MicrobiologyBytes

Herpes simplex virus (HSV) is an important pathogenic agent that causes recurrent oral and genital lesions, blindness and encephalitis. It is a member of the family Herpesviridae, which contains three subfamilies (alpha- beta- and gammaherpesvirinae) whose members infect humans to cause a variety of ailments, from benign rashes to nasopharyngeal carcinoma. Although this review focuses on HSV, the assembly steps that occur in the nucleus and the proteins involved are highly conserved among all family members, which suggests that antiviral agents that block these steps might be effective against many different herpesviruses and their associated diseases. Despite this potential, a broadly effective compound has yet to be realized, in part because many of the processes are only poorly understood in sufficient molecular detail. This review outlines these intranuclear assembly steps and illustrate potential and existing antiviral strategies that exploit them.

Herpes simplex virus capsid assembly and DNA packaging: a present and future antiviral drug target. (2011) Trends Microbiol. 19(12) :606-613

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Epstein-Barr virus (EBV) and Kaposi’s Sarcoma Associated Herpesvirus (KSHV) are DNA tumor viruses that provide risk factors for Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, Kaposi’s Sarcoma and post-transplant lymphoproliferative disease. EBV infection has also been associated with multiple sclerosis. Healthy carriers consistently shed virus in saliva that infects naïve individuals despite being exposed to virus-specific antibody. This lack of neutralization contrasts completely with non-persistent mucosal infections such as that of poliovirus, and implies that gammaherpesviruses have evolved specific antibody evasion mechanisms.

Our understanding of EBV and KSHV is limited by their narrow species tropisms. Related animal viruses are therefore an important source of information. Two of the best established experimental models are provided by Murid herpesvirus 4 (MuHV-4) and Bovine herpesvirus 4 (BoHV-4). The homologs of gp350 are gp150 in MuHV-4 and gp180 in BoHV-4 are diverse in sequence but seem to be related in function, being involved in both binding to a cellular receptor and in blocking the infection of cells that do not express this receptor. So a non-essential glycoprotein hides some epitopes on cell-free virions from neutralization.

Antibody Evasion by a Gammaherpesvirus O-Glycan Shield. (2011) PLoS Pathog 7(11): e1002387. doi:10.1371/journal.ppat.1002387
All gammaherpesviruses encode a major glycoprotein homologous to the Epstein-Barr virus gp350. These glycoproteins are often involved in cell binding, and some provide neutralization targets. However, the capacity of gammaherpesviruses for long-term transmission from immune hosts implies that in vivo neutralization is incomplete. In this study, we used Bovine Herpesvirus 4 (BoHV-4) to determine how its gp350 homolog – gp180 – contributes to virus replication and neutralization. A lack of gp180 had no impact on the establishment and maintenance of BoHV-4 latency, but markedly sensitized virions to neutralization by immune sera. Antibody had greater access to gB, gH and gL on gp180-deficient virions, including neutralization epitopes. Gp180 appears to be highly O-glycosylated, and removing O-linked glycans from virions also sensitized them to neutralization. It therefore appeared that gp180 provides part of a glycan shield for otherwise vulnerable viral epitopes. Interestingly, this O-glycan shield could be exploited for neutralization by lectins and carbohydrate-specific antibody. The conservation of O-glycosylation sites in all gp350 homologs suggests that this is a general evasion mechanism that may also provide a therapeutic target.

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Herpes simplex virus (HSV) type-1 and type-2 have evolved numerous strategies to infect a wide range of hosts and cell types. The result is a very successful prevalence of the virus in the human population infecting 40-80% of people worldwide. HSV entry into host cell is a multistep process that involves the interaction of the viral glycoproteins with various cell surface receptors. Based on the cell type, HSV enter into host cell using different modes of entry. The combination of various receptors and entry modes has resulted in a virus that is capable of infecting virtually all cell types. Identifying the common rate limiting steps of the infection may help the development of antiviral agents that are capable of preventing the virus entry into host cell. This review describes the major features of HSV entry that have contributed to the wide susceptibility of cells to HSV infection.

Herpes simplex virus infects most cell types in vitro: clues to its succes. (2011) Virology Journal 8: 481 doi:10.1186/1743-422X-8-481

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HCMV infection dramatically alters cellular metabolism, this review focuses on how the virus alters glucose and glutamine metabolism and fatty acid synthesis. Changes to glucose metabolism include increased glucose uptake through the induction of the glucose transporter GLUT4, upregulation of glycolytic enzymes and probable allosteric activation of glycolysis. Although these changes are rather dramatic they are likely to represent only a fraction of the metabolic changes wrought by HCMV infection. Such changes are likely to contribute to forms of HCMV pathogenesis that could be very different from those that have been studied and documented to this point. For example, HCMV and other viruses which induce metabolic changes similar to HCMV might play a greater role in oncogenesis than previously recognized. At this point, our understanding of the mechanisms used by HCMV to alter metabolic processes is very limited and requires further study.

Viral effects on metabolism: changes in glucose and glutamine utilization during human cytomegalovirus infection. Trends Microbiol. May 11 2011
Human cytomegalovirus (HCMV) infection causes dramatic alterations of intermediary metabolism, similar to those found in tumor cells. In infected cells, glucose carbon is not completely broken down by the tricarboxylic acid (TCA) cycle for energy; instead, it is used biosynthetically. This process requires increased glucose uptake, increased glycolysis and the diversion of glucose carbon, in the form of citrate, from the TCA cycle for use in HCMV-induced fatty acid biosynthesis. The diversion of citrate from the TCA cycle (cataplerosis) requires induction of enzymes to promote glutaminolysis, the conversion of glutamine to α-ketoglutarate to maintain the TCA cycle (anaplerosis) and ATP production. Such changes could result in heretofore uncharacterized pathogenesis, potentially implicating HCMV as a subtle cofactor in many maladies, including oncogenesis. Recognition of the effects of HCMV, and other viruses, on host cell metabolism will provide new understanding of viral pathogenesis and novel avenues for antiviral therapy.

Interfering RNAs (RNAi) are meant to match the sequence of the messenger RNAs made from genes, and then to block or inactivate the mRNA, keeping it from being translated into a harmful protein. One of the main hurdles has been delivering the agents specifically to the cells in which they are needed. An article in this Tuesday’s New York Times drew attention to this problem when reporting that many pharmaceutical companies have suspended their research into RNA interference. But what if you could use a common bacteria to deliver the payload? In work reported in this week’s Proceedings of the National Academies of Sciences, researchers led by Fenyong Liu at UC Berkeley made a modified strain of Salmonella to deliver interfering RNA exactly where it was needed. The result: they inhibited cytomegaloviral infection in mice.

ArsTechnica: Meet the newest virus fighter: Salmonella

See: Oral delivery of RNase P ribozymes by Salmonella inhibits viral infection in mice. PNAS USA February 7, 2011 doi: 10.1073/pnas.1014975108