HIV/SARS-CoV-2 co-infection: T cell profile, cytokine dynamics and role of exhausted lymphocytes

Abstract

Objectives: The aim was to investigate if there is synergy in HIV infection and COVID-19 in their influence on human immunity, if there is an exacerbation of HIV patients' immune status caused by SARS-CoV-2; and if HIV infection without antiretroviral therapy (ART) leads to a more serious COVID-19 course than HIV infection with ART.

Design: Anonymised blood samples and clinical data were collected in 47 hospitals, clinics and medical centres in six Russian cities/regions in the period from 20 March to 15 June 2020. Three hundred and seventy-six HIV/COVID-19 patients were studied (171 without ART and 205 with ART). The control group consisted of 382 SARS-CoV-2-positive patients without HIV infection. Lymphocyte and cytokine amounts were measured by flow cytometry and ELISA. This work is a retrospective study.

Results: COVID-19 led to rapid augmentation of the process of T-cell exhaustion initially caused by HIV, and this T cell degradation was most pronounced in patients without ART. A rise in IL-10 and TGFβ serum concentrations was observed. Diminishing CD4⁺/CD8⁺ cell and Th1/Th2 cell ratios characteristic for HIV progression were accompanied by a surge in exhausted T cell count with simultaneous exacerbation of COVID-19-related respiratory distress.

Conclusions: HIV infection without ART may be a very serious comorbidity of COVID-19, whereas immunity of HIV/COVID-19 patients with proper ART is not generally affected by SARS-CoV-2. HIV-1 and SARS-CoV-2 are likely to exhibit a synergic effect, and exhausted T lymphocyte dynamics may be its effective marker.

Keywords: Co-infection; Cytokine; HIV-1; Immune status; SARS-CoV-2; T cell.

Figure 1

T lymphocyte response to HIV/SARS-CoV-2 co-infection. The onset of COVID-19 symptoms is taken as the starting point. The confidence interval is 95%. Whiskers show the standard error of mean. (A) Dynamics of Th1 cell [distinctive membrane phenotype CD3⁺CD4⁺CD94⁺CD183 (CXCR3)⁺CD195 (CCR5)⁺CCR3^–CCR4^–CXCR4^–] count in serum. (B) Dynamics of T killer cells [CD3⁺CD8⁺CD45RA⁺CD27^–CD28^–CCR7^–CD178 (FasL)⁺CD107a (LAMP-1)⁺IFNγ⁺⁺GZMB⁺⁺PRF1⁺⁺] count in serum. (C) Dynamics of CD4⁺/CD8⁺ ratio. (D) Distribution of exhausted T cells (distinctive cytometry markers PD1 and TIM-3) and dynamics of exhausted T cell count in serum (count versus percentage of patients). (E) Relationship between exhausted T cell count in serum and respiratory score (see the “Methods” section for a detailed description). (F) Change of composition of CD4⁺ T cells in serum between the states at the beginning of COVID-19 (1–2 days), during the disease (1 week) and after it (4 weeks): 1, Th1 cells (distinctive membrane phenotype see above); 2, Th2 cells [CD3⁺CD4⁺CD193 (CCR3)⁺CD194 (CCR4)⁺CD184 (CXCR4)⁺]; 3, Th17 cells [CD3⁺CD4⁺CD161⁺CD194 (CCR4)⁺CD196 (CCR6)⁺]; 4, CD4⁺ naive lymphocytes [CD3⁺CD4⁺CD27⁺CD28⁺ CD45RA⁺ CD45RO^–CD127⁺ CD197 (CCR7)⁺]; 5, CD4⁺ regulatory T cells [CD3⁺CD4⁺CD27⁺CD25⁺CD152 (CTLA-4)⁺CD127^lowFOXP3⁺]; 6, CD4⁺ memory T cells [CD3⁺CD4⁺CD95⁺ T cells, detected as central memory CD27⁺CD28⁺CD57^–CD62L⁺CD127⁺CD197 (CCR7)⁺ T cells, effector memory CD28–CD57⁺CD62L^–CD197 (CCR7)^– T cells and effector memory CD27^–CD28^–CD57⁺CD62L^–CD127^–CD197 (CCR7)^–CD45RO^–CD45RA⁺ lymphocytes]. The Th1/Th2 cell ratio is provided in the centres of the corresponding doughnuts.

Figure 2

Dynamics of serum concentrations and induced lymphocytic production of certain cytokines. COVID-19 symptom onset is taken as the starting point. The confidence interval is 95%. Whiskers show the standard error of mean. (A) IL-2 serum amounts. (B) IL-2 production by lymphocytes. Mitogen: phytohaemagglutinin (10 μg/ml); 2.5 × 10⁶ cells/ml; 24 h of exposure. (C) Percentage of T lymphocytes capable of producing IL-2. (D) Production ability of T cells with regard to IL-2, TNFα and IFNγ. (E) IL-10 serum amounts. (F) TGFβ1 serum amounts.