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      Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption

      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
      New England Journal of Medicine
      Massachusetts Medical Society

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          Abstract

          Background The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). Methods We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. Results A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 μg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. Conclusions VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).

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          Most cited references17

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          Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy

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            Antibody-based Protection Against HIV Infection by Vectored ImmunoProphylaxis

            Despite tremendous efforts, development of an effective vaccine against HIV has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing the vast majority of circulating HIV strains 1–5 . These antibodies all exhibit an unusually high level of somatic mutation 6 , presumably due to extensive affinity maturation over the course of continuous exposure to an evolving antigen 7 . While substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes 8–10 , it remains uncertain whether a conventional vaccine will be able to elicit analogs of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus (AAV) vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.
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              Recovery of Replication-Competent HIV Despite Prolonged Suppression of Plasma Viremia

              J Wong (1997)
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                Author and article information

                Journal
                New England Journal of Medicine
                N Engl J Med
                Massachusetts Medical Society
                0028-4793
                1533-4406
                November 24 2016
                November 24 2016
                : 375
                : 21
                : 2037-2050
                Article
                10.1056/NEJMoa1608243
                5292134
                27959728
                5f88686d-9013-45c0-ac43-092358b20484
                © 2016
                History

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