Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques
| العنوان: | Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques |
|---|---|
| المؤلفون: | Robin J. Shattock, Christiane Moog, Norman L. Letvin, Gary Landucci, Merlin L. Robb, Ryan Duffy, Georgia D. Tomaras, Elena E. Giorgi, Pinghuang Liu, Lily M. Blair, Guido Ferrari, Robert J. Schutte, Shi-Mao Xia, Supachai Rerks-Ngarm, M. A. Moody, Kelly A. Soderberg, S. Munir Alam, Nathan I. Nicely, Punnee Pitisuttithum, David C. Montefiori, Donald N. Forthal, Hui Li, Ruijun Zhang, Jerome H. Kim, Andrew Chao, Ranjit Warrier, Bette T. Korber, George M. Shaw, Amit Kumar, Nelson L. Michael, Sarah L. Cocklin, Kora Vidnovic, Hua-Xin Liao, Justin Pollara, James E. Robinson, Katja Klein, Jaranit Kaewkungwal, Charles W. Pemble, S. Moses Dennison, Joern E. Schmitz, Xiaoying Shen, Abbey Evans, Sorachai Nitayaphan, Feng Gao, Sampa Santra, Barton F. Haynes |
| المصدر: | PLoS Pathogens PLoS Pathogens, Vol 11, Iss 8, p e1005042 (2015) |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | lcsh:Immunologic diseases. Allergy, CD4-Positive T-Lymphocytes, medicine.drug_class, Protein Conformation, viruses, Immunology, Simian Acquired Immunodeficiency Syndrome, Fluorescent Antibody Technique, medicine.disease_cause, Gp41, Monoclonal antibody, Antibodies, Viral, Microbiology, Virus, Immune system, Viral Envelope Proteins, Virology, Genetics, medicine, Animals, Humans, Intestinal Mucosa, Molecular Biology, lcsh:QH301-705.5, biology, Reverse Transcriptase Polymerase Chain Reaction, Rectum, Antibodies, Monoclonal, Simian immunodeficiency virus, Surface Plasmon Resonance, Vaccine efficacy, Macaca mulatta, 3. Good health, Mucosal Infection, lcsh:Biology (General), biology.protein, HIV-1, Parasitology, Simian Immunodeficiency Virus, Antibody, lcsh:RC581-607, Research Article |
| الوصف: | 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. Author Summary Antibodies specifically recognize antigenic sites on pathogens and can mediate multiple antiviral functions through engagement of effector cells via their Fc region. Current HIV-1 vaccine candidates induce polyclonal antibody responses with multiple antiviral functions, but do not induce broadly neutralizing antibodies. An improved understanding of whether certain types of non-neutralizing HIV-1 specific antibodies can individually protect against HIV-1 infection may facilitate vaccine development. Here, we test whether non-neutralizing antibodies with multiple antiviral functions mediated through FcR engagement and recognition of virus particles or virus-infected cells can limit infection, despite lacking classical virus neutralization activity. In a passive antibody infusion-rhesus macaque challenge model, we tested the ability of non-neutralizing monoclonal antibodies to limit virus acquisition. We demonstrate that two different types of non-neutralizing antibodies, one that recognizes both virus particles and infected cells (7B2) and another that recognizes only infected cells (A32) were capable of decreasing the number of transmitted founder viruses. Further, we provide the structure of 7B2 in complex with the gp41 cyclical loop motif, a motif critical for entry. These findings provide insights into the role that antibodies with antiviral properties, including virion capture and FcR mediated effector function, may play in protecting against HIV-1 acquisition. |
| تدمد: | 1553-7374 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8534548eaf5d098f2604e39d18961d3f https://pubmed.ncbi.nlm.nih.gov/26237403 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8534548eaf5d098f2604e39d18961d3f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 |
|---|