Extreme Genetic Fragility of the HIV-1 Capsid

PLoS Pathogens

Frazer J. Rixon¹  Nick J. Loman¹  Suzannah J. Rihn¹  Robert J. Gifford²  Saskia E. Bakker³  Mudathir Alim⁴  Paul D. Bieniasz⁴  Sam J. Wilson⁴  David Bhella⁵ 

[1] Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, United States of America;Centre for Systems Biology, University of Birmingham, Birmingham, United Kingdom;Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, New York, United States of America;Laboratory of Retrovirology, The Rockefeller University, New York, New York, United States of America;MRC Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom

关键词: HIV-1;    Viral replication;    Virions;    Viral packaging;    Amino acid substitution;    Substitution mutation;    Microbial mutation;    293T cells;   

DOI  :  10.1371/journal.ppat.1003461

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Genetic robustness, or fragility, is defined as the ability, or lack thereof, of a biological entity to maintain function in the face of mutations. Viruses that replicate via RNA intermediates exhibit high mutation rates, and robustness should be particularly advantageous to them. The capsid (CA) domain of the HIV-1 Gag protein is under strong pressure to conserve functional roles in viral assembly, maturation, uncoating, and nuclear import. However, CA is also under strong immunological pressure to diversify. Therefore, it would be particularly advantageous for CA to evolve genetic robustness. To measure the genetic robustness of HIV-1 CA, we generated a library of single amino acid substitution mutants, encompassing almost half the residues in CA. Strikingly, we found HIV-1 CA to be the most genetically fragile protein that has been analyzed using such an approach, with 70% of mutations yielding replication-defective viruses. Although CA participates in several steps in HIV-1 replication, analysis of conditionally (temperature sensitive) and constitutively non-viable mutants revealed that the biological basis for its genetic fragility was primarily the need to coordinate the accurate and efficient assembly of mature virions. All mutations that exist in naturally occurring HIV-1 subtype B populations at a frequency >3%, and were also present in the mutant library, had fitness levels that were >40% of WT. However, a substantial fraction of mutations with high fitness did not occur in natural populations, suggesting another form of selection pressure limiting variation in vivo. Additionally, known protective CTL epitopes occurred preferentially in domains of the HIV-1 CA that were even more genetically fragile than HIV-1 CA as a whole. The extreme genetic fragility of HIV-1 CA may be one reason why cell-mediated immune responses to Gag correlate with better prognosis in HIV-1 infection, and suggests that CA is a good target for therapy and vaccination strategies.

【 授权许可】

CC BY