Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice
Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice
Abstract Antibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy was 31% and the sole primary correlate of reduced risk was shown to be vigorous antibody response targeting the V1V2 region of HIV-1 envelope. Antibodies against V3 also were inversely correlated with infection risk in subsets of vaccinees. Antibodies recognizing these regions, however, do not exhibit potent neutralizing activity. Therefore, we examined the antiviral potential of poorly neutralizing monoclonal antibodies (mAbs) against immunodominant V1V2 and V3 sites by passive administration of human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells, followed by mucosal challenge with an HIV-1 infectious molecular clone (IMC) expressing the envelope of a tier 2 resistant HIV-1 strain. Treatment with anti-V1V2 mAb 2158 or anti-V3 mAb 2219 did not prevent infection, but both reduced the virus burden, and V3 mAb 2219 displayed a superior potency compared to V1V2 mAb 2158. While these mAbs had no or weak neutralizing activity and elicited undetectable levels of antibody-dependent cellular cytotoxicity (ADCC), V3 mAb 2219 displayed a greater capacity to bind virus- and cell-associated HIV-1 envelope and to mediate antibody-dependent cellular phagocytosis (ADCP) and C1q complement binding as compared to V1V2 mAb 2158. Mutations in the Fc region of 2219 abolished these effector activities and abrogated virus control in humanized mice. These results demonstrate the importance of Fc functions other than ADCC for antibodies without potent neutralizing activity.
Hioe Catarina E.、Li Guangming、Liu Xiaomei、Tsahouridis Ourania、Klingler J¨|romine、Heindel Daniel W.、Wang Xiao-Hong、Hessell Ann、Zolla-Pazner Susan、Alvarez Raymond、Spencer David A.、Lu Shan、He Xiuting、Su Lishan、Funaki Masaya、Upadhyay Chitra、Chen Benjamin K.、Finzi Andr¨|s、Wang Shixia、Feyznezhad Roya、Satija Namita、Pr¨|vost J¨|r¨|mie、Tang Alex F.、Hu Guangna
Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai||James J. Peters VA Medical CenterInstitute of Human Virology, University of Maryland||Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North CarolinaDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiLineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North CarolinaDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai||James J. Peters VA Medical CenterDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiVA New York Harbor Healthcare System ¨C ManhattanDivision of Pathobiology & Immunology, Oregon Health & Science University, Oregon National Primate Research CenterDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiDivision of Pathobiology & Immunology, Oregon Health & Science University, Oregon National Primate Research CenterDepartment of Medicine, University of Massachusetts Medical SchoolInstitute of Human Virology, University of MarylandInstitute of Human Virology, University of Maryland||Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North CarolinaInstitute of Human Virology, University of MarylandDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiCentre de recherche du Centre hospitalier de l?ˉUniversit¨| de Montr¨|al (CRCHUM)||D¨|partement de Microbiologie, Infectiologie et Immunologie, Universit¨| de Montr¨|alDepartment of Medicine, University of Massachusetts Medical SchoolDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount SinaiCentre de recherche du Centre hospitalier de l?ˉUniversit¨| de Montr¨|al (CRCHUM)||D¨|partement de Microbiologie, Infectiologie et Immunologie, Universit¨| de Montr¨|alDivision of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai||School of Medicine, University of CaliforniaDepartment of Medicine, University of Massachusetts Medical School
基础医学生物科学研究方法、生物科学研究技术微生物学
Hioe Catarina E.,Li Guangming,Liu Xiaomei,Tsahouridis Ourania,Klingler J¨|romine,Heindel Daniel W.,Wang Xiao-Hong,Hessell Ann,Zolla-Pazner Susan,Alvarez Raymond,Spencer David A.,Lu Shan,He Xiuting,Su Lishan,Funaki Masaya,Upadhyay Chitra,Chen Benjamin K.,Finzi Andr¨|s,Wang Shixia,Feyznezhad Roya,Satija Namita,Pr¨|vost J¨|r¨|mie,Tang Alex F.,Hu Guangna.Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/2021.05.24.445493.点此复制
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