Standard vaccines increase HIV-1 transcription during antiretroviral therapy

Abstract

Objectives: Curative strategies using agents to perturb the HIV reservoir have demonstrated only modest activity, whereas increases in viremia after standard vaccination have been described. We investigated whether vaccination against non-HIV pathogens can induce HIV transcription and thereby play a role in future eradication strategies.

Design: A randomized controlled trial (NCT00329251) was performed to compare the effects of clinical vaccines with placebo on HIV transcription and immune activation.

Methods: Twenty-six HIV-infected individuals on suppressive antiretroviral therapy were randomized to receive a vaccination schedule (n = 13) or placebo (n = 13). Cell-associated RNA and DNA were extracted from peripheral blood mononuclear cells, and HIV was quantified by droplet digital PCR using primers for gag and 2-LTR (for HIV DNA), unspliced gag RNA (gag usRNA), multispliced tat-rev RNA (tat-rev msRNA) and polyA mRNA.

Results: Significant increases in gag usRNA after influenza/hepatitis B vaccination (P = 0.02) and in gag usRNA (P = 0.04) and polyA mRNA (P = 0.04) after pneumococcus/hepatitis B vaccination were seen in vaccinees but not controls. HIV DNA and plasma HIV RNA did not change in either group. Increases in CD4 and CD8 T-cell activation markers (P = 0.08 and P < 0.001, respectively) and HIV-specific CD8 responses (P = 0.04 for p24 gag, P = 0.01 for p17 gag and P = 0.04 for total gag) were seen in vaccinees but not controls.

Conclusion: In this study, vaccination was associated with increases in HIV cell-associated RNA and HIV-specific responses during antiretroviral therapy. Using standard vaccines to stimulate HIV transcription may therefore be a useful component of future eradication strategies.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

Fig. 1. Diagrammatic representation of vaccination schedule

Red bar indicates study duration with study visits labeled (months 0–12). Syringes denote vaccination time points; text below describes vaccines delivered at each time point. Hep B, hepatitis B; MMR, measles–mumps–rubella; TD, tetanus–diphtheria; VZV, Varicella zoster virus.

Fig. 2. Changes in HIV cell-associated RNA with vaccination

(a–c) Changes in gag usRNA at time points corresponding to vaccine or placebo administration: vaccinees after influenza/hepatitis B vaccination (a), controls at matched time points to influenza/hepatitis B vaccination (b) and vaccinees after pneumococcus/hepatitis B vaccination (c). Filled circles represent individual participants. Different colors are assigned to each vaccinee, with color-coding preserved throughout. Controls are denoted by blue filled circles. P values by Wilcoxon test. (d) Median gag usRNA levels with interquartile ranges of vaccinees (red line and bars) and controls (blue line and bars) throughout study period. Vaccinee and control data for each month coincides chronologically but are layered so as to display medians and ranges without overlap. Black arrows denote vaccination time points. (e) Average effect (on HIV transcription) per vaccine (or placebo). Regression coefficient with interquartile range represented by box plots, P value by Mann–Whitney test.

Fig. 3. T-cell responses with vaccination

(a and b) Percentage of CD4+CD38+HLA-DR+ T cells (a) and CD8+CD38+HLA-DR+ T cells (b) in vaccinees (red filled circles) and controls (blue filled circles). P values by Wilcoxon test for within-group comparisons (vaccinees only and controls only) and Mann–Whitney test for intergroup comparisons (vaccinees versus controls); only P values less than 0.1 are shown. (c–e) Changes in CD8+ T-cell IFN-γ production in vaccinees as measured by enzyme-linked immunospot (spot-forming units) in response to stimulation with p24 gag (c), p17 gag (d) and total gag (e) between study months 0 and 3. P values by Wilcoxon test. Color-coding is preserved throughout and with respect to Fig. 2. (f–h) Changes in CD8+ T-cell IFN-γ production in response to p24 gag (f), p17 gag (g) and total gag (h) between study months 0 and 3 in controls.