Strain-Specific V3 and CD4 Binding Site Autologous HIV-1 Neutralizing Antibodies Select Neutralization-Resistant Viruses

• Published in: Cell host & microbe Vol. 18; no. 3; pp. 354 - 362
• Main Authors: Moody, M. Anthony, Gao, Feng, Gurley, Thaddeus C., Amos, Joshua D., Kumar, Amit, Hora, Bhavna, Marshall, Dawn J., Whitesides, John F., Xia, Shi-Mao, Parks, Robert, Lloyd, Krissey E., Hwang, Kwan-Ki, Lu, Xiaozhi, Bonsignori, Mattia, Finzi, Andrés, Vandergrift, Nathan A., Alam, S. Munir, Ferrari, Guido, Shen, Xiaoying, Tomaras, Georgia D., Kamanga, Gift, Cohen, Myron S., Sam, Noel E., Kapiga, Saidi, Gray, Elin S., Tumba, Nancy L., Morris, Lynn, Zolla-Pazner, Susan, Gorny, Miroslaw K., Mascola, John R., Hahn, Beatrice H., Shaw, George M., Sodroski, Joseph G., Liao, Hua-Xin, Montefiori, David C., Hraber, Peter T., Korber, Bette T., Haynes, Barton F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.09.2015; Elsevier
• Subjects: 60 APPLIED LIFE SCIENCES; Antibodies, Neutralizing - immunology; BASIC BIOLOGICAL SCIENCES; Binding Sites; CD4-Positive T-Lymphocytes - virology; HIV Antibodies - immunology; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - immunology; HIV-1 - genetics; HIV-1 - immunology; Molecular Sequence Data; Mutation; RNA, Viral - genetics; Selection, Genetic; Sequence Analysis, DNA; Virus Attachment
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2015.08.006

The third variable (V3) loop and the CD4 binding site (CD4bs) of the HIV-1 envelope are frequently targeted by neutralizing antibodies (nAbs) in infected individuals. In chronic infection, HIV-1 escape mutants repopulate the plasma, and V3 and CD4bs nAbs emerge that can neutralize heterologous tier 1 easy-to-neutralize but not tier 2 difficult-to-neutralize HIV-1 isolates. However, neutralization sensitivity of autologous plasma viruses to this type of nAb response has not been studied. We describe the development and evolution in vivo of antibodies distinguished by their target specificity for V3 and CD4bs epitopes on autologous tier 2 viruses but not on heterologous tier 2 viruses. A surprisingly high fraction of autologous circulating viruses was sensitive to these antibodies. These findings demonstrate a role for V3 and CD4bs antibodies in constraining the native envelope trimer in vivo to a neutralization-resistant phenotype, explaining why HIV-1 transmission generally occurs by tier 2 neutralization-resistant viruses. [Display omitted] •Broad and restricted neutralizing antibodies isolated from chronic HIV-1-infected subjects•Antibodies were tested for their ability to neutralize a large panel of autologous viruses•Antibodies with limited heterologous breadth potently neutralize autologous viruses•Such antibodies can select for neutralization-resistant autologous viruses The V3 loop and the CD4 binding site of the HIV-1 envelope are frequently targeted by neutralizing antibodies. Moody et al. show that V3 and CD4bs antibodies from chronically infected individuals, which display limited heterologous neutralization breadth, can inhibit autologous HIV-1. Such antibodies can select neutralization-resistant autologous viruses.