title: HIV-1 adaptation to low levels of CCR5 results in V3 and V2 loop changes that increase envelope pathogenicity, CCR5 affinity and decrease susceptibility to Maraviroc.
abstract: Variability in CCR5 levels in the human population is suggested to affect virus evolution, fitness and the course of HIV disease. We previously demonstrated that cell surface CCR5 levels directly affect HIV Envelope mediated bystander apoptosis. In this study, we attempted to understand HIV evolution in the presence of low levels of CCR5, mimicking the limiting CCR5 levels inherent to the host. HIV-1 adaptation in a T cell line expressing low levels of CCR5 resulted in two specific mutations; N302Y and E172K. The N302Y mutation led to accelerated virus replication, increase in Maraviroc IC50 and an increase in Envelope mediated bystander apoptosis in low CCR5 expressing cells. Analysis of subtype B sequences showed that N302Y is over-represented in CXCR4 tropic viruses in comparison to CCR5 tropic isolates. Considering the variability in CCR5 levels between individuals, our findings have implications for virus evolution, MVC susceptibility as well as HIV pathogenesis.
authors.affiliation: Center of Emphasis in Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, United States.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Garg
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, Singapore.
authors.forename: Raphael T C
authors.initials: RT
authors.lastname: Lee
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Maurer-Stroh
authors.affiliation: Center of Emphasis in Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905, United States. Electronic address: anjali.joshi@ttuhsc.edu.
authors.forename: Anjali
authors.initials: A
authors.lastname: Joshi
mesh_terms: D000222:Adaptation, Physiological; D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D055029:Inverted Repeat Sequences; D000077592:Maraviroc; D008958:Models, Molecular; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014230:Triazoles / Q000494:pharmacology; D014774:Virulence; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D014230:Triazoles; D000077592:Maraviroc
keywords: AIDS; CCR5; Co-receptor; Envelope; HIV; Maraviroc; Virus evolution