© 2004 American Thoracic Society
The Brume Surrounding Respiratory Syncytial Virus PersistenceCenters for Disease Control and Prevention National Center for Infectious Diseases Atlanta, Georgia Respiratory syncytial virus (RSV) is the most important cause of serious lower respiratory tract illness in infants and young children worldwide causing repeat infections throughout life with serious complications occurring in the elderly and immune compromised patient (1). There are two major groups of RSV: strains A and B. Both strains may circulate concurrently within a community causing repeat infections with the same or different strains of virus (2). Because RSV does not engender a robust immune response that resists reinfection, it is likely RSV may alter aspects of immunity or immune recognition as a strategy to permit replication and/or persistence in host cells. Most viruses contain genes whose proteins disrupt aspects of the host immune response. There are several immune evasion strategies used by viruses to establish persistent or latent infections including replication in immune-privileged sites, downregulation of immune molecules, and antigenic variation. RSV primarily infects respiratory epithelial cells by interaction of heparin-binding domains on its surface attachment protein (G glycoprotein) with glycosaminoglycans on the cell surface (3). The G glycoprotein, however, contains a CX3C chemokine motif that may facilitate infection by interacting with the CX3C chemokine receptor, CX3CR1 (4), which is expressed on a variety of cell types including leukocytes (5). In addition, the G glycoprotein may interact with L-selectin (CD62L) and annexin II (6) suggesting that RSV may infect a variety of privileged cell types expressing these molecules, e.g., T cells, monocytes/macrophages, and dendritic cells. Several studies suggest that RSV may become latent or persist in vivo. In addition to the study of RSV latency and persistence in mice by Schwarze and coworkers (7) reported in this issue of the Journal (pp. 801–805), RSV protein and genomic RNA have been detected in the lungs within alveolar macrophages in experimentally inoculated guinea pigs for at least 60 days after infection (8), in murine macrophage-like cells (P388D1) and macrophage cultures (9), and in B lymphocytes following infection with bovine RSV (10). These features allude to the possibility that persistence may be important in the pathogenesis of chronic wheezing and asthma in children who have experienced acute RSV bronchiolitis (11), and may serve as a reservoir for RSV transmission and ostensibly reinfection. RSV has evolved several strategies to resist host antiviral mechanisms including modulation of the type I interferon Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway (12), expression of nonstructural (NS1 and NS2) proteins that cooperatively antagonize the antiviral effects of interferon (13), G glycoprotein CX3C chemokine mimicry (4), and during replication RSV displays a conformationally altered mature envelope that is less susceptible to an anti-F glycoprotein neutralizing antibody response (14). In addition, G glycoprotein expression is associated with altered cytokine and chemokine mRNA expression in leukocytes responding to infection, and altered pulmonary leukocyte trafficking (15, 16). These findings suggest that immune evasion may be important to the biology of RSV and to disease pathogenesis. To provide additional insight into RSV persistence and potentially the delayed effects of severe RSV disease, Schwarze and coworkers report their examination of RSV latency (genomic RNA) and persistence (messenger RNA) in BALB/c mice (7). Using reverse transcription polymerase chain reaction, the presence of genomic and messenger RNA encoding the two major RSV surface proteins, i.e., G and F glycoprotein, the matrix protein, and NS1 and NS2 proteins were detected in the lungs of mice up to 100 days after infection. These findings alone are not exceptional; however, Schwarze and coworkers show that low levels of infectious virus were recoverable from the lungs of some mice depleted of T cells 150 days after infection, suggesting that RSV persists by means of low-grade replication in the lungs despite the presence of RSV-specific cytotoxic T lymphocytes and RSV-specific serum IgG. Because cytotoxic T lymphocyte escape mutants may explain RSV persistence, Schwarze and coworkers sequenced the immunodominant matrix (M2) epitope using RNA isolated from mice with persistent infection. Although two mutations in the major M2 epitope were detected, the amino acid change from SYIGSINNI to SYIGSINNN did not significantly affect cytotoxic T lymphocyte recognition, nor act as an antagonist for the major M2 epitope, SYIGSINNI. The results from the study by Openshaw and coworkers (7) provide further evidence that viruses that are minimally or non-cytopathic in vivo often establish persistent infections in their hosts despite initial control by cytotoxic T lymphocytes. The results, however, do not address the possibility that persistence may be associated with neutralizing antibody-escape variants or be mediated by replication in immune-privileged sites. It is clear that immune evasion through antigenic variation of neutralizing epitopes is a major force driving the evolution of influenza viruses in humans, and is likely important in the response to RSV infection. The G glycoprotein exhibits extensive antigenic and genetic diversity, and variation exists not only in gene-coding sequences, but also in the signals that control gene expression (17). As noted previously, leukocytes may serve as privileged cell types hosting RSV, although neurons that innervate the lung should also be considered. Neurons express glycosaminoglycans (18) and CX3CR1 (19), and thus are potentially susceptible to RSV infection. Although RSV infection of neuronal cells was not investigated by Schwarze and coworkers, or been confirmed by other investigators, several members of the Morbillivirus, Rubulavirus, and Respirovirus subfamilies infect neurons. Several important questions have emerged from the study by Schwarze and coworkers (7) relating to the reservoir(s) of RSV latency or persistence, the role of neutralizing antibody-escape variants, and the factors that induce or mediate RSV reactivation. The answers to these and other important questions await future studies. FOOTNOTES Conflict of Interest Statement: R.A.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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