Viral Replication and Persistence

V iruses have evolved a wide range of mechanisms to evade host defenses and to promote their replication, and for some viruses, to persist in host cells. Over recent years, virologists and immunologists have been making considerable progress in advancing our understanding of this complex interplay between the virus and the host. In the current issue of Viral Immunology, three articles specifically address this important topic. The first paper, by Rochford and colleagues, investigates the mechanism by which a murine gammaherpesvirus (γHV-68) is able to utilize host immunity to regulate viral programs of latency and reactivation. Infection of adult mice with γHV-68 resulted in long-term latency, primarily in the spleen, whereas infection of neonatal mice resulted in persistence of the virus in both the spleen and the lungs. The authors go on to demonstrate that stimulation of the toll-like receptor 9 (TLR9) in infected mice leads to differences in viral gene expression between the spleens of neonatal and adult mice. The data suggest that heterologous infections that elicit TLR9 stimulation lead to abortive γHV-68 reactivation and transient expansion of the latently-infected cell pool. The data further indicate that heterologous infections may affect viral latency in an age-dependent manner. This has important implications for gammaherpesvirus pathogenesis in developing countries, where most people are infected early in life. An article by Padwad and associates examines the factors that regulate dengue virus replication in infected hosts. The authors show that dengue virus infection of human monocytes results in a stress response that induces a number of host stress proteins, including the cellular chaperone Hsp70. Interestingly, it appears that the virus uses the increased level of Hsp70 expression in dengue-virus-infected cells to escape the antiviral effect of type 1 interferon and to enhance viral replication. In a third article on this topic, Piasecki and co-workers have analyzed the replication of vesicular stomatitis virus (VSV) in isolated human leukocytes. Earlier studies indicated that human immunodeficiency virus (HIV) infection inhibited VSV replication. The data in the current article confirm that VSV replication capacity reflects the progression of HIV infection. Importantly, the study highlights the potential secondary effects of successful antiretroviral therapies that decrease HIV viremia. The authors postulate that VSV replication may be used as an assay to evaluate the stage of HIV infection.

Several articles in this issue address the adaptive immune response to viral infection. Green and colleagues used a mouse retroviral model to show that alternative translational reading frames can serve as a novel source of epitopes for an expanded CD8 T-cell response. Wang and associates have identified conserved DR1501-restricted CD4⁺ T-cell epitopes from highly pathogenic avian influenza H5N1 viruses. Srikiatkhachorn and co-workers show that CD8⁺ T-cell-mediated pulmonary immunopathology in the lung is mediated in large part by antigen-specific TNF expression by antiviral effector T cells. Interference with TNF-α signaling exclusively in distal airway epithelial cells during influenza virus infection resulted in abrogation of CD8⁺ T-cell-mediated lung injury and viral clearance. T-cell function can also be inhibited by membrane vesicles released by rotavirus-infected intestinal epithelial cells (see the article by Barreto and colleagues), or by activation of the Notch signaling pathway (see the article by Eriksson and co-workers).

Three articles focus on HIV infection. Schellens and associates longitudinally evaluated HIV-specific T-cell immunity after discontinuation of highly active antiretroviral therapy (HAART). The data indicate that individuals capable of maintaining a low viral load after treatment discontinuation have increased CD8⁺ T-cell function 4 weeks after treatment interruption, compared to those who experienced a rapid increase in viral load. Shirasaka and colleagues analyzed serum interferon-γ (IFN-γ) levels during HIV-1 infection in Japanese adults. They show that IFN-γ levels in some patients increased and remained high, even after the initiation of HAART, a pattern that was distinct from the pattern seen with other cytokines. In other studies, the binding of murine IgM monoclonal antibodies to five different clades of HIV-1 was examined by Rao and co-workers.

Finally, a study by Albayrak and associates shows that high-mobility group box 1 (HMGB1) is a marker that can be used to identify advanced fibrosis in chronic hepatitis B virus patients. The authors suggest that fibrosis progression in chronic liver patients may be prevented by the inhibition of HMGB1.