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. 2021 Oct 14;13(10):2074.
doi: 10.3390/v13102074.

CCR5+ T-Cells Homed to the Liver Exhibit Inflammatory and Profibrogenic Signatures in Chronic HIV/HCV-Coinfected Patients

Shikha Shrivastava  1 , Shyam Kottilil  2   3 , Kenneth E Sherman  4 , Henry Masur  5 , Lydia Tang  2   3
Affiliations

CCR5+ T-Cells Homed to the Liver Exhibit Inflammatory and Profibrogenic Signatures in Chronic HIV/HCV-Coinfected Patients

Shikha Shrivastava et al. Viruses. .

Abstract

Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to the inflamed liver and contribute to enhanced fibrogenesis. We compared the peripheral and intrahepatic CCR5 expression on CD4+ and CD8+ T cells in 21 HIV/HCV-coinfected patients with 14 chronic HCV monoinfected patients. Using 12-color flow cytometry, phenotypic and functional characterization of CCR5+ and negative cells pre- and post-stimulation with HCV genotype specific overlapping pooled peptides was conducted. Patients with HIV/HCV coinfection had significantly more CD4+CCR5+ and CD8+CCR5+ T cells in the liver as compared with peripheral blood (p = 0.0001 for both). Compared with patients with HCV monoinfection, patients with HIV/HCV coinfection also had fewer peripheral CD4+CCR5+ and CD8+CCR5+ T cells (p = 0.02, p = 0.001 respectively), but more intrahepatic CD4+CCR5+ and CD8+CCR5+ cells (p = 0.0001 for both). Phenotypic analysis of CCR5+ sorted cells demonstrated an increased expression of markers of exhaustion, senescence, immune activation and liver homing (PD1, CD57, CD38, HLADR, and CXCR3). Post-stimulation with HCV peptides, CCR5+ T cells secreted more proinflammatory and profibrogenic cytokines and chemokines rather than antiviral cytokines. Phenotypic and functional analyses of CCR5+ T cells in HIV/HCV-coinfected patients revealed a pathogenic role for CCR5+ T cells in hepatic fibrogenesis. These cells are functionally proinflammatory, pro-fibrogenic and preferentially accumulate in liver, accelerating fibrosis. These findings suggest that targeting CCR5 may be a therapeutic strategy for be ameliorating liver fibrosis.

Keywords: CCR5; HIV; HIV/HCV coinfection; fibrosis; hepatic fibrogenesis; hepatitis C.

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Conflict of interest statement

L.T. receives grants paid to institution from Gilead Sciences. K.S. receives grants paid to institution from AbbVie, Gilead, and Intercept, and is on the advisory boards and consultant for Gilead Sciences and Theratechnologies, S.K. receives grants paid to institution from Arbutus Pharmaceuticals, Gilead Sciences and Merck, and is on the advisory boards for Merck and Regeneron. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Peripheral blood analysis of CCR5+ and CCR5 negative CD4+ and CD8+ T cells in patients with HIV/HCV coinfection and HCV monoinfection. Flow cytometry plots from a patient and bar graphs with HCV monoinfection, HIV/HCV coinfection, HIV monoinfection and healthy controls demonstrating the differences in the percentages of (A) CCR5 on CD4 and CD8 T cells (B) Percentages of PD1 on CD4+CCR5+ and CD8+CCR5+ T cells (C) Percentages of CD57 on CD4+CCR5+ and CD8+CCR5+ T cells. Data are expressed as (Mean ± SEM) and differences in percentage of T cells expressing different markers between the two groups were analyzed using non-parametric Man-Whitney test in Graph Pad Prism version 6. p value less than 0.05 was considered as significant.
Figure 2
Figure 2
Differences in the frequencies of CD38/HLADR, CXCR3 and PD1+CXCR3+ on CCR5+ and CCR5 negative CD4+ and CD8+ T cells in patients with HIV/HCV coinfection and HCV monoinfection. Flow cytometry plots of a patient and bar graphs with HCV monoinfection, HIV/HCV coinfection, HIV monoinfection and healthy controls demonstrating the differences in the percentages of (A) CD38+HLADR+ on CD4+CCR5+ and CD8+CCR5+ T cells (B) CXCR3 on CD4+CCR5+ and CD8+CCR5+ T cells (C) CXCR3+PD1+ on CD4+CCR5+ and CD8+CCR5+ T cells. Data are expressed as (mean ± SEM) and differences in the percentage of T cells expressing different markers between the two groups were analyzed using a non-parametric Mann–Whitney test in Graph Pad Prism version 6. The Wilcoxon matched-pair signed rank test was used for analyzing the differences between the CCR5+ and CCR5 negative T cells within the same group. p values less than 0.05 were considered significant.
Figure 3
Figure 3
Functional analysis of HCV specific CCR5+ and CCR5 negative CD4+ T cells in HIV/HCV coinfection and HCV monoinfection. (A) Flow cytometry figures of a patient and bar graphs with HCV monoinfection, HIV/HCV coinfection and healthy controls demonstrating the differences in the functional response of CD4+CCR5+ after in-vitro stimulation with HCV peptides and media (served as negative control) in terms of IL-2, IFN-gamma and TGF-β production. (B) Bar graphs demonstrating the differences in the secretion of pro-Inflammatory (IL-1β, TNF-A, IL-8) and pro-fibrotic (IL-4 and IL-13) cytokines and Chemokines (RANTES and IP-10) by CCR5+ T cells in HIV/HCV coinfection, HCV monoinfection and healthy controls. Data are expressed as (mean ± SEM) and the Wilcoxon matched-pair signed rank test was used to evaluate the functional differences between CCR5+ and CCR5 negative T cells within the same group and to analyze the differences between the two different groups non-parametric Mann–Whitney test was used. p values less than 0.05 were considered significant.
Figure 4
Figure 4
Peripheral blood vs. liver analysis in HIV/HCV coinfection and HCV monoinfection. Dot plot graphs showing the differences in the frequencies of CCR5 on CD4+ and CD8+ T cells in the peripheral and intrahepatic compartment and XY scatter plots showing the correlation (Pearson correlation analysis) between CCR5 frequencies in the liver and fibrosis stage in (A) HIV/HCV-coinfected patients (n = 21) and (B) HCV monoinfected (n = 14) patients who underwent paired liver and peripheral blood sampling. (C) The intrahepatic differences in the frequencies of CCR5 on CD4+ and CD8+ T cells in the 14 monoinfected and 21 HIV/HCV-coinfected patients.
Figure 5
Figure 5
Graphical summary of this study. Hepatitis C virus infection in the liver of HIV infected patients stimulates the production of chemokines including CCL5 (RANTES), IP-10 (CXL10), which induces migration of CCR5+CXCR3+ T cells from the peripheral blood to the liver. These CCR5+CXCR3+ T cells infiltrating into the liver are chronically activated, terminally differentiated and have an exhausted phenotype. Upon HCV peptide stimulation, these cells secrete more pro-fibrogenic cytokine (TGF-β) rather than antiviral cytokines (IFN-γ and IL-2), which may favor a profibrogenic intrahepatic microenvironment in HIV/HCV coinfection, causing advanced liver disease.
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