HIV Infection of Hepatocytes Results in a Modest Increase in Hepatitis C Virus Expression In Vitro

Abstract

Previous studies demonstrate that soluble HIV proteins impact both hepatocyte function and HCV replication in vitro. It has also been reported that HIV can productively infect hepatocytes. We therefore investigated the impact of HIV infection of hepatocytes on HCV expression. The Huh7.5JFH1 cell line that constitutively expresses infectious HCV was infected with the lab-adapted strains HIVNL4-3 or HIVYK-JRCSF. HCV expression was quantified via HCV core antigen ELISA, Western blot, and strand-specific real-time PCR for positive-sense and negative-sense HCV RNA. After HIVNL4-3 infection of Huh7.5JFH1 cells, positive-sense and negative-sense HCV RNA levels were elevated compared to HIV uninfected cells. Increased HCV RNA synthesis was also observed after infection of Huh7.5JFH1 cells with HIVYK-JRCSF. HIV-induced HCV core production was decreased in the presence of the anti-HIV drugs AZT, T20, and raltegravir, although these medications had a minimal effect on HCV expression in the absence of HIV. HCV core, NS3, and NS5A protein expression were increased after HIV infection of Huh7.5JFH1 cells. Chemically inactivated HIV had a minimal effect on HCV expression in Huh7.5JFH1 cells suggesting that ongoing viral replication was critical. These data demonstrate that HIV induces HCV RNA synthesis and protein production in vitro and complement previous in vivo reports that HCV RNA levels are elevated in individuals with HIV/HCV co-infection compared to those with HCV mono-infection. These findings suggest that HIV suppression may be a critical factor in controlling liver disease, particularly if the underlying liver disease is not treated.

Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol‐Induced Liver Damage, Steatosis, and Inflammation in Mice

“…(33,34) Multiple mechanisms have been identified that lead to steatosis in ALD, of which CCL2 is one of the mediators identified. (11) Consistent with previous reports that showed CCR2/5 expression on hepatocytes in HCV-infected patients, (35,36) we confirmed by flow cytometry that primary hepatocytes in mice express CCR2 and CCR5, and their surface expression was up-regulated after chronic alcohol exposure (Fig. 6A).…”

“…Cenicriviroc (CVC) is a new, oral, dual CCR2/ CCR5 antagonist with nanomolar potency against both receptors, and a long plasma half-life (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) hours in humans) (14) with bioavailability and bioactivity in both oral and injectable administration, as demonstrated in preclinical rodent studies. (15)(16)(17) Phase II studies 652-2-201 (NCT01092104) and 652-2-202 (NCT01338883), conducted in human immunodeficiency virus (HIV)-infected participants, have shown CCR2 blockade, associated with a reciprocal increase in CCL2 levels, and CCR5 blockade, demonstrated by reduction in HIV-1 RNA levels.…”

HIV influences clustering and intracellular replication of hepatitis C virus

“…In contrast with previous studies, here we could also analyse the HCV RNA content per infected hepatocyte and found the median to be 2.8 IU and 8.2 IU, in monoinfected and coinfected participants, respectively. This may indicate that HIV enhances (directly or indirectly) intracellular HCV RNA accumulation, consistent with previous results 5,6,36 . Our modelling results also support the idea that HIV inhibits export of HCV leading to a higher accumulation of HCV (+)‐RNA in infected cells.…”

“…This may indicate that HIV enhances (directly or indirectly) intracellular HCV RNA accumulation, consistent with previous results. 5,6,36 Our modelling results also support the idea that HIV inhibits export of HCV lead- participants compared to coinfected participants. 33 However, it still needs to be investigated if this is enough to explain the lower clustering tendency in coinfected participants, or whether other host and/or viral processes are also crucial for the way HCV infection spreads in coinfected participants.…”

Consequence of HIV and HCV co-infection on host immune response, persistence and current treatment options

“…Recently, in vivo study results revealed that the level of HCV RNA was elevated in HIV/HCV infected individuals as compared to those with HCV mono-infection. Based on the findings, the suppression of HIV could be a novel strategy in liver disease control [22].Very little information is available about the genomic basis of HIV/HCV co-infection and its regulation by microRNA (miRNA). Recently, the role of specific miRNAs in co-infection has been demonstrated which were correlated with important gene targets particularly playing a crucial role and functional relationships to many pathways in cancer, immunefunction, and metabolism.…”