Most studies of HIV infection outcome reported have described the importance of class I gene products particularly HLA-B. In this regard in a large number of HIV-1 infected individuals from southern Africa, it was reported that HLA-B alleles influence the potential co-evolution of HIV and HLA, providing advantage to pathogen defense mediated by CD8+ T cells. These results were consistent with the findings in B-clade infected Caucasians with non-progression/low viral load or progression/high viral loads . The authors claimed that the dominant effect for HLA-B alleles in HIV infection was unlikely due to differences in NK cell activation through the HLA-Bw4 motif. They mentioned the fact that it was reported that there is epistatic interaction between KIR3DS1 and some HLA-Bw4 alleles that mediated protection were entirely independent of this interaction . Since there is a protective role of certain Bw4 alleles, B*2705, B*13 and B*44, as well as those that carry Ile-80, such a protective role should involve the mechanism described of NKG2A with the leader peptide threonine. See diagram. In both reports [26, 48], the authors did not consider the fact that there are two kinds of NK receptors, immunoglobulin receptors such as KIR3DS1 and the lectin receptors such as NKG2A. We have described herein that the alleles of Bw4, B*27 and B*57 as well as some Bw6 alleles carry threonine in the second position of their leader peptide that would interact with NKG2A. This mechanism should be studied together with the dominant role of HLA-B alleles influencing HIV specific CD8 T cell responses in the outcome of HIV infection. The use of cross-sectional studies has limitations of statistical power that are corrected when using longitudinal studies and this explains to some extent the major inconsistencies in published reports related to the HIV infection outcome. Perhaps the SCID mouse model could resolve some of these problems but this model also has limitations related to the fact that the experiments are limited to the particular tissues grafted and do not necessarily include the large number of ARGs present in individuals of the population at large [82, 83]. However, the engraftment of CD34+ or even of CD133+ cells give rise to multiple lineages of cells following spontaneous differentiation in vivo that may identify the source of ARGs.
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