Evidence of Differential HLA Class I-Mediated Viral Evolution in Functional and Accessory/Regulatory Genes of HIV-1

Open Access
Publisher Website
Google Scholar
Abstract
Despite the formidable mutational capacity and sequence diversity of HIV-1, evidence suggests that viral evolution in response to specific selective pressures follows generally predictable mutational pathways. Population-based analyses of clinically derived HIV sequences may be used to identify immune escape mutations in viral genes; however, prior attempts to identify such mutations have been complicated by the inability to discriminate active immune selection from virus founder effects. Furthermore, the association between mutations arising under in vivo immune selection and disease progression for highly variable pathogens such as HIV-1 remains incompletely understood. We applied a viral lineage-corrected analytical method to investigate HLA class I-associated sequence imprinting in HIV protease, reverse transcriptase (RT), Vpr, and Nef in a large cohort of chronically infected, antiretrovirally naïve individuals. A total of 478 unique HLA-associated polymorphisms were observed and organized into a series of “escape maps,” which identify known and putative cytotoxic T lymphocyte (CTL) epitopes under selection pressure in vivo. Our data indicate that pathways to immune escape are predictable based on host HLA class I profile, and that epitope anchor residues are not the preferred sites of CTL escape. Results reveal differential contributions of immune imprinting to viral gene diversity, with Nef exhibiting far greater evidence for HLA class I-mediated selection compared to other genes. Moreover, these data reveal a significant, dose-dependent inverse correlation between HLA-associated polymorphisms and HIV disease stage as estimated by CD4+ T cell count. Identification of specific sites and patterns of HLA-associated polymorphisms across HIV protease, RT, Vpr, and Nef illuminates regions of the genes encoding these products under active immune selection pressure in vivo. The high density of HLA-associated polymorphisms in Nef compared to other genes investigated indicates differential HLA class I-driven evolution in different viral genes. The relationship between HLA class I-associated polymorphisms and lower CD4+ cell count suggests that immune escape correlates with disease status, supporting an essential role of maintenance of effective CTL responses in immune control of HIV-1. The design of preventative and therapeutic CTL-based vaccine approaches could incorporate information on predictable escape pathways. One of the greatest challenges facing HIV-1 vaccine design today is the formidable capacity of the virus for mutation and adaptation, a characteristic that has contributed to the extensive worldwide genetic variability of HIV-1 strains observed today. On an individual basis, evolutionary selective pressures imposed by each infected person's unique immune response results in the selection and outgrowth of viral “escape” mutants capable of evading immune recognition, while on a population basis, complex evolutionary selective pressures imposed by the highly polymorphic genes of the human immune system shape HIV-1 diversity on a global level. Making sense of the seemingly infinite complexity of HIV immune escape is of paramount importance in our goal of developing a successful HIV vaccine. The current study uses cutting-edge statistical methods to identify specific sites and patterns of human leukocyte antigen (HLA) class I-restricted escape mutations in various HIV genes. Researchers summarize their findings in the form of “immune escape maps,” which highlight the differential contribution of immune imprinting to HIV genetic diversity, as well as identify specific sites in the viral genome under active immune selection pressure. Results from the present study contribute to our understanding of how human immune selective pressure contributes to variation in different HIV genes, and could help inform the development of HIV vaccines that take into consideration viral diversity.