ernest-chivero@uiowa.edu
Mentor: Jack Stapleton, M.D.
Lab Room: Bldg. 40, Room 104
Lab Phone: 319-338-0581

Interactions of GB virus C with host cells: insights into the protective effect against HIV infection

GB virus C (GBV-C) is a lymphotropic human flavivirus that is most closely related to hepatitis C virus (HCV). GBV-C infection is common, about 1%-3% of U.S. healthy blood donors are viremic, however; due to the shared route of transmission GBV-C prevalence is much higher among people with blood-borne or sexually transmitted diseases, for example prevalence among HIV-infected individuals is about 20%-40%. GBV-C infection is not convincingly associated with any disease, however; several studies found a beneficial effect of persistent GBV-C infection in HIV-positive individuals. Although the mechanisms for this protective effect of GBV-C infection is not clearly understood, studies of the effects of GBV-C on host cells have described several potential mechanisms by which GBV-C may alter HIV infection. Recent studies provide new insights into the protective effect of GBV-C infection in HIV-positive individuals. GBV-C viremic HIV infected individuals have reduced expression of T and B cell activation markers and in vitro GBV-C E2 protein expression alters T cell activation pathways suggesting GBV-C may modulate immune activation pathways which can potentially limit HIV infection. Ex vivo GBV-C is produced by peripheral blood mononuclear cells (PBMCs) from infected individuals, however; GBV-C replication is very inefficient in PBMCs from healthy donors. Since its discovery over a decade ago, the GBV-C entry receptor has not been identified. To better understand the protective effects of GBV-C infection against HIV, it is necessary to determine the primary target cells for GBV-C infection and its effects on T and B cell activation pathways.

The goals of this study are to characterize primary target cells for GBV-C infection, understand effects of GBV-C infection on B cell activation pathways and identify viral factors important for the beneficial effect against HIV infection. Our preliminary data suggest that GBV-C RNA is enriched in naïve (CD45RA+) CD4 and CD8 T cells, and B cells. Our hypothesis is that GBV-C infects immature lymphocyte precursor cells or naïve lymphocytes and regulates immune activation and the effect is mediated at least in part by the envelope glycoprotein E2. To test this hypothesis we propose three specific aims. In aim 1, we will characterize the primary target cells for GBV-C infection in-vivo. In aim 2, we will examine the effects of GBV-C infection and envelope glycoprotein E2 on B cell signaling pathways. In aim 3, we will study processing of GBV-C envelope proteins. GBV-C envelope protein E2 appears to modulate immune activation and alters T cell signaling pathways; however, mechanisms for this function are not clear. GBV-C envelope proteins are cleaved and processed from a long polyprotein but the sites of cleavage are not known. We plan to study how GBV-C envelope proteins are processed which may provide insights into their function and their role in regulating immune homeostasis.

Understanding effects of GBV-C infection on B cells and other immune cells may provide insights into the protective effect of GBV-C in HIV infected individuals and lead to develop novel cellular based therapy approaches to treat HIV infection and other immunologically mediated diseases.

Publications:

Stapleton JT, Xiang J, McLinden JH, Bhattarai N, Chivero ET, Klinzman D, Kaufman TM, Chang Q. A novel T cell evasion mechanism in persistent RNA virus infection. Trans Am Clin Climatol Assoc. 2014;125:14-24; discussion 24-6. PubMed PMID: 25125715; PubMed Central PMCID: PMC4112695.

Chivero ET, Bhattarai N, Rydze RT, Winters MA, Holodniy M, Stapleton J. Human Pegivirus (HPgV or GB virus C) RNA is found in multiple blood mononuclear cells in vivo and serum-derived viral RNA containing particles are infectious in vitro. J Gen Virol. 2014 Mar 25. doi: 10.1099/vir.0.063016-0. [Epub ahead of print] PubMed PMID: 24668525.

Bhattarai N, McLinden JH, Xiang J, Landay AL, Chivero ET, Stapleton JT. GB virus C particles inhibit T cell activation via envelope E2 protein-mediated inhibition of TCR signaling. J Immunol. 2013 Jun 15;190(12):6351-9. doi: 10.4049/jimmunol.1300589. Epub 2013 May 17. PubMed PMID: 23686495; PubMed Central PMCID: PMC3965330.

Bhattarai N, Rydze RT, Chivero ET, Stapleton JT. GB virus C viremia is associated with higher levels of double-negative T cells and lower T-cell activation in HIV-infected individuals receiving antiretroviral therapy. J Infect Dis. 2012 Nov;206(9):1469-72. doi: 10.1093/infdis/jis515. Epub 2012 Aug 20. PubMed PMID: 22927453; PubMed Central PMCID: PMC3466998.

Abstracts:

Chivero ET, Bhattarai N, Stapleton JT. GB virus C infects NK cells and alters IL12-induced NK cell function. Keystone, Colorado. 2014.

Chivero ET, Bhattarai N, Stapleton JT. GB virus C is present in and produced by natural killer (NK) cells and reduces activation-induced NK cell death. Keystone, Boston. 2013.

Chivero ET, Bhattarai N, Stapleton JT. GB virus C infects monocytes and NK cells in vivo, and prevents activation-induced cell death of NK and T cells ex vivo. 19th International Symposium on Hepatitis C Virus and Related Viruses. Venice, Italy. 2012.

Chivero ET, Bhattarai N, Stapleton JT. GBV-C RNA is enriched in naïve CD4 and CD8 T cells in cART treated HIV-positive individuals. Keystone Symposia on Viral Immunity and Host Gene Influence. Keystone, Colorado. 2012.

Bhattarai N, McLinden JH, Xiang J, Landay A, Chivero ET, Stapleton JT. Identification of a novel mechanism by which GB virus C (hepatitis G virus) inhibits T cell activation. 19th International Symposium on Hepatitis C Virus and Related Viruses. Venice, Italy. 2012.

Bhattarai N, Rydz, Chivero ET, Stapleton JT. GBV-C viremia is associated with higher levels of double negative T cells, and lower T cell activation in HIV-infected individuals on antiretroviral therapy. XIX International AIDS Conference. Washington D.C. 2012.