Although HIV does not directly infect the liver, HIV and hepatitis C virus (HCV) co-infection is associated with more severe HCV-induced liver fibrosis than is HCV infection alone.
This may occur through transforming growth factor-beta-1 (TGF-beta-1) receptors on hepatocytes, on which HIV acts and which trigger HCV replication. HCV replication, in turn, leads to hepatic fibrosis.
The findings of a team at Harvard Medical School and Massachusetts General Hospital in Boston, describing the pathway through which HIV co-infection leads to HCV-related liver fibrosis, are reported in the March issue of Gastroenterology.
Principal investigator Dr. Raymond T. Chung and colleagues used both HIV- and HCV-infected cell cultures and HCV replicons to examine the effects of HIV and gp120 – an HIV envelop protein — on HCV replication and TGF-beta-1 expression.
“We show that HIV increases HCV replication through TGF-beta-1 independently of its effects on cellular immunity,” Dr. Chung’s team reports.
“This proviral effect of HIV and gp120 on HCV replication is neutralized by antibodies to (the chemokines) CCR5 or CXCR4. However, HIV and gp120 did not alter type I interferon-mediated signaling in these HCV models, indicating that HIV regulates HCV replication through an alternative mechanism,” they say.
“Interestingly, we found that human TGF-beta-1 also enhanced HCV replication,” Dr. Chung added in an interview with Reuters Health. “The effect of HIV on HCV replication was blocked by a neutralizing antibody to TGF-beta-1, indicating that its effects on HCV replication are TGF-beta-1-dependent.”
“The observation has long been made that HCV viral loads are higher, up to 10-fold on average, in persons co-infected with HIV compared to those without HIV. It had been previously assumed that this happens because of the impaired T-cell immunity associated with HIV infection,” Dr. Chung explained.
“These findings suggest that HIV, which does not infect liver cells, can still signal through cell surface receptors on hepatocytes to moderately drive up levels of HCV replication, and that this occurs through the production of TGF-beta-1, a molecule known to have a critical role in driving the production of hepatic fibrosis.”
“Thus, these findings offer a potential means by which HIV itself could influence both HCV levels and drive fibrosis progression in persons with HCV infection,” Dr. Chung continued.
“They may offer some rationale for strategies to suppress HIV effectively to slow liver disease progression — this of course needs confirmation in clinical studies.”
Gastroenterology 2008;134:803-811.
Reviewed by Dr. Ramaz Mitaishvili
http://www.rmgh.net
