ADCC Develops Over Time during Persistent Infection with Live-Attenuated SIV and Is Associated with Complete Protection against SIVmac251 Challenge

PLoS Pathogens

W. Anderson Lauer¹  Ronald C. Desrosiers¹  Jackson D. Harvey¹  Michael D. Alpert¹  Keith G. Mansfield²  Angela Carville²  R. Paul Johnson³  R. Keith Reeves³  David T. Evans⁴  Jeffrey D. Lifson⁵  Michael Piatak Jr.⁵  Wenjun Li⁶ 

[1] Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America;Department of Pathology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America;Immunology Division, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America;Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, and Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America;SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland, United States of America;University of Massachusetts Medical School, Worcester, Massachusetts, United States of America

关键词: Antibodies;    SIV;    Macaque;    Enzyme-linked immunoassays;    Inoculation;    Antibody response;    Viral load;    HIV-1;   

DOI  :  10.1371/journal.ppat.1002890

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Live-attenuated strains of simian immunodeficiency virus (SIV) routinely confer apparent sterilizing immunity against pathogenic SIV challenge in rhesus macaques. Understanding the mechanisms of protection by live-attenuated SIV may provide important insights into the immune responses needed for protection against HIV-1. Here we investigated the development of antibodies that are functional against neutralization-resistant SIV challenge strains, and tested the hypothesis that these antibodies are associated with protection. In the absence of detectable neutralizing antibodies, Env-specific antibody-dependent cell-mediated cytotoxicity (ADCC) emerged by three weeks after inoculation with SIVΔnef, increased progressively over time, and was proportional to SIVΔnef replication. Persistent infection with SIVΔnef elicited significantly higher ADCC titers than immunization with a non-persistent SIV strain that is limited to a single cycle of infection. ADCC titers were higher against viruses matched to the vaccine strain in Env, but were measurable against viruses expressing heterologous Env proteins. In two separate experiments, which took advantage of either the strain-specificity or the time-dependent maturation of immunity to overcome complete protection against SIVmac251 challenge, measures of ADCC activity were higher among the SIVΔnef-inoculated macaques that remained uninfected than among those that became infected. These observations show that features of the antibody response elicited by SIVΔnef are consistent with hallmarks of protection by live-attenuated SIV, and reveal an association between Env-specific antibodies that direct ADCC and apparent sterilizing protection by SIVΔnef.

【 授权许可】

CC BY