22 research outputs found
Loss of IL-17–Producing CD8 T Cells during Late Chronic Stage of Pathogenic Simian Immunodeficiency Virus Infection
Diminished Viral Control during Simian Immunodeficiency Virus Infection Is Associated with Aberrant PD-1 hi
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
<div><p>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.</p><p>Trial Registration</p><p>clinicaltrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01378156" target="_blank">NCT01378156</a></p></div
Temporal magnitudes of vaccine stimulated T cell and Ab responses.
<p>Panels A-D: medians with interquartile ranges for Gag-stimulated T cell responses scored using ICS. IFNγ (panel A) and IFNγ + IL-2 co-producing (Panel B) CD8+ cells as % of total CD8+ T cells. IFNγ (Panel C) and IFNγ + IL-2 (Panel D) co-producing CD4+ cells as % of total CD4+ T cells. Panels E and F: gp120 and gp41 Ab (μg/ml). Data are for the vaccination, treatment interruption (indicated in grey) and treatment reinstitution phases of the trial. Dotted lines indicate the timing of DNA (D) and MVA (M) immunizations. All 9 participants are included in T cell data through the 1<sup>st</sup> MVA inoculation after which data are for the 8 participants that completed the trial. The Ab data are for the 8 participants that completed the trial.</p
CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus (SIV) Vaccine Enhances Protection against Neutralization-Resistant Mucosal SIV Infection
Sequence changes consistent with CD8+ T cell selection of re-emergent virus in 01–4 and 01–8.
<p>Sequence changes consistent with CD8+ T cell selection of re-emergent virus in 01–4 and 01–8.</p
Temporal Levels of Absolute CD4+ and CD8+ T Cells Throughout the Study.
<p>All data are means with the error bars indicating standard deviations. Panels A and B present absolute CD4+ and CD8+ T cell counts as cells/μl. Panels C and D present activated cells as a percent of total CD4+ and CD8+ T cells respectively. Cells displaying CD38+ and HLA-DR surface markers are considered activated T cells.</p
Ratio of Absolute CD4+ to Absolute CD8+ T cell Counts<sup>1</sup>.
<p>Ratio of Absolute CD4+ to Absolute CD8+ T cell Counts<sup>1</sup>.</p
Trial Schema.
<p>The phases of the trial are indicated for screening, vaccination, treatment interruption and treatment reinstitution. An efavirenz washout period occurred for those on an efavirenz-containing regimen. ART, antiretroviral treatment; EFV, efavirenz.</p