PerspectiveVirology

Even Viruses Can Learn to Cope with Stress

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Science  02 Jan 1998:
Vol. 279, Issue 5347, pp. 40-41
DOI: 10.1126/science.279.5347.40

More than 5 years ago, a commentary in Science announced that viruses engage in “Star Wars” strategies against the immune system. Some of the viral invaders make receptors (viroceptors) that imitate normal cellular receptors and so can sequester and inactivate molecules that the immune system tries to use to fight the virus (1). Since that time, numerous other viral subterfuges for evading or subverting host defense mechanisms have been exposed (2–4), and viruses now are known to use an extraordinary spectrum of proteins to target immune molecules of the host cells. One particularly effective host defense is for the infected cell to self-destruct by programmed cell death, and in fact, cell death is triggered by infection with a wide variety of viruses (5). In response some viruses use specific proteins to suppress the cell suicide that would normally curtail the infection (5, 6). Other classes of intracellular responses have elicited their own array of viral countermeasures as well (see the table). To this growing list, we can now add reactive oxidative species (oxidative stress) as a worthy target for viral inhibition. On page 102 of this issue, Shisler et al. (7) report that molluscum contagiosum virus (MCV) encodes a novel anti-oxidant protein (MC066L) that functions as a scavenger of reactive oxygen metabolites and protects cells from ultraviolet- or peroxide-induced damage. Equally intriguing, MC066L is also the first bona fide selenoprotein expressed by a virus.

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The story began last year when B. Moss and his colleagues at the National Institutes of Health sequenced the genome of MCV, a human poxvirus that causes benign tumorlike skin lesions that can become problematic in immunosuppressed patients, including those with AIDS (8). Given the proclivity of the larger DNA viruses to engage in widespread gene piracy, it was expected that MCV would encode a variety of host-derived proteins. But what was most unexpected was how extraordinarily different the nonessential gene repertoire of MCV was from those of previously sequenced poxviruses, particularly vaccinia and variola (9). Not only was MCV bereft of most of the better studied immunoregulators, such as the secreted viroceptors that precipitated the original Star Wars analogy, but 77 of the 182 predicted MCV open reading frames had no obvious viral counterparts at all. Moreover, some of these novel candidates were predicted to antagonize immune responses on the basis of their sequence similarities to other known host genes, and this list included such luminaries as a major histocompatability complex-1 heavy chain homolog, a β-chemokine, and two related death effector domain-containing proteins (8, 9). Particularly notable among these host-derived candidates was a predicted gene product (MC066L) that was 74% identical to human glutathione peroxidase, a major cellular scavenger of reactive and toxic oxygen metabolites and one of the few known enzymes that requires covalently bound selenium as a cofactor.

The importance of this remarkable sequence similarity was further underscored by the discovery of a predicted stem-loop selenocysteine insertion sequence (SECIS) motif within the 3′ untranslated region of MC066L. Hairpin SECIS structures in mRNA allow cellular translational machinery that makes the protein to read through an internal UGA codon that would ordinarily stop translation. By inserting a specific selenocysteine suppressor tRNA instead of stopping when the UGA occurs, the ribosome continues to the next downstream stop to make the full-length selenoprotein. Similar sequence motifs have been reported for other viruses (10), notably human immunodeficiency virus-1 (HIV-1) and Ebola, but actual synthesis of viral selenoproteins had never been demonstrated. The MCV gene has an in-frame UGA at codon 64, and the incorporation of 75Se into expressed 30-kD MC066L protein (7) supported the contention that at least some of the translated viral protein resulted from readthrough all the way to the downstream stop at codon 221. Furthermore, transfection experiments in HeLa cells and immortalized HaCaT keratinocytes revealed that MC066L expression protects against cell death induced by ultraviolet treatment or hydrogen peroxide but not by either tumor necrosis factor ligand or FAS-antibody, which act by triggering programmed cell death (7).

So what does glutathione peroxidase actually do for MCV? Unfortunately, MCV does not grow in cultured cells, and no animal models exist to test the effects of gene deletions on viral pathogenesis. Nevertheless, certain predictions can be made from what is known about the glutathione peroxidase-reductase cycle that couples peroxide and hydroxyl radical detoxification with the oxidation of reduced glutathione. Along with catalase and superoxide dismutase, glutathione peroxidase is a major protectant against reactive oxygen metabolites, which can not only damage viral macromolecules directly, but are also potent inducers of apoptosis by virtue of their ability to trigger mitochondrial membrane permeability transitions (11, 12). In fact, reduced glutathione peroxidase activity caused by selenium deficiency is associated with increased susceptibility to apoptosis (13) and excessive oxidant-induced cellular damage in HIV-1 infection (14).

Shisler et al. (7) speculate that MC066L might protect MCV—an exclusively dermatrophic virus that replicates only in suprabasal layers of differentiating keratinocytes—from intracellular peroxide toxicity or free radicals generated directly by ultraviolet light exposure. However, there is another possibility that is difficult to dismiss—that MC066L also serves as an intracellular protective mechanism against the toxic effects of diffused peroxide produced from dermal phagocytic leukocytes (15). Before regression, MCV lesions contain few inflammatory cells, although some tissue phagocytes may patrol below the basement membrane. Because hydrogen peroxide released during an oxidative burst by activated phagocytic cells can readily penetrate membrane barriers and produce damaging hydroxyl radicals within infected target cells, even small amounts could be significantly toxic for the relatively slow-growing MCV, particularly because virus replication likely represses the expression of all cellular anti-oxidant genes. Thus, in a manner that is analogous to how some tumor cells have hijacked the glutathione redox system to protect against peroxide cytotoxicity (16), active viral glutathione peroxidase could be the most effective countermeasure against phagocyte-derived peroxide for a virus-infected cell.

Taken in this light, it seems appropriate that the biological treasure-trove of the poxvirus family has not only introduced us to the extracellular Star Wars technologies, but is also the first to teach us that viruses can be equally adept at the kind of intracellular hand-to-hand combat normally associated with ground-level warfare as well.

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