HIV increases HCV replication in a TGF-beta1-dependent manner.
OBJECTIVE
Human immunodeficiency virus (HIV) coinfection increases hepatitis C virus (HCV)-related progression of hepatic fibrosis, increases HCV persistence, and decreases response rates to interferon-based anti-HCV therapy. It has remained unclear how HIV, a nonhepatotropic virus, accelerates the progression of liver disease by HCV.


METHODS
We explored the possibility that circulating HIV and/or its proteins contribute to the pathogenesis of HCV through engagement of extracellular coreceptors on hepatocytes.


RESULTS
In this study, we found that inactivated HIV or gp120 increases HCV replication and enhances HCV-regulated transforming growth factor (TGF)-beta1 expression in both a replicon and an infectious model of HCV. This proviral effect of HIV and gp120 on HCV replication is neutralized by antibodies to 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. Interestingly, we found that human TGF-beta1 also enhanced HCV replication. The effect of HIV on HCV replication was blocked by a neutralizing antibody to TGF-beta1, indicating that its effects on HCV replication are TGF-beta1 dependent.


CONCLUSIONS
These results suggest a novel mechanism by which HIV not only enhances HCV replication but also contributes to progression of hepatic fibrosis.
Lin
Wenyu
W
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Weinberg
Ethan M
EM
Tai
Andrew W
AW
Peng
Lee F
LF
Brockman
Mark A
MA
Kim
Kyung-Ah
KA
Kim
Sun Suk
SS
Borges
Carolina B
CB
Shao
Run-Xuan
RX
Chung
Raymond T
RT
D000906:Antibodies; D045744:Cell Line, Tumor; D005355:Fibrosis; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication
D000906:Antibodies; D015699:HIV Envelope Protein gp120; D016898:Interferon-alpha; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C514793:gp120 protein, Human immunodeficiency virus 1