Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Moody MA

PROVIDER: S-EPMC4567706 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Moody M Anthony MA Gao Feng F Gurley Thaddeus C TC Amos Joshua D JD Kumar Amit A Hora Bhavna B Marshall Dawn J DJ Whitesides John F JF Xia Shi-Mao SM Parks Robert R Lloyd Krissey E KE Hwang Kwan-Ki KK Lu Xiaozhi X Bonsignori Mattia M Finzi Andrés A Vandergrift Nathan A NA Alam S Munir SM Ferrari Guido G Shen Xiaoying X Tomaras Georgia D GD Kamanga Gift G Cohen Myron S MS Sam Noel E NE Kapiga Saidi S Gray Elin S ES Tumba Nancy L NL Morris Lynn L Zolla-Pazner Susan S Gorny Miroslaw K MK Mascola John R JR Hahn Beatrice H BH Shaw George M GM Sodroski Joseph G JG Liao Hua-Xin HX Montefiori David C DC Hraber Peter T PT Korber Bette T BT Haynes Barton F BF

Cell host & microbe 20150901 3

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 descr ...[more]

PMID: 26355218

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Project description:Attachment inhibitor (AI) BMS-626529 (fostemsavir) represents a novel class of antiretrovirals which target human immunodeficiency virus type 1 (HIV-1) gp120 and block CD4-induced conformational changes required for viral entry. It is now in phase III clinical trials and is expected to be approved by the U.S. Food and Drug Administration (FDA) in the near future. Although fostemsavir is very potent against HIV in vitro and in vivo, a number of resistant mutants have already been identified. Broadly neutralizing HIV antibodies (bNAbs) can potently inhibit a wide range of HIV-1 strains by binding to viral Env and are very promising candidates for HIV-1 prevention and therapy. Since both target viral Env to block viral entry, we decided to investigate the relationship between these two inhibitors. Our data show that Env mutants resistant to BMS-626529 retained susceptibility to bNAbs. A single treatment of bNAb NIH45-46G54W completely inhibited the replication of these escape mutants. Remarkable synergy was observed between BMS-626529 and CD4 binding site (CD4bs)-targeting bNAbs in neutralizing HIV-1 strains at low concentrations. This synergistic effect was enhanced against virus harboring mutations conferring resistance to BMS-626529. The mechanistic basis of the observed synergy is likely enhanced inhibition of CD4 binding to the HIV-1 Env trimer by the combination of BMS-626529 and CD4bs-targeting bNAbs. This work highlights the potential for positive interplay between small- and large-molecule therapeutics against HIV entry, which may prove useful as these agents enter clinical use.IMPORTANCE As the worldwide HIV pandemic continues, there is a continued need for novel drugs and therapies. A new class of drug, the attachment inhibitors, will soon be approved for the treatment of HIV. Broadly neutralizing antibodies are also promising candidates for HIV prevention and therapy. We investigated how this drug might work with these exciting antibodies that are very potent in blocking HIV infection of cells. These antibodies worked against virus known to be resistant to the new drug. In addition, a specific type of antibody worked really well with the new drug in blocking virus infection of cells. This work has implications for both the new drug and the antibodies that are poised to be used against HIV.

Project description:Antibodies that neutralize (nAbs) genetically diverse HIV-1 strains have been recovered from a subset of HIV-1 infected subjects during chronic infection. Exact mechanisms that expand the otherwise narrow neutralization capacity observed during early infection are, however, currently undefined. Here we characterized the earliest nAb responses in a subtype A HIV-1 infected Rwandan seroconverter who later developed moderate cross-clade nAb breadth, using (i) envelope (Env) glycoproteins from the transmitted/founder virus and twenty longitudinal nAb escape variants, (ii) longitudinal autologous plasma, and (iii) autologous monoclonal antibodies (mAbs). Initially, nAbs targeted a single region of gp120, which flanked the V3 domain and involved the alpha2 helix. A single amino acid change at one of three positions in this region conferred early escape. One immunoglobulin heavy chain and two light chains recovered from autologous B cells comprised two mAbs, 19.3H-L1 and 19.3H-L3, which neutralized the founder Env along with one or three of the early escape variants carrying these mutations, respectively. Neither mAb neutralized later nAb escape or heterologous Envs. Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions. Resistance to mAb neutralization arose in later Envs through alteration of two glycans spatially adjacent to the initial escape signatures. The cross-neutralizing nAbs that ultimately developed failed to target any of the defined V3-proximal changes generated during the first year of infection in this subject. Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env. This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection.

Dataset Information

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

Publications

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

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