Transmitted Virus Fitness and Host T Cell Responses Collectively Define Divergent Infection Outcomes in Two HIV-1 Recipients

PLoS Pathogens

George M. Shaw¹  Beatrice H. Hahn¹  Paul Goepfert²  Jianming Tang²  Joshua Baalwa²  Persephone Borrow³  Susan A. Allen³  Ling Yue⁴  Catherine C. Dong⁴  Rong Rong⁴  Cynthia A. Derdeyn⁴  Daniel T. Claiborne⁴  Jessica L. Prince⁴  Emmanuel Cormier⁵  Jill Gilmour⁵  Katja J. Pfafferott⁶  Karen Conrod⁶  Cecilia Chui⁶  Eric Hunter⁶  Etienne Karita⁷  Alan S. Perelson⁸  Ruy M. Ribeiro⁸ 

[1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Medicine, University of Alabama, Birmingham, Alabama, United States of America;Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America;Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America;Human Immunology Laboratory, International AIDS Vaccine Initiative, London, United Kingdom;Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom;Rwanda-Zambia HIV Research Project, Project San Francisco, Kigali, Rwanda;Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America

关键词: T cells;    Viral replication;    HIV-1;    Infectious disease control;    Immune response;    Sequence analysis;    Microbial mutation;    Cytotoxic T cells;   

DOI  :  10.1371/journal.ppat.1004565

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.

【 授权许可】

CC BY