DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus

• Type of Material: Article
• Authors: Melanie Thompson, AIDS Research Consortium Atlanta; Sonya L. Heath, University of Alabama Birmingham; Bentley Sweeton, AIDS Research Consortium Atlanta; Kathy Williams, AIDS Research Consortium Atlanta; Pamela Cunningham, University of Alabama Birmingham; Brandon F. Keele, Frederick National Laboratory for Cancer Research; Sharon Sen, University of Colorado; Brent E. Palmer, University of Colorado; Nicolas Chomont, Université de Montréal; Yongxian Xu, Emory University; Rahul Basu, GeoVax Inc; Michael S. Hellerstein, GeoVax Inc; Suefen Kwa, GeoVax Inc; Harriet Robinson, Emory University
• Language: English
• Date: 2016-10-06
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0163164
• Title of Journal or Parent Work: PLOS ONE
• Volume: 11
• Issue: 10
• Start Page: e0163164
• End Page: e0163164
• Grant/Funding Information: Funding for MT and SLH was provided by GeoVax, Inc.; GeoVax, Inc. provided support in the form of employee salaries for YX, RB, MSH, SK, and HLR.; Funding for BFK was provided by the National Cancer Institute: HHSN261200800001E.
• Keywords: HIV TYPE-1; T-CELL EXHAUSTION; Science & Technology - Other Topics; INFLUENZA VACCINATION; VACCINES; IMMUNOGENICITY; Multidisciplinary Sciences; EXPRESSION; INFECTION; DISEASE PROGRESSION; REPLICATION; PLACEBO-CONTROLLED TRIAL; Science & Technology
• Research Categories: Biology, Cell; Health Sciences, Immunology; Biology, Virology

Abstract

GV-TH-01, a Phase 1 open-label trial of a DNA prime - Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.