Herpes simplex virus-1 (herpes labialis), which visits mankind with recurrent cold sores, is virtually universal. In AIDS, which usually accompanies HSV-2 (herpes genitalis), complications include dire infections of the esophagus, colon, lungs and nervous system in the human race. HSV-2, HSV-1's genomic partner, infects male and female genitalia with painful, but usually transient, ulcers.
At first, a cold sore tingles or itches for a few hours, then heals in eight to 12 days. What causes labial herpes (HSV-1) to erupt on the lip's vermilion borderline is a perennial puzzle. It also can bring on pink eye, or conjunctivitis. Hypothetical triggers run from overdosing on bright sunlight to fever, to immunosuppression or physical or emotional stress.
Herpes simplex genitalis (HSV-2) is no such mystery. Its etiology, impure and simple, is unprotected sexual intercourse. Mainly among young adults, it causes vulval, vaginal and cervical ulcers in afflicted females and painful penile lesions in their male consorts. In newborn infants, it can inflict severe and lasting infections.
Almost by definition, AIDS accompanies herpes genitalis, severely infecting the esophagus, gastrointestinal tract, lungs and central nervous system with HIV. Between these sporadic raids on the human body, both HSV-1 and HSV-2 hole up and lie latent, in nerve ganglia. But every time they emerge, they disseminate their infective virulence like an advancing army. Napoleon allegedly said, "An army marches on its stomach." Virologist Bernard Roizman observes, "Herpes proteins travel on the messenger RNA [mRNA], to which their cells bind. The virus," he explained, "invades a cell and takes over its machinery to make more virus particles. The particles assemble within the cell before they break out in search of new, neighboring target cells. Inside the viral capsule are the genetic information and proteins needed to co-opt that next cell."
Roizman, who holds an endowed chair of virology at the University of Chicago, is senior author of a paper in the Proceedings of the National Academy Of Sciences (PNAS), dated June 11, 2002. Its title: "Of the three tegument proteins that package mRNA in herpes simplex virions, one (VP22) transports the mRNA to uninfected cells for expression prior to viral infection."
"This particular virion protein, known as VP22," Roizman told BioWorld Today, "has been known to be transported from cell to cell. But it wasn't known why it was being transported, or what it did. This paper is the first indication that VP22 has a purpose, that one of the things it does is transport mRNA from cell to cell. When a cell becomes infected," he explained, "this VP22 protein - part of a virus particle - is made. It's like an advance army that moves to adjacent cells with RNA. We don't know exactly why it's doing it, or the use that RNA has, but it predisposes the cell to be infectious, and facilitates life for the virus."
Herpes Simplex Virus - Not So Simple
"The mRNA, so far we have found, carries large numbers of RNAs, not just one. So it's a family of proteins that are being transported out. To me," Roizman said, "herpes simplex has always been a sophisticated virus, which carefully takes over the cells in many different ways. And this finding is just one more way. It's like a Boy Scout's Swiss army knife, with so many different blades and gadgets on it. And the virus actually has a large number of genes that are designed to pacify its target cell and render it submissive.
"The tegument," Roizman explained, "is the layer of proteins located between the capsid of the virus and its envelope. The capsid is a protein shell that protects the DNA inside. It's something unique to herpes viruses." (VP22, the viral RNA-binding protein, is a major component - 2,000 copies per virion of the tegument.)
"The objective of these in vitro experiments was to identify the virion proteins capable of binding RNA, and therefore likely to be involved in packing the RNA into the HSV-1 virions. Our obvious next step is to find out what role this mRNA plays. This hasn't been done elsewhere. We are now actively working on it. The protocol is very simple. We are trying to determine where in the protein's DNA, RNA binds to VP 22. And then mutate those sequences to make sure that the RNA is no longer bound. And see whether this has an effect on the ability of the virus to, let's say, spread to the central nervous system, or in the genital lesions of mice or other experimental animals. In this paper we have demonstrated only that VP22 binds RNA, transports it and expresses it - which is the key finding. The rest is much simpler. Once we know that this protein has a function, we can probe the role of that function."
Herpes Sows Human Immunodeficiency Virus
"The chimeric gene we mention," he continued, "is a fusion between two different genes, and it's useful if you want to trace something. For example, in this particular study we made a fusion between two genes. In one, we know that its RNA is bound by this VP22 protein, and the other one - GFP, green fluorescent protein - will allow us to detect expression. By making this fusion of two genes we have solved two problems: First, we have an RNA that we know is bound by VP22. It's one of the ones that is being carried. Second, we have a quick way to determine that this RNA is actually expressed, whether it makes proteins or not."
Roizman then turned to the relevance of HIV's tat gene for the herpes protein. "The discovery that VP22 can transport mRNA from cell to cell raises questions regarding proteins of other viruses that are similarly transported," he observed. "The Tat protein also migrates from cell to cell in advance of infection. It is conceivable that one of the Tat functions is to facilitate initiation of infection with HIV by transport and expression of viral RNA in advance of viral infection. But that determination is for HIV people to do."
He concluded: "It makes life for the virus much easier."