Editorial
VIRAL IMMUNOLOGY Volume 27, Number 6, 2014 ª Mary Ann Liebert, Inc. P. 255 DOI: 10.1089/vim.2014.1503
Hepatitis C Virus Infection of B-Cells David L. Woodland
H
epatitis C virus (HCV), a single-stranded, positivesense RNA virus, is primarily spread through blood transfusions, poorly sterilized medical equipment, and intravenous drug use. It has infected almost 200 million people worldwide, and is a significant medical problem due to its capacity to cause cirrhosis, hepatocellular carcinoma, or endstage liver disease. The infection is generally chronic in about 80% of infected individuals and is normally treated with pegylated interferon, ribavirin, and NS3/4A protease inhibitors. However, treatment only results in a cure in approximately half to two-thirds of patients, and there is still no effective vaccine against the virus. It is well established that HCV robustly infects hepatocytes in the liver, and may also cause a systemic immune complex-mediated disorder characterized by B-cell proliferation that may evolve into overt Bcell non-Hodgkin’s lymphoma. Indeed, HCV-RNA is often found to be associated with peripheral blood lymphocytes, suggesting a possible interaction with peripheral blood mononuclear cells (PBMCs), especially B-cells. Yet, it remains controversial whether HCV directly infects B-cells. In the current issue of Viral Immunology, Nakai et al. have directly addressed this question using a recombinant strain of HCV. The authors show that human B-cells isolated from the peripheral blood of normal volunteers supported a low level of HCV replication, as measured both by reverse transcription polymerase chain reaction and NS5A protein expression. Furthermore, this infection was dependent on HCV particles binding with its receptor CD81, is not mediated by nonspecific entry (e.g., exosomal mediated), and replication could be blocked by type I interferon. These findings considerably advance our understanding of the biology of HCV infection. Several papers in the current issue address the role of innate immune responses during viral infection. Shin et al. have investigated why Hantaviruses, which are not generally considered neurotropic, can occasionally cause neurological complications. Their analysis of the innate immune response to Hantavirus infection of either human astrocytic cells or suckling mice suggest that neurological effects may result from the direct modulation of innate immune responses in the brain. Liu et al. have analyzed the innate response to Enterovirus 71 (EV71) infection, which can cause severe disease and lead to death in children. Interestingly, interferon treatments have a limited ability to inhibit EV71. The authors now show that EV71 inhibits the innate type I interferon pathway by downregulating JAK1 in EV71-infected cells. Dendritic cells (DC) play a key role in orchestrating innate immune responses and mediating a connection between innate and
adaptive immune responses. Lin and Lee point out that DC are essential for the innate response to influenza virus infection and speculate that the greater susceptibility of infants and neonates to severe infection may be partly attributed to defective DC function. Consistent with this idea, they show that monocyte-derived DC from umbilical cord blood showed defective upregulation of CD40, CD80, CD86, and HLA-DR, deficient TNF-alpha production, and increased apoptosis following influenza virus infection compared to monocytederived DC from adult peripheral blood. Two manuscripts in this issue address the roles of CD4 and CD8 cells in controlling human immunodeficiency virus (HIV) infection. Jiao et al. investigated the relationship between the distribution of HIV-1 proviral DNA in CD4 subsets during acute HIV-1 infection and HIV disease progression. The authors compared two groups of patients in which the CD4 counts either fell below 200 cells/lL within 2 years (rapid progressors) or were maintained above 500 cells/lL (slow progressors). The data indicated that HIV-1 DNA content was higher in memory T-cells than in naı¨ve cells in both groups, and a higher HIV DNA content was found in naı¨ve CD4 T-cells during acute HIV-1 infection in rapid progressors. The authors suggest that higher HIV DNA levels in naı¨ve CD4 T-cells may be associated with rapid progression. Nagashima et al. point out that HIV-1 infection stimulates strong immune responses, and CD8 T-cells including HIV-1-specific cytotoxic T-lymphocytes (CTLs) play important roles in controlling viral replication in HIV-1-infected individuals. Previous studies have shown that CD8 T-cells of asymptomatic HIV-1 carriers suppress HIV-1 replication in autologous PBMCs. Here, they show that allo-antigen stimulated CD8 T-cells are able to suppress both NF-jB and Ets-1 DNA binding activities in autologous CD4 T-cells, potentially explaining their HIV-1-suppressive activity. Finally, qusiak-Szelachowska et al. present a technical study to determine whether phage therapies to control bacterial infections concomitantly induce antiphage antibodies. Patients were administered phages orally, parenterally, intrarectally, or via a combination of routes, and their sera was subsequently tested for its ability to inactivate phages. The data indicated that the antiphage activity in patients’ sera depends on the route of phage administration and phage type. Interestingly, generally low inactivation rates were observed in the sera of patients that had been infected orally, suggesting that this might be an appropriate route for phage therapy in general. I would like to thank all of the authors for their interesting contributions to the journal.
Keystone Symposia on Molecular and Cellular Biology, Silverthorne, Colorado.
255
VIRAL IMMUNOLOGY Volume 27, Number 6, 2014 ª Mary Ann Liebert, Inc. P. 255 DOI: 10.1089/vim.2014.1503
Hepatitis C Virus Infection of B-Cells David L. Woodland
H
epatitis C virus (HCV), a single-stranded, positivesense RNA virus, is primarily spread through blood transfusions, poorly sterilized medical equipment, and intravenous drug use. It has infected almost 200 million people worldwide, and is a significant medical problem due to its capacity to cause cirrhosis, hepatocellular carcinoma, or endstage liver disease. The infection is generally chronic in about 80% of infected individuals and is normally treated with pegylated interferon, ribavirin, and NS3/4A protease inhibitors. However, treatment only results in a cure in approximately half to two-thirds of patients, and there is still no effective vaccine against the virus. It is well established that HCV robustly infects hepatocytes in the liver, and may also cause a systemic immune complex-mediated disorder characterized by B-cell proliferation that may evolve into overt Bcell non-Hodgkin’s lymphoma. Indeed, HCV-RNA is often found to be associated with peripheral blood lymphocytes, suggesting a possible interaction with peripheral blood mononuclear cells (PBMCs), especially B-cells. Yet, it remains controversial whether HCV directly infects B-cells. In the current issue of Viral Immunology, Nakai et al. have directly addressed this question using a recombinant strain of HCV. The authors show that human B-cells isolated from the peripheral blood of normal volunteers supported a low level of HCV replication, as measured both by reverse transcription polymerase chain reaction and NS5A protein expression. Furthermore, this infection was dependent on HCV particles binding with its receptor CD81, is not mediated by nonspecific entry (e.g., exosomal mediated), and replication could be blocked by type I interferon. These findings considerably advance our understanding of the biology of HCV infection. Several papers in the current issue address the role of innate immune responses during viral infection. Shin et al. have investigated why Hantaviruses, which are not generally considered neurotropic, can occasionally cause neurological complications. Their analysis of the innate immune response to Hantavirus infection of either human astrocytic cells or suckling mice suggest that neurological effects may result from the direct modulation of innate immune responses in the brain. Liu et al. have analyzed the innate response to Enterovirus 71 (EV71) infection, which can cause severe disease and lead to death in children. Interestingly, interferon treatments have a limited ability to inhibit EV71. The authors now show that EV71 inhibits the innate type I interferon pathway by downregulating JAK1 in EV71-infected cells. Dendritic cells (DC) play a key role in orchestrating innate immune responses and mediating a connection between innate and
adaptive immune responses. Lin and Lee point out that DC are essential for the innate response to influenza virus infection and speculate that the greater susceptibility of infants and neonates to severe infection may be partly attributed to defective DC function. Consistent with this idea, they show that monocyte-derived DC from umbilical cord blood showed defective upregulation of CD40, CD80, CD86, and HLA-DR, deficient TNF-alpha production, and increased apoptosis following influenza virus infection compared to monocytederived DC from adult peripheral blood. Two manuscripts in this issue address the roles of CD4 and CD8 cells in controlling human immunodeficiency virus (HIV) infection. Jiao et al. investigated the relationship between the distribution of HIV-1 proviral DNA in CD4 subsets during acute HIV-1 infection and HIV disease progression. The authors compared two groups of patients in which the CD4 counts either fell below 200 cells/lL within 2 years (rapid progressors) or were maintained above 500 cells/lL (slow progressors). The data indicated that HIV-1 DNA content was higher in memory T-cells than in naı¨ve cells in both groups, and a higher HIV DNA content was found in naı¨ve CD4 T-cells during acute HIV-1 infection in rapid progressors. The authors suggest that higher HIV DNA levels in naı¨ve CD4 T-cells may be associated with rapid progression. Nagashima et al. point out that HIV-1 infection stimulates strong immune responses, and CD8 T-cells including HIV-1-specific cytotoxic T-lymphocytes (CTLs) play important roles in controlling viral replication in HIV-1-infected individuals. Previous studies have shown that CD8 T-cells of asymptomatic HIV-1 carriers suppress HIV-1 replication in autologous PBMCs. Here, they show that allo-antigen stimulated CD8 T-cells are able to suppress both NF-jB and Ets-1 DNA binding activities in autologous CD4 T-cells, potentially explaining their HIV-1-suppressive activity. Finally, qusiak-Szelachowska et al. present a technical study to determine whether phage therapies to control bacterial infections concomitantly induce antiphage antibodies. Patients were administered phages orally, parenterally, intrarectally, or via a combination of routes, and their sera was subsequently tested for its ability to inactivate phages. The data indicated that the antiphage activity in patients’ sera depends on the route of phage administration and phage type. Interestingly, generally low inactivation rates were observed in the sera of patients that had been infected orally, suggesting that this might be an appropriate route for phage therapy in general. I would like to thank all of the authors for their interesting contributions to the journal.
Keystone Symposia on Molecular and Cellular Biology, Silverthorne, Colorado.
255
