The Herpes Simplex Virus incorporates a variety of mechanisms to systematically evade inherent cellular defenses, utilizing “genetic capital” to counter interferon response and autophagy, said David Leib, professor from the Department of Ophthalmology and Visual Sciences at Washington University in St. Louis, on a Thursday immunology seminar last month at DHMC.
The Herpes Simplex Virus (HSV) currently affects almost one in four adults in the United States, resulting in sores, encephalitis, and other phenotypes associated with oral herpes. The virus survives in a variety of hosts ranging from humans to catfish and has a characteristic latency period during which the virus can jump between hosts asymptomatically.
Initially, Leib’s research team used X-ray crystallography to examine the structure of the virus, including its glycoprotein envelope involved in establishing contact with the host cell and the encapsulated 140-240 kb strand of DNA, which encodes for 85 viral genes.
HSV is spread via a mucousal surface. After this initial contact, the neurologically infective virus becomes retroactively transported from axons at the mandibular branch of the lips to soma at the trigeminal ganglion. After integration at the cell body, the virus utilizes anterograde transport to spread back into the mandibular branch, and in serious cases, into the ophthalmic branch. In its ocular manifestation, the virus can produce dendritic ulcers within the cornea, stromal keratitis (severe ocular inflammation), and, in severe cases, retinal necrosis.
The virus not only expresses this acute form, but can also assume a latent phenotype, in which there is little or no evidence of viral infection. However, during latency, the virus can both spread between hosts and easily become reactivated in the presence of certain stimuli.
This latent phase is both the source of the disorder’s relative mildness and its tenacity, since drugs targeting the virus cannot easily eliminate the virus at this stage. Latency is a dynamic process, resulting from the battle between the host immune system and the viral immune modulation. Immune modulation characterizes a return of viral phenotype, while host immune control results in reestablishment of latency.
According to Leib, the virion initially attempts to counter the interferon response via a host interferon shutoff gene. Interferons, a group of cytokines, traditionally respond to viral invasion through inhibition of viral replication and recruitment of lymphocytes.
HSV-1 interferes with this pathway by preventing phosphorylation of translation initiation factor, EIF2alpha, which is critical to mounting an interferon response. ICP 34.5, the protein responsible for phosphorylation prevention, can also actively dephosphorylate EIF2 alpha by activating the phosphatase ppIalpha, which further inhibits interferon response.
The host cell also utilizes MHC or major immunohistocompatibility complexes to repel foreign agents. MHC can present antigens to helper or killer T cells, which can coordinate or directly engage in pathogen destruction.
HSV avoids this problem through expression of VHS, or virion host shutoff protein, which can actively degrade mRNA via endoribonuclease activity and downregulate expression of MHC. The importance of this viral protein is illustrated in VHS knockouts which show significantly attenuated virus activity.
In the final portion of his lecture, Leib explored the mechanisms through which HSV can avoid a final cellular defense, autophagy.
When a cell incorporates a foreign agent, it will decrease protein synthesis by inhibiting translation machinery, to prevent further translation of viral DNA. This process relies on phosphorylation of EIF2alpha, which can be reversed via ICP 34.5.
The cell can also produce a membrane around the pathogen and fuse the membrane with a lysosome, to degrade the invader in a low pH environment, releasing key amino acids. To prevent this process, HSV utilizes binding between ICP 34.5 and the protein beclin, which can actively prevent internal autophagy.
Therapy targeting these viral methods of immune modulation may be effective in slowing or even halting the progression of HSV.
I hope I haven’t misunderstood this article but it would seem that since we know all the ways this virus can avoid our bodies immune response, is there no way that people can administer the required amounts of the EIF2alpha to the point where the amount of HSV cannot over run the immune defense?
Given that this virus requires a host cell to reproduce and infect, is it not possible to isolate the differences between the healthy and infected cells and engineer antibodies to destroy the virus?