Oxidized low-density lipoprotein prevented hepatitis C virus from entering liver cells and predicted interferon response among patients with chronic HCV infection, researchers reported online in the May issue of Cellular and Molecular Gastroenterology and Hepatology (2015 March 14 [doi:10.1016/j.jcmgh.2015.03.002]).
“Even as all-oral regimens begin to reach the market, interferon-based treatment will continue to be used in cost-restrained settings. Thus, there is a need for predictors of who is likely to respond to interferon and who will require a more expensive direct-acting antiviral combination regimen,” said Dr. Philipp Solbach of Medizinische Hochschule Hannover and the German Center for Infection Research and his associates. Combinations of interferon and viral entry inhibitors might benefit patients with chronic HCV infection (CHC), the investigators added.
Hepatitis C virus spreads between hepatocytes with the help of several cell surface receptors, including scavenger receptor class B type 1 (SR-BI). Research has shown that oxidized low-density lipoprotein (oxLDL) noncompetitively inhibits the interaction between SR-B1 and HCV. To further study the role of oxLDL in CHC pathology, the investigators used a commercial enzyme-linked immunosorbent assay test to measure serum levels in 379 patients with genotype 1 CHC from the INDIV-2 study. Patients in that study received a pegylated interferon-ribavirin combination for 24-72 weeks, depending on baseline viral load. Dr. Solbach and his associates also studied the effects of oxLDL on HCV replication in hepatoma cells.
Average serum oxLDL levels were significantly higher among patients who achieved SVR on peg-IFN/RBV than in those who did not (7.1 mU/L [standard deviation, 3.2] vs. 5.9 mU/L [SD, 2.6]; P < .001), the researchers reported. In the multivariate analysis, oxLDL levels independently predicted SVR, but were not associated with increased ALT or ferritin levels, both of which point to liver inflammation. Increased serum oxLDL also was linked to decreased infected cell loss rate, further supporting the idea that oxLDL helps inhibit cell-to-cell spread of HCV in chronically infected patients, they said.
Area under the receiver operative curve (AUROC) values were similar for LDL and oxLDL, indicating that one value was a good clinical indicator of the other, the investigators said. The optimal cutoff points to predict SVR in their model were 8.85 mU/L for oxLDL and 3.6 mmol/L for LDL.
In the in vitro study, oxLDL did not affect the sensitivity of HCV replication to interferon, but strongly inhibited the spread of HCV between adjacent hepatocytes, the investigators reported. “We found that oxLDL but not LDL potently inhibits cell-to-cell spread between neighboring cells,” they noted. “Cell-to-cell spread is thought to be the dominant route of new cell infection within the chronically infected liver.”
Taken together, the findings suggest that HCV needs to interact with SR-BI in order to spread between hepatocytes, that oxLDL can impede that interaction and thereby limit infection of naive cells, and that oxLDL is neither an inflammatory marker nor a modulator of interferon response, Dr. Solback and his associates said. “The slower second-phase decline of viral load during interferon-based therapy is thought to reflect a declining pool of infected hepatocytes, and the slope of second-phase decline and even more the estimated viral kinetic parameter describing the infected cell loss rate is predictive of eventual SVR,” they added. “The presence of an agent reducing the rate at which naive cells get infected might thus be beneficial.”
The Germany Center for Infection Research partially funded the study. Five coauthors reported having served as clinical researchers, consultants, or speakers for MSD/Merck and Roche. The other authors declared no conflicts of interest.