A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection

Abstract

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.

Keywords: CD4 T cell; anti retro viral therapy; coinfection (HIV infection); direct acting antiviral; hepatitis C; human immunodeficiency virus; liver fibrosis.

Figure 1

Mechanisms underlying acceleration of liver disease progression by HIV in HCV/HIV coinfection. (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.