Innate Immunity to Viral Infections

M any viruses replicate very rapidly, posing enormous challenges to host defense mechanisms. Therefore the nature and quality of the host's immediate response to infection and the capacity of a virus to subvert that response has a major impact on the outcome for the host. In this regard, innate immune responses are of considerable importance for essentially all viral infections. The current issue of Viral Immunology has a strong focus on different aspects of innate immunity.

Affabris and colleagues have examined the role of the human immunodeficiency virus type 1 (HIV-1) nef protein in regulating immune responses. Previous studies have shown that nef expression in human macrophages activated intracellular signaling pathways that modulated the production and secretion of various chemokines and cytokines. The authors now show that similar events occur in murine macrophages, opening up new opportunities for studying the role of nef and advancing our understanding of HIV-1 infections in general. Another retrovirus that causes human disease is human T-cell leukemia virus type I (HTLV-I). HTLV-1 causes adult T-cell leukemia, although the underlying pathogenic mechanisms remain largely unknown. Inagaki and associates now show that culture supernatants from HTLV-I-infected breast milk macrophages inhibit monocyte differentiation into dendritic cells. The authors note that identification of the factors that impair monocyte differentiation may be helpful to understand HTLV-I pathogenesis. Virus infection typically results in substantial cytokine production by the host. However, the triggers for this response are poorly understood. In this regard, Zheng and colleagues investigated the induction of cytokine expression following human cytomegalovirus (HCMV) infection. Using RNA interference technology the authors show that the HCMV-encoded protein UL128 enhances interleukin (IL)-6 and tumor necrosis factor-α expression and viability in peripheral blood mononuclear cells. It is thought that the expression of host cytokines aid in the replication and dissemination of the virus.

The relationship between the innate immune response and viral infection offers considerable opportunities for clinical intervention. Jablonowska and co-workers studied the influence of pegylated interferon-alfa and ribavirin on neutrophil function and death in patients that are co-infected with human immunodeficiency virus and hepatitis C virus. They show that this treatment increased the activation phenotype of circulating neutrophils, and also increased their level of apoptosis, but not necrosis. These studies advance our understanding of the impact of antiviral drugs on modulating the innate immune response. A key role of the innate immune response is to induce and regulate adaptive immune responses to infection. Therefore, most vaccines include agents that induce innate immune responses in addition to the antigen. Wang and associates investigated whether IL-21, a T-cell-derived cytokine that modulates T-cell, B-cell, and natural killer cell responses, could act as an adjuvant and enhance antigen-specific immune responses to an HIV DNA vaccine. The authors show that while IL-21 enhanced CD8⁺ T-cell immunity, it also inhibited humoral responses, potentially by blocking the differentiation from B cells to plasma cells. These studies illustrate the complexities of clinically modulating innate responses.

Three additional articles in the current issue of Viral Immunology address other aspects of clinical immunology, vaccination, and diagnostics. Marquez and colleagues have developed a therapeutic peptide against human papillomavirus (HPV) comprised of multivalent peptide mixtures. The authors show that this peptide vaccine elicited potent HPV-specific CD4⁺ and CD8⁺ responses. Importantly, it appears that the vaccine is therapeutically efficacious in a mouse HPV tumor model. Shukla and co-workers have developed high-affinity monoclonal antibodies against recombinant E2 protein (rE2) of the Chikungunya virus. The authors note that these reagents will be useful for early clinical diagnosis and epidemiological studies of Chikungunya virus in developing countries. Finally, Aghamohammadi and colleagues present a case study of a patient with common variable immunodeficiency, a disease characterized by decreased serum immunoglobulin levels and increased susceptibility to recurrent bacterial infections, autoimmune disorders, and malignancies. In this case, the immunodeficiency was associated with a clinical polyclonal lymphocytic infiltration phenotype, severe and irreversible pancytopenia, and cytomegalovirus retinitis. The authors discuss the treatment of this spectrum of disorders.

In summary, the articles presented in the current issue of Viral Immunology highlight the critical role of innate immunity in the host's defense against viral infections. Not only do innate immune responses control viral replication, but they also regulate the engagement of adaptive immune responses with important implications for vaccine design.