Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences.

Recognition of genetically diverse pathogens by the adaptive immune system represents a primary strategy for host defense; however, pathogens such as HIV-1 can evade these responses to achieve persistent infection. The HIV-1 nef gene and the HLA class I locus rank among the most diverse genes of virus and host, respectively. The HIV-1 Nef protein interacts with the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules to evade cellular immunity. By combining molecular, genetic, and in silico analyses, we demonstrate that patient-derived Nef clones downregulate HLA-A more effectively than HLA-B molecules. This in turn modulates the ability of HIV-specific T cells to recognize HIV-infected cells. We also identify a naturally polymorphic site at Nef codon 202 and HLA cytoplasmic motifs (GG314,315 and CKV339-341) that contribute to differential HLA downregulation by Nef. Our results highlight new interactions between HIV-1 and the human immune system that may contribute to pathogenesis.