Microbiology and Infectious Disease

HIV-specific CD8+ T-cell responses soon after treatment initiation during acute HIV infection are associated with viral reservoir decline

Department of Experimental Immunology, Amsterdam UMC, Amsterdam, Netherlands
Amsterdam Institute for Infection and Immunity, Amsterdam UMC, Amsterdam, Netherlands
Department of Medical Microbiology and Infection Prevention, Laboratory of Experimental Virology, Amsterdam UMC, Amsterdam, Netherlands
Department of Medical Microbiology, Translational Virology, University Medical Center Utrecht, Utrecht Netherlands
Department of Biochemistry and Department of Pathology, Erasmus Medical Center, Rotterdam, Netherlands
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
Department of Internal Medicine and Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, Netherlands
Department of Internal Medicine, Section Infectious Diseases, Amsterdam UMC, Location AMC, Amsterdam, Netherlands
Apheresis Unit, Dianet, Location Amsterdam UMC, Amsterdam, Netherlands
Department of Internal Medicine, section Nephrology, Amsterdam UMC, Location AMC, Amsterdam, Netherlands

https://doi.org/10.7554/eLife.106402.1

Open access
Copyright information

Figures and data

Baseline characteristics of NOVA participants included in this study.
*) participants of whom both a 24 and 156 week time point was available; **) Fiebig, E. W. et al. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS 17, 1871–1879 (2003).

Paired viral reservoir assessments at 24 and 156 weeks (x-axis): Total HIV DNA (copies/million PBMC); Intact and defect provirus (copies/million PBMC); US RNA (cell-associated unspliced RNA copies/µg total RNA); US/TD (unspliced RNA/total DNA ratio).
Open symbols represent values below the detection limit of the assay. The four participants with a positive qVOA at 24 weeks are marked with a color (purple, blue, green, red). Wilcoxon rank test (paired analysis) was performed to determine significant differences between the time points (* if p<0.05 or ** if p<0.01).

Correlation matrix of all viral reservoir assessments performed in the participants at 24 weeks (A) and 156 weeks (B) after start ART: Total HIV DNA (copies/million PBMC); Intact and defect provirus (copies/million PBMC); US RNA (unspliced RNA copies/µg total RNA; US/TD (unspliced RNA/total DNA ratio).
The correlation coefficient (R²) determined by Pearson correlation is shown. Positive and negative correlations (R²) are indicated by the color shade displayed in the legend. Significant correlations are indicated by * if p<0.05 or ** if p<0.01.

Correlation matrix of reservoir measurements and HIV-specific CD8+ T-cell responses as determined by IFN-Υ release assay, AIM and proliferation assay (proliferating cells and precursor cells).
The immune responses are defined as the sum of the responses to Env, Gag, Nef and Pol combined at 24 weeks (A) and 156 weeks (B). The correlation coefficient (R²) determined by Pearson correlation is shown. Positive and negative correlations (R²) are indicated by the color shade displayed in the legend. Significant correlations are indicated by * if p<0.05 or ** if p<0.01.

Correlation matrix of changes in reservoir size between 24 and 156 weeks (delta Δ) and HIV-specific CD8+ T-cell responses as determined by IFN-Υ release assay, AIM and proliferation assay (proliferating cells and precursor cells) at 24 weeks (A) and 156 weeks (B).
The immune responses are defined as the sum of the immune responses to Env, Gag, Nef and Pol combined. The correlation coefficient (R²) determined by Pearson correlation is shown. Positive and negative correlations (R²) are indicated by the color shade displayed in the legend. Significant correlations are indicated by * if p<0.05 or ** if p<0.01.

Overview of NOVA cohort study procedures for study groups 2 and 3.
ART, combination antiretroviral therapy; GALT, gut-associated lymphoid tissue; PBMC, peripheral blood mononuclear cells. Retrieved from: Dijkstra M. et al. Cohort profile: the Netherlands Cohort Study on Acute HIV infection (NOVA), a prospective cohort study of people with acute or early HIV infection who immediately initiate HIV treatment. BMJ Open. 2021;11(11):e048582.

A. Plasma viral load (pVL) B. CD4 T-cell count (x10^6/mL) and C. CD4/CD8 ratio at baseline, 24 weeks and 156 weeks post ART initiation. Participant X (green dot) had detectable loads of 200 and 100 cp/mL at 24 and 156 weeks. Participant Y (pink dot) had detectable loads of 74 and 98 cp/mL at 24 and 156 weeks. Lower limit of quantification of the assays used ranged between 40 copies (earlier) and 20 copies (later time points) (see Methods).

Longitudinal analysis of frequencies of activated and naive, memory and effector subsets within the CD4+ (A) and CD8+ T-cell (B) populations.
Wilcoxon signed rank test (p<0.05) was used to determine significant differences between the timepoints.

A. The frequency of dextramer+ CD8+ T-cells at 24 and 156 weeks after ART. B. The expression of exhaustion markers (upregulation of PD-1, CTLA-4, and CD160 expression; loss of CD28 expression) on HIV-dextramer specific CD8+ T-cells at 24 and 156 weeks after ART. For participants that were HLA-A*2 and HLA-B*7 positive, HLA-A*2 and HLA-B*7 dextramer staining was included separately. HLA-A*2 dextramer is marked as a triangle and HLA-B*7 dextramer as a square in both figures.

HIV-specific T-cell responses upon HIV-peptide stimulation (Env, Gag, Nef, Pol) at 24 and 156 weeks after ART: IGRA/IFN-γ release (A), AIM reactive CD8+ T-cells (B), precursor frequency (C) and the proportion of proliferating CD8+ T-cells (D).
Frequencies of proliferating cells in response to Env, Gag, Nef and Pol peptides were combined. Overall, no significant difference in IGRA over time was observed.

Correlation matrix of reservoir measurements and the frequency of dextramer+ CD8+ T-cell responses at 24 and 156 weeks after ART initiation.
The correlation coefficient (R²) determined by Pearson correlation is shown. Positive and negative correlations (R²) are indicated by the color shade displayed in the legend. Significant correlations are indicated by * if p<0.05 or ** if p<0.01.

Sign up for email alerts