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

doi:10.1016/j.chom.2015.08.006

. 2015 Sep 9;18(3):354-62.

doi: 10.1016/j.chom.2015.08.006.

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

M Anthony Moody¹, Feng Gao², Thaddeus C Gurley³, Joshua D Amos³, Amit Kumar³, Bhavna Hora³, Dawn J Marshall³, John F Whitesides³, Shi-Mao Xia³, Robert Parks³, Krissey E Lloyd³, Kwan-Ki Hwang³, Xiaozhi Lu³, Mattia Bonsignori³, Andrés Finzi⁴, Nathan A Vandergrift⁵, S Munir Alam⁶, Guido Ferrari⁷, Xiaoying Shen³, Georgia D Tomaras⁸, Gift Kamanga⁹, Myron S Cohen¹⁰, Noel E Sam¹¹, Saidi Kapiga¹², Elin S Gray¹³, Nancy L Tumba¹³, Lynn Morris¹⁴, Susan Zolla-Pazner¹⁵, Miroslaw K Gorny¹⁶, John R Mascola¹⁷, Beatrice H Hahn¹⁸, George M Shaw¹⁸, Joseph G Sodroski¹⁹, Hua-Xin Liao⁵, David C Montefiori²⁰, Peter T Hraber²¹, Bette T Korber²¹, Barton F Haynes²²

Affiliations

¹ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: moody007@mc.duke.edu.
² Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: feng.gao@dm.duke.edu.
³ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
⁴ Centre de Recherche du CHUM and Department of Microbiology, Infectology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada and Department of Microbiology and Immunology, McGill University, Montreal, QC H2X 1P1, Canada.
⁵ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
⁶ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
⁷ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
⁸ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
⁹ University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi.
¹⁰ Departments of Medicine, Epidemiology, Microbiology, and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
¹¹ Kilimanjaro Christian Medical Center, Moshi 25102, Tanzania.
¹² London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
¹³ National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
¹⁴ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
¹⁵ Department of Pathology, New York University School of Medicine, New York, NY 10010, USA; Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA.
¹⁶ Department of Pathology, New York University School of Medicine, New York, NY 10010, USA.
¹⁷ Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
¹⁸ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁹ Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
²⁰ Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
²¹ Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
²² Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: hayne002@mc.duke.edu.

PMID: 26355218
PMCID: PMC4567706
DOI: 10.1016/j.chom.2015.08.006

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

M Anthony Moody et al. Cell Host Microbe. 2015.

. 2015 Sep 9;18(3):354-62.

doi: 10.1016/j.chom.2015.08.006.

Authors

Affiliations

¹ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: moody007@mc.duke.edu.
² Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: feng.gao@dm.duke.edu.
³ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA.
⁴ Centre de Recherche du CHUM and Department of Microbiology, Infectology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada and Department of Microbiology and Immunology, McGill University, Montreal, QC H2X 1P1, Canada.
⁵ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
⁶ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
⁷ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
⁸ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
⁹ University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi.
¹⁰ Departments of Medicine, Epidemiology, Microbiology, and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
¹¹ Kilimanjaro Christian Medical Center, Moshi 25102, Tanzania.
¹² London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
¹³ National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
¹⁴ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; National Institute for Communicable Diseases, Johannesburg 2131, South Africa.
¹⁵ Department of Pathology, New York University School of Medicine, New York, NY 10010, USA; Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA.
¹⁶ Department of Pathology, New York University School of Medicine, New York, NY 10010, USA.
¹⁷ Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.
¹⁸ Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁹ Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
²⁰ Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
²¹ Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
²² Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: hayne002@mc.duke.edu.

PMID: 26355218
PMCID: PMC4567706
DOI: 10.1016/j.chom.2015.08.006

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.

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Figures

**Figure 1. Clonal lineages derived from CH0457**
A: The kite-shaped gate shows a diagonal of gp120_ConC core+/+ memory B cells that were sorted as single cells. Antigen-specific cell frequency was similar in both samples; wk 8 shown. B: IgG1 gp120 V3 mAbs (CH14, CH48) were not related to other isolated mAbs. Lineage CH13 had 6 IgG1 mAbs (V_H1~69/J_H3; V_K1~39/J_K4); mean heavy chain (HC) mutation frequency = 9.8%. Lineage CH27 had 3 mAbs—2 IgA2 (CH27, CH28) and a IgG1 (CH44) (V_H3~66/J_H2; V_K3~20/J_K1); mean HC mutation frequency = 15.7%. Trees plotted on the same scale. C: Residues critical for lineage CH13 and lineage CH27 mAb binding (Tables S2–3) highlighted in the structure of gp120_C.YU2 (CD4 light gray, gp120 light blue, mAb 17b not shown). Mapped residues are largely located within the CD4-gp120 contact surface. V1/V2 not shown because it was absent in the crystal structure. D. CH14 and CH48 binding to peptides reflective of multiple HIV-1 clades. Both bound V3 loop peptides (residues 301–325) across multiple clades; no binding found for other epitopes.

**Figure 2. Heterologous neutralization by mAbs from CH0457**
Neutralization of mAbs against tier 1 and tier 2 viruses from diverse clades shown in colored boxes (EC50). Control (HIVIG-C) and CH0457 serum from wks 8 and 96 shown; serum shown as reciprocal ED50. Lineage CH13 mAbs and non-lineage mAbs (CH14, CH48) potently neutralized tier 1 viruses but only neutralized one tier 2 virus (C.246F_C1G). Lineage CH27 neutralized one tier 1 virus but 23/40 (58%) tier 2 viruses. CH0457 serum from wks 8 and 96 neutralized all tier 1 viruses at >1:20, and 37/40 (93%) and 31/40 (78%) of tier 2 viruses, respectively.

**Figure 3. Heterologous neutralization by mAbs from CH505**
V3 mAbs DH151 and DH228 from CH505 tested against heterologous HIV isolates. Tier 1 isolates (2/4) neutralized; 0/16 tier 2 isolates neutralized.

**Figure 4. Autologous neutralization and Env sequence phylogenies**
Neutralization heat map of autologous serum and mAbs shown (AC). Each row in the neutralization panel (A) of 84 CH0457 pseudoviruses and phylogeny tree (B) is a distinct Env isolate spanning wk 0 (enrollment; red) to wk 96 after enrollment (purple). PBMC provirus sequences are grey. Autologous serum neutralization (reciprocal dilution) and isolated mAbs (µg/mL) shown for (A) lineage CH13 mAbs (tier 1 CD4bs), lineage CH27 mAbs (tier 2 CD4bs), and CH14 and CH48 (tier 1 V3); and (C) CH505 mAbs DH151 and DH228 (tier 1 V3) and lineage CH103 (tier 2 CD4bs). (D) CH505 Env phylogeny spans transmission (wk 0, red) through wk 100 (purple). A high fraction of circulating viruses were sensitive to autologous mAbs.

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References

1. Balla-Jhagjhoorsingh SS, Corti D, Heyndrickx L, Willems E, Vereecken K, Davis D, Vanham G. The N276 glycosylation site is required for HIV-1 neutralization by the CD4 binding site specific HJ16 monoclonal antibody. PLoS ONE. 2013;8:e68863. - PMC - PubMed
1. Bouvin-Pley M, Morgand M, Meyer L, Goujard C, Moreau A, Mouquet H, Nussenzweig M, Pace C, Ho D, Bjorkman PJ, et al. Drift of the HIV-1 envelope glycoprotein gp120 toward increased neutralization resistance over the course of the epidemic: a comprehensive study using the most potent and broadly neutralizing monoclonal antibodies. J Virol. 2014;88:13910–13917. - PMC - PubMed
1. Derdeyn CA, Moore PL, Morris L. Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection. Curr Opin HIV AIDS. 2014;9:210–216. - PMC - PubMed
1. Gao F, Bonsignori M, Kumar A, Xia S-M, Lu X, Cai F, Hwang K-K, Song H, Zhou T, Lynch RM, et al. Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies. Cell. 2014;158:481–491. - PMC - PubMed
1. Gilbert PB, Peterson ML, Follmann D, Hudgens MG, Francis DP, Gurwith M, Heyward WL, Jobes DV, Popovic V, Self SG, et al. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J Infect Dis. 2005;191:666–677. - PubMed

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[1] Balla-Jhagjhoorsingh SS, Corti D, Heyndrickx L, Willems E, Vereecken K, Davis D, Vanham G. The N276 glycosylation site is required for HIV-1 neutralization by the CD4 binding site specific HJ16 monoclonal antibody. PLoS ONE. 2013;8:e68863. - PMC - PubMed

[2] Balla-Jhagjhoorsingh SS, Corti D, Heyndrickx L, Willems E, Vereecken K, Davis D, Vanham G. The N276 glycosylation site is required for HIV-1 neutralization by the CD4 binding site specific HJ16 monoclonal antibody. PLoS ONE. 2013;8:e68863. - PMC - PubMed

[3] Bouvin-Pley M, Morgand M, Meyer L, Goujard C, Moreau A, Mouquet H, Nussenzweig M, Pace C, Ho D, Bjorkman PJ, et al. Drift of the HIV-1 envelope glycoprotein gp120 toward increased neutralization resistance over the course of the epidemic: a comprehensive study using the most potent and broadly neutralizing monoclonal antibodies. J Virol. 2014;88:13910–13917. - PMC - PubMed

[4] Bouvin-Pley M, Morgand M, Meyer L, Goujard C, Moreau A, Mouquet H, Nussenzweig M, Pace C, Ho D, Bjorkman PJ, et al. Drift of the HIV-1 envelope glycoprotein gp120 toward increased neutralization resistance over the course of the epidemic: a comprehensive study using the most potent and broadly neutralizing monoclonal antibodies. J Virol. 2014;88:13910–13917. - PMC - PubMed

[5] Derdeyn CA, Moore PL, Morris L. Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection. Curr Opin HIV AIDS. 2014;9:210–216. - PMC - PubMed

[6] Derdeyn CA, Moore PL, Morris L. Development of broadly neutralizing antibodies from autologous neutralizing antibody responses in HIV infection. Curr Opin HIV AIDS. 2014;9:210–216. - PMC - PubMed

[7] Gao F, Bonsignori M, Kumar A, Xia S-M, Lu X, Cai F, Hwang K-K, Song H, Zhou T, Lynch RM, et al. Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies. Cell. 2014;158:481–491. - PMC - PubMed

[8] Gao F, Bonsignori M, Kumar A, Xia S-M, Lu X, Cai F, Hwang K-K, Song H, Zhou T, Lynch RM, et al. Cooperation of B Cell Lineages in Induction of HIV-1-Broadly Neutralizing Antibodies. Cell. 2014;158:481–491. - PMC - PubMed

[9] Gilbert PB, Peterson ML, Follmann D, Hudgens MG, Francis DP, Gurwith M, Heyward WL, Jobes DV, Popovic V, Self SG, et al. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J Infect Dis. 2005;191:666–677. - PubMed

[10] Gilbert PB, Peterson ML, Follmann D, Hudgens MG, Francis DP, Gurwith M, Heyward WL, Jobes DV, Popovic V, Self SG, et al. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J Infect Dis. 2005;191:666–677. - PubMed

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

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

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