Autologous IgG antibodies block outgrowth of a substantial but variable fraction of viruses in the latent reservoir for HIV-1
| Autor: | Jennifer A. White, Kenneth Lynn, Sarah E. Sweet, Robert F. Siliciano, Janet D. Siliciano, Luis J. Montaner, Jacqueline K Brockhurst, Lynn N. Bertagnolli, Subul A. Beg, Karam Mounzer, Ian Frank, Pablo Tebas, Katharine J. Bar, Francesco R. Simonetti, Joseph Varriale |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
CD4-Positive T-Lymphocytes Male Anti-HIV Agents viruses Primary Cell Culture HIV Infections Viremia HIV Antibodies Virus Replication Immunoglobulin G Virus Blood Transfusion Autologous Immune system medicine Humans Leukapheresis Neutralizing antibody Cells Cultured Multidisciplinary biology env Gene Products Human Immunodeficiency Virus Biological Sciences Middle Aged medicine.disease Antibodies Neutralizing Combined Modality Therapy Virology Virus Latency Viral replication Viral evolution HIV-1 biology.protein Female Antibody |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2020617117 |
| Popis: | In untreated HIV-1 infection, rapid viral evolution allows escape from immune responses. Viral replication can be blocked by antiretroviral therapy. However, HIV-1 persists in a latent reservoir in resting CD4(+) T cells, and rebound viremia occurs following treatment interruption. The reservoir, which is maintained in part by clonal expansion, can be measured using quantitative viral outgrowth assays (QVOAs) in which latency is reversed with T cell activation to allow viral outgrowth. Recent studies have shown that viruses detected in QVOAs prior to treatment interruption often differ from rebound viruses. We hypothesized that autologous neutralizing antibodies directed at the HIV-1 envelope (Env) protein might block outgrowth of some reservoir viruses. We modified the QVOA to reflect pressure from low concentrations of autologous antibodies and showed that outgrowth of a substantial but variable fraction of reservoir viruses is blocked by autologous contemporaneous immunoglobulin G (IgG). A reduction in outgrowth of >80% was seen in 6 of 15 individuals. This effect was due to direct neutralization. We established a phylogenetic relationship between rebound viruses and viruses growing out in vitro in the presence of autologous antibodies. Some large infected cell clones detected by QVOA carried neutralization-sensitive viruses, providing a cogent explanation for differences between rebound virus and viruses detected in standard QVOAs. Measurement of the frequency of reservoir viruses capable of outgrowth in the presence of autologous IgG might allow more accurate prediction of time to viral rebound. Ultimately, therapeutic immunization targeting the subset of variants resistant to autologous IgG might contribute to a functional cure. |
| Databáze: | OpenAIRE |
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