Human Pegivirus (HPgV; formerly known as GBV-C) inhibits IL-12 dependent natural killer cell function

Abstract

Human Pegivirus (HPgV, formally GB virus C) infects lymphocytes and NK cells in vivo, and infection is associated with reduced T cell and NK cell activation in HIV-infected individuals. The mechanism by which HPgV inhibits NK cell activation has not been assessed. Following IL-12 stimulation, IFNγ expression was lower in HIV-HPgV co-infected subjects compared to HIV mono-infected subjects (p=0.02). In addition, HPgV positive human sera, extracellular vesicles containing E2 protein, recombinant E2 protein and synthetic E2 peptides containing a predicted Tyk2 interacting motif inhibited NK cell IL-12-mediated IFNγ release. E2 protein also inhibited Tyk2 activation following IL-12 stimulation. In contrast, cytolytic NK cell function was not altered by HPgV. Inhibition of NK cell-induced proinflammatory/antiviral cytokines may contribute to both HPgV persistence and reduced immune activation during HIV-coinfection. Understanding mechanisms by which HPgV alters immune activation may contribute towards novel immunomodulatory therapies to treat HIV and inflammatory diseases.

Human pegivirus isolates characterized by deep sequencing from hepatitis C virus‐RNA and human immunodeficiency virus‐RNA–positive blood donations, France

“…Of note, however, human immunodeficiency (HIV)‐HPgV association studies were extensively explored, due to a possible beneficial effect in HIV infection motivating investigations about HIV‐HPgV interactions at the molecular level . Mechanisms of viral persistence and host‐immune modulation remain also poorly characterized . Previous studies allowed the identification of the viral genome in liver, spleen, bone marrow, and peripheral blood mononuclear cells, including T and B lymphocytes, NK cells, and monocytes; the infection of progenitor hematopoietic stem cells as possible primary targets of the virus had been also suggested …”

“…[15][16][17][18][19][20][21][22] Mechanisms of viral persistence and host-immune modulation remain also poorly characterized. [23][24][25] Previous studies allowed the identification of the viral genome in liver, spleen, bone marrow, and peripheral blood mononuclear cells, including T and B lymphocytes, NK cells, and monocytes; the infection of progenitor hematopoietic stem cells as possible primary targets of the virus had been also suggested. 26,27 Exploration of diversity, distribution, and potential hosts of pegiviruses is in perpetual re-evaluation.…”

Human pegivirus (HPgV, GBV-C) RNA prevalence, genome characterization and association with HIV coinfection among volunteer blood donors from a public hemotherapy service in Northern Brazil.

“…The high prevalence of HPgV among HIV-1 individuals has been reported in several studies in Brazil and the world [40][41][42]. The association between the presence of HPgV and HIV is owing to the fact that HPgV likely acts as a protective factor for the development of HIV [40,43,44].…”

Human pegivirus (HPgV) infection in sub‐Saharan Africa—A call for a renewed research agenda

“…Furthermore, HPgV activates the endogenous interferon system, resulting in partial control of HIV replication . Recent data demonstrate the ability of HPgV positive human sera and E2 protein to inhibit IL‐12‐mediated NK cell function, thereby contributing to the reduced immune activation observed during HPgV/HIV coinfection …”

“…83 Furthermore, HPgV activates the endogenous interferon system, resulting in partial control of HIV replication. [84][85][86][87] Recent data demonstrate the ability of HPgV positive human sera and E2 protein to inhibit IL-12-mediated NK cell function, 88 thereby contributing to the reduced immune activation observed during HPgV/HIV coinfection. [89][90][91] Despite these HPgV-HIV interactions, the potential contribution Studies of HIV demonstrate that viral diversity is an important determinant of altered cell tropism, virulence, and/or drug susceptibility.…”