Viral Infections: Impact on Chemokines and Chemokine Receptors

C hemokines and chemokine receptors play an important role in the immune response to viral infections by regulating the migration of inflammatory cells. Perturbation of the chemokine response can have a significant impact on the course of a viral infection and subsequent immunopathology. Consequently, there are numerous examples of viruses perturbing these pathways to modulate the host's response to the virus. In the current issue of Viral Immunology two articles investigate the impact of viral infections on chemokines and chemokine receptors. Barrios and colleagues have analyzed the production of two key transcriptional regulatory gene products, Tax1 and Tax2, by human T-cell leukemia viruses types 1 (HTLV-1) and 2 (HTLV-2). The authors show that both Tax1 and Tax2 induced high levels of three CC-chemokines (CCL3, CCL4, and CCL5) in cultured peripheral blood mononuclear cells. Furthermore, lymphocytes treated with Tax2, as well as lymphocytes from HTLV-2-infected donors, showed a significantly lower percentage of CCR5-positive cells compared to those of uninfected donors. These results suggest that Tax1 and Tax2 could promote innate immunity in the extracellular environment during HTLV-1 and HTLV-2 infections via CC-chemokine ligands and receptors. Furthermore, decreases in the numbers of CCR5-positive cells may have implications for human immunodeficiency virus (HIV)/HTLV co-infections since CCR5 is a co-receptor for HIV. HIV infection is also commonly associated with hepatitis C virus (HCV) infection. HIV/HCV co-infection increases the rate and severity of HCV-associated morbidities, including progression to liver cirrhosis, hepatobiliary carcinoma, and end-stage liver disease. Because the chemokine receptor CXCR3 participates in lymphocyte trafficking during hepatic inflammation, Kimball and colleagues investigated CXCR3 expression on lymphocytes from healthy and co-infected individuals. The authors show that CD8⁺ lymphocytes from HIV/HCV-infected patients expressed increased levels of CXCR3, and that CXCR3 was more rapidly upregulated following activation of the cell. They speculate that the atypical CXCR3 expression and upregulation in co-infected patients could potentially stimulate increased lymphocyte migration during hepatic inflammation.

Three articles in this issue of Viral Immunology focus on the adaptive immune response. Wang and colleagues present the identification of three new CD8⁺ T-cell epitopes from the nucleocapsid protein of Hantaan virus. The epitopes were highly conserved among other hantaanviruses, including Dobrava-Belgrade virus and Seoul virus, suggesting that they may be useful for future vaccine development. Wang and colleagues have undertaken a comparative analysis of the influence of proteasome inhibitor MG132 and ganciclovir on cytomegalovirus (CMV)-specific CD8⁺ T-cell immune responses. These authors show that in contrast to the traditional CMV replication inhibitor, ganciclovir, MG132 reduces IFN-γ production in CMV-infected fibroblasts. These findings might have important implications for efforts to reduce CMV-associated immunopathology through the application of selective proteasome inhibitors. Although T cells may make useful vaccine targets, the foundation of most vaccines lies in the elicitation of antibody responses. In this regard, Prakash and associates have investigated antibody responses to the immunogenic regions of the viral envelope in HIV-1-infected Indian children. Analysis of 75 HIV-1-infected (35 treated with antiretroviral therapy and 40 untreated) children revealed that antibodies to V3 and the immunodominant loop region of the envelope protein were found in the majority of the infected children. In contrast, antibodies to the membrane proximal external region of the envelope protein were found in only one-third of the children studied. Higher antibody titers to the immunogenic regions corresponded to the symptomatic stages of HIV-1 infection in both untreated and antiretroviral therapy-treated children. The data extend our understanding of the humoral immune responses to the HIV-1 viral envelope protein.

Finally, two articles in this issue of Viral Immunology address questions related to innate and clinical immunity. Binjawadagi and colleagues investigate the consequences of intranasal delivery of an adjuvanted modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine. The authors show that the vaccine reduces the production of reactive oxygen species (ROS) by phagocytic cells. While ROS can have potent antimicrobial properties, excess production induces the apoptosis/necrosis of bystander cells, resulting in inflammatory pathology. The reduced ROS production associated with the tested vaccine was sufficient to protect pigs against both homologous and virulent heterologous PRRSV challenge, but did not exacerbate lung pathology. This issue of Viral Immunology closes with a case report of Griscelli syndrome type 2 (GS2) in an 11-year-old girl with hypopigmentation, immunodeficiency, hepatosplenomegaly, severe neurological impairment and fatal multi-organ failure. Szczawinska-Poplonyk and colleagues report the diagnosis of pulmonary lymphomatoid granulomatosis (LG), an Epstein-Barr virus (EBV)-related lymphoproliferative disorder, in this patient. The authors note that although EBV-related malignancies are common in immunocompromised patients, this is the first report on the diagnosis of pulmonary LG in a patient with GS2.