Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.
Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3364956?pdf=render |
| _version_ | 1818033644688637952 |
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| author | Katharine J Bar Chun-yen Tsao Shilpa S Iyer Julie M Decker Yongping Yang Mattia Bonsignori Xi Chen Kwan-Ki Hwang David C Montefiori Hua-Xin Liao Peter Hraber William Fischer Hui Li Shuyi Wang Sarah Sterrett Brandon F Keele Vitaly V Ganusov Alan S Perelson Bette T Korber Ivelin Georgiev Jason S McLellan Jeffrey W Pavlicek Feng Gao Barton F Haynes Beatrice H Hahn Peter D Kwong George M Shaw |
| author_facet | Katharine J Bar Chun-yen Tsao Shilpa S Iyer Julie M Decker Yongping Yang Mattia Bonsignori Xi Chen Kwan-Ki Hwang David C Montefiori Hua-Xin Liao Peter Hraber William Fischer Hui Li Shuyi Wang Sarah Sterrett Brandon F Keele Vitaly V Ganusov Alan S Perelson Bette T Korber Ivelin Georgiev Jason S McLellan Jeffrey W Pavlicek Feng Gao Barton F Haynes Beatrice H Hahn Peter D Kwong George M Shaw |
| author_sort | Katharine J Bar |
| collection | DOAJ |
| description | Single genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC(50)) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one. |
| first_indexed | 2024-12-10T06:26:33Z |
| format | Article |
| id | doaj.art-3b0dc36fc26244f580f06b3696c32358 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-10T06:26:33Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-3b0dc36fc26244f580f06b3696c323582022-12-22T01:59:12ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742012-01-0185e100272110.1371/journal.ppat.1002721Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.Katharine J BarChun-yen TsaoShilpa S IyerJulie M DeckerYongping YangMattia BonsignoriXi ChenKwan-Ki HwangDavid C MontefioriHua-Xin LiaoPeter HraberWilliam FischerHui LiShuyi WangSarah SterrettBrandon F KeeleVitaly V GanusovAlan S PerelsonBette T KorberIvelin GeorgievJason S McLellanJeffrey W PavlicekFeng GaoBarton F HaynesBeatrice H HahnPeter D KwongGeorge M ShawSingle genome sequencing of early HIV-1 genomes provides a sensitive, dynamic assessment of virus evolution and insight into the earliest anti-viral immune responses in vivo. By using this approach, together with deep sequencing, site-directed mutagenesis, antibody adsorptions and virus-entry assays, we found evidence in three subjects of neutralizing antibody (Nab) responses as early as 2 weeks post-seroconversion, with Nab titers as low as 1∶20 to 1∶50 (IC(50)) selecting for virus escape. In each of the subjects, Nabs targeted different regions of the HIV-1 envelope (Env) in a strain-specific, conformationally sensitive manner. In subject CH40, virus escape was first mediated by mutations in the V1 region of the Env, followed by V3. HIV-1 specific monoclonal antibodies from this subject mapped to an immunodominant region at the base of V3 and exhibited neutralizing patterns indistinguishable from polyclonal antibody responses, indicating V1-V3 interactions within the Env trimer. In subject CH77, escape mutations mapped to the V2 region of Env, several of which selected for alterations of glycosylation. And in subject CH58, escape mutations mapped to the Env outer domain. In all three subjects, initial Nab recognition was followed by sequential rounds of virus escape and Nab elicitation, with Nab escape variants exhibiting variable costs to replication fitness. Although delayed in comparison with autologous CD8 T-cell responses, our findings show that Nabs appear earlier in HIV-1 infection than previously recognized, target diverse sites on HIV-1 Env, and impede virus replication at surprisingly low titers. The unexpected in vivo sensitivity of early transmitted/founder virus to Nabs raises the possibility that similarly low concentrations of vaccine-induced Nabs could impair virus acquisition in natural HIV-1 transmission, where the risk of infection is low and the number of viruses responsible for transmission and productive clinical infection is typically one.http://europepmc.org/articles/PMC3364956?pdf=render |
| spellingShingle | Katharine J Bar Chun-yen Tsao Shilpa S Iyer Julie M Decker Yongping Yang Mattia Bonsignori Xi Chen Kwan-Ki Hwang David C Montefiori Hua-Xin Liao Peter Hraber William Fischer Hui Li Shuyi Wang Sarah Sterrett Brandon F Keele Vitaly V Ganusov Alan S Perelson Bette T Korber Ivelin Georgiev Jason S McLellan Jeffrey W Pavlicek Feng Gao Barton F Haynes Beatrice H Hahn Peter D Kwong George M Shaw Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. PLoS Pathogens |
| title | Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. |
| title_full | Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. |
| title_fullStr | Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. |
| title_full_unstemmed | Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. |
| title_short | Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. |
| title_sort | early low titer neutralizing antibodies impede hiv 1 replication and select for virus escape |
| url | http://europepmc.org/articles/PMC3364956?pdf=render |
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