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

Journal Article · · PLoS Pathogens
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  1. Univ. of Pennsylvania, Philadelphia, PA (United States). Perelman School of Medicine
  2. Duke Univ., Durham, NC (United States). School of Medicine
  3. Univ. of Alabama, Birmingham, AL (United States)
  4. National Institutes of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Disease. Vaccine Research Center
  5. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  6. National Cancer Institute, Frederick, MD (United States). SAIC-Frederick Inc.
  7. Univ. of Tennessee, Knoxville, TN (United States)
+ Show Author Affiliations

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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1627903
Journal Information:
PLoS Pathogens, Vol. 8, Issue 5; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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  • F., Salazar-Gonzalez, Jesus; P., Busch, Michael; S., Perelson, Alan
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/f6s9-vz03
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Cited By (15)

Estimating the mutational fitness effects distribution during early HIV infection journal July 2018
Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens journal March 2016
B-cell restriction – an alternative piece to the puzzle journal April 2019
Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses journal March 2018
A multiple-alignment based primer design algorithm for genetically highly variable DNA targets journal January 2013
HIV evolution and diversity in ART-treated patients journal January 2018
In vivo mutation rates and the landscape of fitness costs of HIV-1 text January 2017
Transmitted Virus Fitness and Host T Cell Responses Collectively Define Divergent Infection Outcomes in Two HIV-1 Recipients journal January 2015
Novel HIV vaccine strategies: overview and perspective journal July 2013
Increasing the Clinical Potential and Applications of Anti-HIV Antibodies journal November 2017
Is hiv Short-Sighted? Insights from a Multistrain Nested Model: Evolution of hiv Virulence journal June 2013
Relative resistance of HIV-1 founder viruses to control by interferon-alpha journal January 2013
Modeling the within-host dynamics of HIV infection journal September 2013
Spatiotemporal hierarchy in antibody recognition against transmitted HIV-1 envelope glycoprotein during natural infection journal February 2016
Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population journal December 2015

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