Herpes Virus in Neurons- does that benefit?

Greetings

 

It has been a long time since I posted some basic virology. There has been a question that I had been asked by a couple of people, and thought it would make a good blog post to answer it. Am sure you have heard of Herpes Virus. Chances are you are infected by at least 2 different Herpes virus and still carry the virus silently without any harm. There are more than 200 different types of herpes virus known, only a handful of the types represents one's which are associated with human infections. There are a variety of Herpes virus in the Earth virome (If I could call it so). Human Herpes virus is classified into α, β and γ sub groups. See Table 1 for details.

So, here's my question. Almost every human is infected with HSV-1 for their lifetime without any significant consequences, unless there is a immuno-compromised condition. Does HSV latency reflect a advantageous position for host? HSV-1 latency is a deeply studied subject. HSV-1 is acquired very early in childhood (less than a year of age). The infection usually resolves by about 2 weeks. The virus then moves axonally (retrograde microtubule-associated transport), reaches the neuronal nucleus and DNA is transported to the nucleus. Once the DNA is in (estimates are that there will be about 10-100 DNA copies in each cell), it circularizes and rests as a extra-chromosomal fraction. Reactivation of virus can lead to retroaxonal transport and establishment of infection.

Fig 1: Events in HSV-1 latency and lytic cycle.

Source

    As per the literature, 3 phases of latency can be recognised- Establishment phase, maintenance phase and reactivation phase. The exact mechanism of how the virus undergoes latency is a question of great research interest. The most common view is that the circular chromosome exhibit a nucleosome like formation, leading to a chromatin like structure. This necessarily implies that factors such as histone modifications are involved in maintenance of latency. This is in good agreement with published results thus far. The only and probably the most important product of HSV detectable inside neurons during latency is the LAT (Latency associated transcript). LAT is a 2 kbp transcript derived by splicing from a less abundant precursor RNA termed minor (m) LAT. The mLAT is transcribed antisense to the ICP0 gene and extends to a polyadenylation signal in the short repeat region. The LAT is a super stable RNA. A summary of events is shown in Fig 1. And how does the Herpes enter activation? Once again, it is not absolutely clear of what is the mechanism. ICP0 was considered as the most likely candidate to date. ICP0, is known to encode a transcriptional activator, which can positively enhance viral mRNA synthesis. More recently VP16 is the favourite candidate.

I have 2 questions to consider here. Taking into account, nearly everyone harbours HSV in their trigeminal neurons, do they represent some sort of benefit to us.

Let us consider the question other way around. If neurons trigger death signals as a form of annihilating the virus inside, the best strategy for virus to be still hanging around is to protect the neurons from destruction. That makes a lot of sense, considering that virus can be sitting down the neuron for decades. For example, In experimental cell lines, it has been shown that CD8 cells are unable to induce apoptosis in latently infected cells. This is thought to be due to LAT’s antiapoptosis activity. This has important implications. For instance, it has been shown in animal models that latency can increase resistance to other infections such as Listeria. I would also think that virus can competitively inhibit other virus trying to gain access into neurons via interference. Such cross protection, might have let us have the trade of benefit.

Second question, Could you some sense consider HSV-1 as a part of neural virome. That is a very tricky question to ask, since the definition of microbiome is not clear. If microbiome is a definition, for microbes that is constituting to be present for a long time in a given niche, then HSV-1 clearly qualifies. It is present for a long-term, and probably beneficial. So why not?

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Roizman B, & Whitley RJ (2013). An inquiry into the molecular basis of HSV latency and reactivation. Annual review of microbiology, 67, 355-74 PMID: 24024635

Wysocka J, & Herr W (2003). The herpes simplex virus VP16-induced complex: the makings of a regulatory switch. Trends in biochemical sciences, 28 (6), 294-304 PMID: 12826401

Thompson, R., Preston, C., & Sawtell, N. (2009). De Novo Synthesis of VP16 Coordinates the Exit from HSV Latency In Vivo PLoS Pathogens, 5 (3) DOI: 10.1371/journal.ppat.1000352

Jiang X, Chentoufi AA, Hsiang C, Carpenter D, Osorio N, BenMohamed L, Fraser NW, Jones C, & Wechsler SL (2011). The herpes simplex virus type 1 latency-associated transcript can protect neuron-derived C1300 and Neuro2A cells from granzyme B-induced apoptosis and CD8 T-cell killing. Journal of virology, 85 (5), 2325-32 PMID: 21177822

Barton ES, White DW, & Virgin HW (2009). Herpesvirus latency and symbiotic protection from bacterial infection. Viral immunology, 22 (1) PMID: 19210221