title: 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.
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.
  
  
  
  clinicaltrials.gov NCT01378156.
authors.affiliation: AIDS Research Consortium of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Thompson
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Sonya L
authors.initials: SL
authors.lastname: Heath
authors.affiliation: AIDS Research Consortium of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Bentley
authors.initials: B
authors.lastname: Sweeton
authors.affiliation: AIDS Research Consortium of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Kathy
authors.initials: K
authors.lastname: Williams
authors.affiliation: Alabama Vaccine Research Clinic, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Pamela
authors.initials: P
authors.lastname: Cunningham
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Sharon
authors.initials: S
authors.lastname: Sen
authors.affiliation: University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.affiliation: Centre de recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.affiliation: Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Yongxian
authors.initials: Y
authors.lastname: Xu
authors.affiliation: GeoVax, Inc., Atlanta, Georgia, United States of America.
authors.forename: Rahul
authors.initials: R
authors.lastname: Basu
authors.affiliation: GeoVax, Inc., Atlanta, Georgia, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hellerstein
authors.affiliation: GeoVax, Inc., Atlanta, Georgia, United States of America.
authors.forename: Suefen
authors.initials: S
authors.lastname: Kwa
authors.affiliation: GeoVax, Inc., Atlanta, Georgia, United States of America.
authors.forename: Harriet L
authors.identifier: 0000-0001-6380-3458
authors.initials: HL
authors.lastname: Robinson
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002452:Cell Count; D005260:Female; D015683:Gene Products, gag / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007117:Immunization, Secondary / Q000009:adverse effects / Q000379:methods*; D008297:Male; D012008:Recurrence; D012449:Safety; D013045:Species Specificity; D014611:Vaccination / Q000009:adverse effects / Q000379:methods*; D019444:Vaccines, DNA / Q000276:immunology*; D019562:Viral Load / Q000187:drug effects / Q000276:immunology; D028761:Withholding Treatment
chemical_list: D019380:Anti-HIV Agents; D015683:Gene Products, gag; D019444:Vaccines, DNA