Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques

PLoS Pathogens

Sorachai Nitayaphan¹  Norman L. Letvin²  Joern E. Schmitz²  Sarah L. Cocklin²  Sampa Santra²  Punnee Pitisuttithum³  Supachai Rerks-Ngarm⁴  Andrew Chao⁵  Hui Li⁵  George M. Shaw⁵  Kora Vidnovic⁵  Ranjit Warrier⁵  Katja Klein⁶  Robin J. Shattock⁶  Abbey Evans⁶  James Robinson⁷  Donald N. Forthal⁸  Gary Landucci⁸  Charles W. Pemble IV⁹  Amit Kumar⁹  Xiaoying Shen⁹  Shi-Mao Xia⁹  David C. Montefiori⁹  Robert J. Schutte⁹  M. A. Moody⁹  Barton F. Haynes⁹  S. Munir Alam⁹  Georgia D. Tomaras⁹  Hua-Xin Liao⁹  Pinghuang Liu⁹  Ruijun Zhang⁹  Ryan Duffy⁹  Justin Pollara⁹  S. Moses Dennison⁹  Kelly A. Soderberg⁹  Feng Gao⁹  Nathan I. Nicely⁹  Guido Ferrari⁹  Elena E. Giorgi^1,10  Lily Blair^1,10  Bette T. Korber^1,10  Jaranit Kaewkungwal^1,11  Christiane Moog^1,12  Nelson L. Michael^1,13  Jerome H. Kim^1,13  Merlin L. Robb^1,13 

[1] Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand;Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America;Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand;Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand;Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Department of Medicine, St Mary’s Campus, Imperial College London, London, United Kingdom;Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, United States of America;Division of Infectious Diseases, Department of Medicine, University of California, Irvine, Irvine, California, United States of America;Duke Human Vaccine Institute, Duke School of Medicine, Durham, North Carolina, United States of America;Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America;Tropical Hygiene, Mahidol University, Bangkok, Thailand;U1109, INSERM University of Strasbourg, Strasbourg, Alsace, France;US Military Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America

关键词: Antibodies;    HIV-1;    Virions;    Macaque;    Rhesus monkeys;    Enzyme-linked immunoassays;    Macrophages;    T cells;   

DOI  :  10.1371/journal.ppat.1005042

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4+ T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate in vivo rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.

【 授权许可】

CC BY