Early Low-Titer Neutralizing Antibodies Impede HIV-1 Replication and Select for Virus Escape

PLoS Pathogens

David C. Montefiori¹  Barton F. Haynes¹  Kwan-Ki Hwang¹  Mattia Bonsignori¹  Jeffrey W. Pavlicek¹  Xi Chen¹  Hua-Xin Liao¹  Chun-yen Tsao¹  Feng Gao¹  Alan S. Perelson²  William Fischer²  Peter Hraber²  Bette T. Korber²  Beatrice H. Hahn³  Shilpa S. Iyer³  Katharine J. Bar³  Hui Li³  Shuyi Wang³  George M. Shaw³  Brandon F. Keele⁴  Julie M. Decker⁵  Sarah Sterrett⁵  Vitaly V. Ganusov⁶  Peter D. Kwong⁷  Jason S. McLellan⁷  Yongping Yang⁷  Ivelin Georgiev⁷ 

[1] Duke University School of Medicine, Durham, North Carolina, United States of America;Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America;Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;SAIC-Frederick Inc, National Cancer Institute, Frederick, Maryland, United States of America;University of Alabama at Birmingham, Birmingham, Alabama, United States of America;University of Tennessee, Knoxville, Tennessee, United States of America;Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: HIV-1;    Microbial mutation;    Sequence alignment;    Antibodies;    Viral replication;    Amino acid sequence analysis;    Sequence motif analysis;    Polymerase chain reaction;   

DOI  :  10.1371/journal.ppat.1002721

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC50) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1–V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one.

【 授权许可】

CC BY