, we believe that cognate immunity as well as innate immunity conferred by NK cells are involved. The main problem is that HLA-Bw4 alleles can be classified according the aminoacid in position 80. Isoleucine determines LTNP, which is a ligand for 3DS1. Such alleles did not include HLA-B*44. B*13 and B*27 which have threonine at that position. The authors have not considered the fact that in addition to the NK immunoglobulin receptors, NK receptors can be of the lectin like such as NKG2A/HLA-E to influence the HIV infection outcome. HLA-Bw4 as well as HLA-Bw6 alleles can be classified into those with threonine or methionine in the second position of their leader peptides. These leader peptides are ligands for NKG2A in which methionine influences the inhibitory role of NKG2A for killing infected targets. Functional studies have not been done as well as studies of these receptors in infected individuals. However, analyses of the leader peptides of HLA-B alleles in published reports, suggested that threonine in the second position can explain the importance of HLA-B*57, B*13, B*44 as well as certain Bw6 alleles in LNTP. In addition, we analyzed the San Francisco database that was reported and found that the association of HLA-B alleles with LNTP or with progressors can be due to the presence of threonine or methionine in their second position. Therefore, studies of outcome of HIV infection should include not only mechanisms of cognate immunity mediated by peptides and CD8+ T cells but also, NK receptors of two types, NKG2A as well as 3DSI. We propose that the SCID mouse should be used to understand mechanisms mediated by many of the ARGs especially the importance of thymus derived cells as well as NK receptor interactions with their ligands in this experimental animal transplanted with human stem cells, thymus or NK cells obtained from individuals of known HLA genotypes.