Unsuppressed HIV infection impairs T cell responses to SARS-CoV-2 infection and abrogates T cell cross-recognition
- Africa Health Research Institute, Nelson R. Mandela School of Medicine, University of Kwa-Zulu Natal, South Africa
- HIV Pathogenesis Program, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, South Africa
- KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Malawi
- Liverpool School of Tropical Medicine, United Kingdom
- Division of Infection and Immunity, University College London, United Kingdom
- Ragon Institute of MGH, MIT and Harvard, United States
Figures
Figure 1
The impact of unsuppressed HIV infection on SARS-CoV-2-specific CD4+ and CD8+ T cell responses.
(A) Representative flowplots gated on IFN-γ/TNF-α dual positive CD4+ and CD8+ T cells. (B) Aggregate data for IFN-γ/TNF-α dual positive CD4+ and CD8+ T cells are shown (HIV-neg, n=14; suppressed, n=16: viremic, n=13). SARS-CoV-2-specific CD4+ and CD8+ T cells producing IFN-γ, TNF-α, and IL-2 cells in various combinations are shown. Pie chart and dot plots for (C) SARS-CoV-2-specific CD4+ and (D) CD8+ T cells. Pie chart represents the mean distribution across subjects of mono-functional, bi-functional, and poly-functional cytokine producing SARS-CoV-2-specific T cells. Size of each pie segment relates to the frequency of a mono-functional, bi-functional, and triple-functional response. Dot plot represents the frequency of combinations of cytokines produced. Wilcoxon test was done among the dot plots using SPICE software (significant p values are highlighted).
Figure 2
Comparison of SARS-CoV-2 protein targeting by T cell responses among HIV-negatives, suppressed and viremic donors.
Magnitude of (A) CD4+ T and (B) CD8+ T cell responses targeting the Membrane (M), Nucleocapsid (N), and Spike (S) SARS-CoV-2 proteins among study groups. P values for differences among the groups are *<0.05; as determined by the Wilcoxon matched-pairs signed rank test (GraphPad Prism version 9.3.0).
Figure 3 with 1 supplement
Poor cross-recognition of SARS-CoV-2-specific CD4+ and CD8+ T cell responses between wt and beta variants in wave 1 and wave 2 COVID-19 participants.
Ex vivo assessment of T cell cross-recognition between the two waves. (A) Intra-donor SARS-CoV-2-specific T cell responses to wt and corresponding Beta variant peptides by wave 1 participants. (B) Intra-donor SARS-CoV-2-specific T cell responses to wt and corresponding Beta variant peptides in wave 2 participants. Next, PBMCs were expanded for 12 days in the presence of S1S2 SARS-CoV-2 peptide pools and tested against wt and corresponding Beta variants at single peptide level. (C) Representative flow plots showing the frequency of SARS-CoV-2-specific CD4+ and CD8+ T cells before and after cultured expansion. (D) T cell responses to single wt (red bars) and corresponding Beta (blue bars) peptide stimulation for a representative donor from wave 1. (E) T cell responses to single wt and corresponding Beta peptide stimulation for a representative donor from wave 2 (positive responses are circled). A response was deemed positive if ≥1% or higher. (F) Number of expanded wt and corresponding Beta responses for each wave 1 donor. (G) Number of expanded wt and corresponding Beta responses for each wave 2 donor. P values calculated using Wilcoxin matched-pairs signed rank T test. PBMC, peripheral blood mononuclear cell; wt, wild-type.
Figure 3—figure supplement 1
Cross-recognition of SARS-CoV-2 CD4+ T cell responses between wt and Beta variants in wave 1 and wave 2 COVID-19 donors: PBMCs were expanded for 12 days in the presence of S1S2 SARS-CoV-2 peptide pools.
Expanded cells were tested against wt and corresponding Beta variants at single peptide level. (A) Intra-donor SARS-CoV-2-specific T cell responses to wt and corresponding Beta variant peptides by wave 1 participants. (B) Intra-donor SARS-CoV-2-specific T cell responses to wt and corresponding Beta variant peptides in wave 2 participants. PBMC, peripheral blood mononuclear cell; wt, wild-type.
Figure 4
The effects of unsuppressed HIV infection on T cell breadth and ability to cross-recognize the Beta variant.
Representative data for a negative donor showing greater, (A) CD8+ and (B) CD4+ T cell breadth. A cross-recognized responses between wt and Beta is circled. Representative data for a suppressed donor showing greater, (C) CD8+ and (D) CD4+ T cell breadth. A cross-recognized response is circled. Representative data for a viremic donor showing greater, (E) CD8+ and (F) CD4+ T cell breadth. (G) Aggregate data comparing breath of SARS-CoV-2-specific CD8+, and (H) CD4+ T cell response between HIV-negative and suppressed versus viremics. Breadth here is simply the number of positive responses among the individual peptides tested.
Figure 5
Identification of Beta mutations associated with reduced cross-recognition between wt and Beta variant.
(A) Side-by-side comparison of SARS-CoV-2-specific CD8+ T cell response between wt and Beta. (B) Side-by-side comparison of SARS-CoV-2-specific CD4+ T cell response between wt. The analysis combined all the 12 participants. P values calculated by Mann-Whitney U-test. wt, wild-type.
Figure 6
Immunodominance hierarchy of SARS-CoV-2 CD8+ and CD4+ T cell responses targeting wt and Beta.
Immunodominance hierarchy of CD8+ T cell responses to, (A) wt and (B) the corresponding Beta variant peptides. Similarly, Immunodominance hierarchy of CD4+ T cell responses to, (C) wt and (D) the corresponding Beta variant. Arrows indicate responses that changed hierarchical position (among the six most dominant responses) between the two waves. Data arranged in descending order of magnitude of responses to wt peptide stimulation. wt, wild-type.
Figure 7 with 1 supplement
The impact of HIV markers of diseases progression on SARS-CoV-2 T cell immunity.
(A) CD4+ T cell activation graphed based on the frequency of CD38/HLA-DR co-expressing cells. (B) Correlation between CD4+ T cell activation and absolute CD4 counts of viremic PLWH. (C) Correlation between CD4+ T cell activation and HIV plasma viral load of viremic PLWH. (D) CD8+ T cell activation measured by CD38/HLA-DR. (E) Correlation between CD8+ T cell activation and absolute CD4 counts of viremic PLWH. (F) Correlation between CD8+ T cell activation and HIV plasma viral load of viremic PLWH. P values calculated by Mann-Whitney U-test and Pearson correlation test. PLWH, people living with HIV.
Figure 7—figure supplement 1
Assessment of the effect of COVID-19 disease severity on, (A) SARS-CoV-2-specific CD4+, and (B) CD8+ T cell responses.
Disease severity categorised as asymptomatic, mild, and on supplemental oxygen or death. (C, D) Analysis of SARS-CoV-2 responses based on gender. Correlation between age and SARS-CoV-2-specific, (E) CD8+T and (F) CD4+ T cell responses. P values calculated by Mann-Whitney U-test and Pearson correlation test.
Tables
Table 1
Donor characteristics stratified by HIV status.
| All (n=48) | HIV-neg (N=17) | HIV+suppressed (n=17) | HIV+viremics (N=14) | Statistics | |
|---|---|---|---|---|---|
| Demographics | |||||
| Age years, median (IQR) | 40.5 (30–51.75) | 45 (27–53.5) | 45 (39.5–54) | 31.5 (26.5–42) | 0.036* (KW) |
| Male sex, n (%) | 14 (29.16) | 8 (47.05) | 3 (17.64) | 3 (21.42) | 0.2 (0.82–10) (F) |
| HIV-associated parameters | |||||
| HIV viral load copies/ml | 19,969 (2335–43,568) | ||||
| CD4 cells/µl median (IQR) | 661 (398.5–836.5) | 834.5 (739.3–1029) | 661 (494–789.5) | 301 (113.8–568) | 0.0002** (KW) |
| Disease severity | |||||
| Asymptomatic, n (%) | 9 (18.75) | 4 (23.52) | 3 (17.64) | 2 (14.28) | 0.6 (0.32–9.53) (F) |
| Mild | 29 (60.42) | 12 (70.59) | 10 (58.82) | 7 (50) | 0.01* (0.13–0.84) (F) |
| Severe/oxygen supplementation | 8 (16.67) | 1 (5.88) | 4 (23.52) | 3 (21–42) | 0.33 (0.48–49.67) (F) |
| Death, n (%) | 1 (2.1) | 0 | 0 | 1 (7.1) | 0.46 (F) |
-
P values calculated by Kruskal-Wallis test for unpaired three groups (KW) or Fischer’s exact test (F).
Additional files
-
Supplementary file 1
Wild-type (wt) Spike overlapping peptides and corresponding Beta variant peptides.
The table contains a list of peptides spanning the receptor-binding domain (RBD) and non-RBD regions of spike with known hotspots for mutations, and a corresponding list of peptides with Beta variant lineage defining mutations. The Beta variants mutations are highlighted in red. The two sets of peptides were used for cultured expansion studies.
- https://cdn.elifesciences.org/articles/78374/elife-78374-supp1-v2.docx
-
MDAR checklist
- https://cdn.elifesciences.org/articles/78374/elife-78374-mdarchecklist1-v2.docx
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Unsuppressed HIV infection impairs T cell responses to SARS-CoV-2 infection and abrogates T cell cross-recognition
eLife 11:e78374.
https://doi.org/10.7554/eLife.78374
