Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection
Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease...
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| Published in | Science translational medicine Vol. 7; no. 319; p. 319ra206 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
23.12.2015
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| Subjects | |
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| Abstract | Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression. |
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| AbstractList | Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression. |
| Author | Douek, Daniel C Boritz, Eli Conan-Cibotti, Michelle DeZure, Adam Freemire, Brandie A Mascola, John R Pandey, Janardan P Hu, Zonghui Enama, Mary E Plummer, Sarah Graham, Barney S Costner, Pamela Gordon, Ingelise Hendel, Cynthia S Casazza, Joseph O'Dell, Sijy Mohan, Sarumathi Koup, Richard A Fauci, Anthony S Lynch, Rebecca M Chun, Tae-Wook Fromentin, Remi Holman, Lasonji Lifson, Jeffrey D Schwartz, Richard M Narpala, Sandeep Chomont, Nicolas Wolf, Gideon Madden, Patrick McDermott, Adrian Capparelli, Edmund Bailer, Robert T Ledgerwood, Julie E Coates, Emily E Migueles, Stephen A Gorelick, Robert J Tressler, Randall |
| Author_xml | – sequence: 1 givenname: Rebecca M surname: Lynch fullname: Lynch, Rebecca M organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 2 givenname: Eli surname: Boritz fullname: Boritz, Eli organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 3 givenname: Emily E surname: Coates fullname: Coates, Emily E organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 4 givenname: Adam surname: DeZure fullname: DeZure, Adam organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 5 givenname: Patrick surname: Madden fullname: Madden, Patrick organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 6 givenname: Pamela surname: Costner fullname: Costner, Pamela organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 7 givenname: Mary E surname: Enama fullname: Enama, Mary E organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 8 givenname: Sarah surname: Plummer fullname: Plummer, Sarah organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 9 givenname: Lasonji surname: Holman fullname: Holman, Lasonji organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 10 givenname: Cynthia S surname: Hendel fullname: Hendel, Cynthia S organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 11 givenname: Ingelise surname: Gordon fullname: Gordon, Ingelise organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 12 givenname: Joseph surname: Casazza fullname: Casazza, Joseph organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 13 givenname: Michelle surname: Conan-Cibotti fullname: Conan-Cibotti, Michelle organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 14 givenname: Stephen A surname: Migueles fullname: Migueles, Stephen A organization: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 15 givenname: Randall surname: Tressler fullname: Tressler, Randall organization: Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 16 givenname: Robert T surname: Bailer fullname: Bailer, Robert T organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 17 givenname: Adrian surname: McDermott fullname: McDermott, Adrian organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 18 givenname: Sandeep surname: Narpala fullname: Narpala, Sandeep organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 19 givenname: Sijy surname: O'Dell fullname: O'Dell, Sijy organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 20 givenname: Gideon surname: Wolf fullname: Wolf, Gideon organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 21 givenname: Jeffrey D surname: Lifson fullname: Lifson, Jeffrey D organization: Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA – sequence: 22 givenname: Brandie A surname: Freemire fullname: Freemire, Brandie A organization: Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA – sequence: 23 givenname: Robert J surname: Gorelick fullname: Gorelick, Robert J organization: Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA – sequence: 24 givenname: Janardan P surname: Pandey fullname: Pandey, Janardan P organization: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA – sequence: 25 givenname: Sarumathi surname: Mohan fullname: Mohan, Sarumathi organization: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA – sequence: 26 givenname: Nicolas surname: Chomont fullname: Chomont, Nicolas organization: Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, and Centre de Recherche du CHUM (Centre hospitalier de l'Université de Montréal), Montreal, Quebec H2X 0A9, Canada – sequence: 27 givenname: Remi surname: Fromentin fullname: Fromentin, Remi organization: Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, and Centre de Recherche du CHUM (Centre hospitalier de l'Université de Montréal), Montreal, Quebec H2X 0A9, Canada – sequence: 28 givenname: Tae-Wook surname: Chun fullname: Chun, Tae-Wook organization: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 29 givenname: Anthony S surname: Fauci fullname: Fauci, Anthony S organization: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 30 givenname: Richard M surname: Schwartz fullname: Schwartz, Richard M organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 31 givenname: Richard A surname: Koup fullname: Koup, Richard A organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 32 givenname: Daniel C surname: Douek fullname: Douek, Daniel C organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 33 givenname: Zonghui surname: Hu fullname: Hu, Zonghui organization: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 34 givenname: Edmund surname: Capparelli fullname: Capparelli, Edmund organization: School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, CA 92110, USA – sequence: 35 givenname: Barney S surname: Graham fullname: Graham, Barney S organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 36 givenname: John R surname: Mascola fullname: Mascola, John R email: jmascola@mail.nih.gov, ledgerwood@mail.nih.gov organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jmascola@mail.nih.gov ledgerwood@mail.nih.gov – sequence: 37 givenname: Julie E surname: Ledgerwood fullname: Ledgerwood, Julie E email: jmascola@mail.nih.gov, ledgerwood@mail.nih.gov organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jmascola@mail.nih.gov ledgerwood@mail.nih.gov |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26702094$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Adolescent Adult Aged Aged, 80 and over Antibodies, Neutralizing - administration & dosage Antibodies, Neutralizing - immunology Antiretroviral Therapy, Highly Active CD4-Positive T-Lymphocytes - immunology Chronic Disease HIV Antibodies - blood HIV Infections - blood HIV Infections - drug therapy HIV Infections - immunology HIV Infections - virology HIV-1 - immunology Humans Kinetics Middle Aged Viral Load - immunology Young Adult |
| Title | Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection |
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