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

M. Anthony Moody1, 2, 3, 19, , , Feng Gao1, 4, 19, , , Thaddeus C. Gurley1, Joshua D. Amos1, Amit Kumar1, Bhavna Hora1, Dawn J. Marshall1, John F. Whitesides1, Shi-Mao Xia1, Robert Parks1, Krissey E. Lloyd1, Kwan-Ki Hwang1, Xiaozhi Lu1, Mattia Bonsignori1, Andrés Finzi7, Nathan A. Vandergrift1, 4, S. Munir Alam1, 4, 5, Guido Ferrari1, 6, Xiaoying Shen1, Georgia D. Tomaras1, 3, 6, Gift Kamanga8, Myron S. Cohen9, Noel E. Sam10, Saidi Kapiga11, Elin S. Gray12, 20, Nancy L. Tumba12, Lynn Morris1, 12, Susan Zolla-Pazner13, 14, 21,
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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.