Characterizing B Cell Phenotype During Chronic HCV Infection

Chronic hepatitis C virus (HCV) infection is characterized by an attenuation of virus-specific T cell responses. The mechanisms leading to T cell attenuation are still not well understood, and likely involve several integrating correlates. We hypothesized that dysfunctions of antigen presenting cells (APC) may contribute to the immunosuppresed phenotype. We also reasoned that direct viral interactions of HCV with immune cells may be responsible for such dysfunction. We employed a strand-specific real time RT-PCR assay and found that virus is frequently associated with B cells (predominantly positive strand was detected). Interestingly, we also found that ex-vivo derived B cells from chronic HCV individuals were better inducers of allogeneic T cell proliferation and this ability correlated with the presence of HCV RNA in those B cells. During such enhanced allostimulation, we also found an increase in the proportion of CD4+CD25+FoxP3+ T cells, which correlated with an increased suppressive capacity thereby demonstrating a paradoxical link between hyperactive B cells and the generation of suppressive T cells. Furthermore, ex-vivo derived chronic HCV B cells had an attenuated response to mitogenic stimulation with associated apoptosis. In an effort to determine direct HCV involvement in immune cell dysfunction, we evaluated the possibility of culture adapted JFH-1 virus to infect PBMC populations. While we found no evidence of viral replication in PBMC, exposure to JFH-1 resulted in vigorous activation of B cells. Interestingly, the B cell activation did not require viable virions, but was dependent upon CD81 availability and the presence of monocytes. We also determined that upon viral exposure, these B cells replicated the hyper-activation of MLR responses found in ex-vivo derived B cells from chronic HCV individuals. In all, our results suggest a novel model wherein HCV-B cell interaction leads to B cell hyper-activation and consequent paradoxical T cell suppression.

Author dc:creator

• Ayers, Christopher Lee

Contributors dc:contributor

• Karandikar, Nitin J.

• Hepacivirus
• Hepatitis C, Chronic
• T-Lymphocytes, Regulatory

Language dc:language

en

Identifier

754105331

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/656