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Review
12 August 2021
A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection
Samaa T. Gobran
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Naglaa H. Shoukry
(A) Direct Mechanisms: gp120 binds to HIV coreceptors (CXCR4 and CCR5) on hepatocytes surface (157) leading to accumulation of ROS which triggers an NF-κβ mediated oxidative stress (158, 159). HIV also activates TNF–related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via upregulation of TRAIL receptor 1 (DR4), and 2 (DR5) (160), aggravating HCV fibrotic complications (161). HIV promotes hepatic stellate cells (HSC) collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein-1 (MCP-1) inducing inflammation and fibrogenesis (162). HIV sensitizes Kupffer cells to lipopolysaccharide (LPS) via gp120 binding to CXCR4 and CCR5 (163) increasing cell surface expression of CD14 and TLR4, resulting in increased secretion of TNF-α and IL-6 (164). This is accompanied by shedding of CD163 in serum (165). (B) Indirect Mechanisms: HIV indirectly augments fibrosis mainly by microbial translocation: LPS translocate through impaired gut epithelium (105) and binds to Toll-like receptor 4 TLR4 on HSCs, leading to upregulated chemokine secretion and Kupffer cells chemotaxis (166). HIV accessory proteins Vpr (167) and Nef (168) enhance HCV RNA replication creating a state of inflammation and tissue damage. HIV causes functional alterations of HCV-specific immune responses with more HCV replication and hepatic inflammation (150, 169). ART elicits insulin resistance by altering mitochondrial function (170, 171) and increased intracellular lipid accumulation (172, 173) leading to enhanced development of liver fibrosis (174). Created with Biorender.com.

Nearly 2.3 million individuals worldwide are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Odds of HCV infection are six times higher in people living with HIV (PLWH) compared to their HIV-negative counterparts, with the highest prevalence among people who inject drugs (PWID) and men who have sex with men (MSM). HIV coinfection has a detrimental impact on the natural history of HCV, including higher rates of HCV persistence following acute infection, higher viral loads, and accelerated progression of liver fibrosis and development of end-stage liver disease compared to HCV monoinfection. Similarly, it has been reported that HCV coinfection impacts HIV disease progression in PLWH receiving anti-retroviral therapies (ART) where HCV coinfection negatively affects the homeostasis of CD4+ T cell counts and facilitates HIV replication and viral reservoir persistence. While ART does not cure HIV, direct acting antivirals (DAA) can now achieve HCV cure in nearly 95% of coinfected individuals. However, little is known about how HCV cure and the subsequent resolution of liver inflammation influence systemic immune activation, immune reconstitution and the latent HIV reservoir. In this review, we will summarize the current knowledge regarding the pathogenesis of HIV/HCV coinfection, the effects of HCV coinfection on HIV disease progression in the context of ART, the impact of HIV on HCV-associated liver morbidity, and the consequences of DAA-mediated HCV cure on immune reconstitution and HIV reservoir persistence in coinfected patients.

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In COVID-19 and HIV infection, total count of natural killer cells, B cells, CD4+ T cells, regulatory T cells, memory T and B cells decrease, whereas the count of follicular helper cells increase. These common changes between HIV and COVID-19 were shown in the central circle. However, distinct changes were shown in total count of macrophage, CD8+ T cells, Th17 cells and naive T cells between people living with HIV (PLWH) and severe COVID-19. (The red arrow indicates a decrease in the number of cells; the blue arrow indicates an increase in the number of cells).
Review
15 December 2020

COVID-19 is a distinctive infection characterized by elevated inter-human transmission and presenting from absence of symptoms to severe cytokine storm that can lead to dismal prognosis. Like for HIV, lymphopenia and drastic reduction of CD4+ T cell counts in COVID-19 patients have been linked with poor clinical outcome. As CD4+ T cells play a critical role in orchestrating responses against viral infections, important lessons can be drawn by comparing T cell response in COVID-19 and in HIV infection and by studying HIV-infected patients who became infected by SARS-CoV-2. We critically reviewed host characteristics and hyper-inflammatory response in these two viral infections to have a better insight on the large difference in clinical outcome in persons being infected by SARS-CoV-2. The better understanding of mechanism of T cell dysfunction will contribute to the development of targeted therapy against severe COVID-19 and will help to rationally design vaccine involving T cell response for the long-term control of viral infection.

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Frontiers in Immunology

HIV and the Gut: Novel Insights into HIV Pathogenesis, Clinical Implications and Therapeutic Approaches
Edited by Sonia Moretti, Gabriella d'Ettorre, Ivan Schietroma, Claudia Matteucci, Wondwossen Amogne Degu
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05 April 2025
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