#1

First time poster here and new rapa user (though postponed at the moment for reasons below). Looking forward to participating in the community.

I have a pregnant wife and I’m concerned with possible reactivation of HSV-1 with my intermittent use of rapamycin, especially in light of the most prevalent side effect - canker or cold sores. As far as I can tell, it seems most believe the sores are aphthous ulcers, though I have come across a few anecdotes of individuals seemingly having a reactivation of HSV in correlation with their rapa use. I have also come across one foreign website listing herpetic ulcers as a possible side effect of rapa. I obviously don’t want to expose my wife to any additional risk during pregnancy or my kid during the first few months, especially a significant one such as HSV.

I’m completely fine with postponing my use of rapa, but I’m hoping to better gauge the risk, to the extent there is one. As an aside, I also thought about simultaneously cycling Acyclovir since its relatively safe and well-tolerated. Though not sure that would nullify the potential risk entirely.

Just for some background, I just started rapa at 1 mg weekly and planned on titrating up to 5-6 mg. Postponed after coming across this issue.

Many thanks for any input!

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#2

Believe it or not, it activated HSV-2 in me where I previously hadn’t even known I had it, popped up on some bloods.

I started using Valacyclovir as a prophylactic and I’ve never had a single sore or outbreak being on 4MG weekly of Rapa.

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#3

@Ryan24 Rapamycin causes aphthous ulcers. These are not caused by a virus and specifically are not the same as canker or cold sores (communicable and caused by HSV-1). So if you are concerned about aphthous ulcers you needn’t be. Also Acyclovir will have no effect on aphtous ulcers.

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#5

Corrected Spelling:
I have had periodic HSV1 ulcers throughout my adult life. I also get aphthous ulcers with high dose rapa/GF/KitchenSink. The aphthous ulcers are qualitatively different. They are wider but not as deep as HSV1. Also HSV1 will travel and appear along the large nerve pathways, whereas the rapa ones don’t follow that pattern. The rapa ulcers can get as painful as the HSV1s but I think its due to a light secondary infection of the ulcer site. Obviously with a pregnant wife don’t take any chances, so no kissing or sharing utensils/cups, use the the dishwasher at hot. One of the many chores that come with being a father:) Congratulations Dad! Its KP time, and washing and cooking, etc. etc. You are a blessed man.

#6

Cellular processes requiring access to the DNA genome are regulated by an overlay of epigenetic modifications, including histone modification and chromatin remodeling. Similar to the cellular host, many nuclear DNA viruses that depend upon the host cell’s transcriptional machinery are also subject to the regulatory impact of chromatin assembly and modification. Infection of cells with alphaherpesviruses (herpes simplex virus [HSV] and varicella-zoster virus [VZV]) results in the deposition of nucleosomes bearing repressive histone H3K9 methylation on the viral genome. This repressive state is modulated by the recruitment of a cellular coactivator complex containing the histone H3K9 demethylase LSD1 to the viral immediate-early (IE) gene promoters. Inhibition of the activity of this enzyme results in increased repressive chromatin assembly and suppression of viral gene expression during lytic infection as well as reactivation from latency in a mouse ganglion explant model. However, available small-molecule LSD1 inhibitors are not originally designed to inhibit LSD1, but rather monoamine oxidases (MAO) in general. Thus, their specificity for and potency to LSD1 is low. In this study, a novel specific LSD1 inhibitor was identified that potently repressed HSV IE gene expression, genome replication, and reactivation from latency. Importantly, the inhibitor also suppressed primary infection of HSV in vivo in a mouse model. Based on common control of a number of DNA viruses by epigenetic modulation, it was also demonstrated that this LSD1 inhibitor blocks initial gene expression of the human cytomegalovirus and adenovirus type 5.

The high prevalence of Herpesviruses in the population and the maintenance of lifelong latent reservoirs are challenges to the control of herpetic diseases, despite the availability of antiviral pharmaceuticals that target viral DNA replication. In addition to oral and genital lesions, herpes simplex virus infections and recurrent reactivations from the latent pool can result in severe pathology including neonatal infection and mortality, blindness due to ocular keratitis, and viral-induced complications in immunosuppressed individuals. Herpesviruses, like their cellular hosts, are subject to the regulatory impacts of chromatin and chromatin modulation machinery that promotes or suppresses gene expression. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 and JMJD2s. Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and a block to infection and reactivation in vitro . Here, the concept of epigenetic suppression of viral infection is demonstrated in three animal models of herpes simplex virus infection and disease. Inhibition of LSD1 via treatment of animals with the monoamine oxidase inhibitor tranylcypromine results in suppression of viral lytic infection, subclinical shedding, and reactivation from latency in vivo . Phenotypic suppression is correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Given the expanding development of epipharmaceuticals, this approach has substantial potential for anti-herpetic treatments with distinct advantages over the present pharmaceutical options.

LSD1 was described as an FAD-dependent MAO homolog by Shi et al. in 2004 as the first histone demethylase [1], confirming that histone methylation is a reversible epigenetic mark. LSD1 possesses three main domains containing the N-terminal SWIRM domain, the C-terminal AOL catalytic domain and a central tower domain that contains the binding sites for the following interacting proteins: CoREST, CtBP1, HDAC1/2 and Snail1 [2]. LSD1 is capable of demethylating mono- and dimethyl H3K4 and H3K9 [1,2], although more recently it has been shown that the neuron-specific isoform LSD1n has a different substrate, histone H4K20 [3]. Moreover, several nonhistone proteins, such as p53, E2F1, DNMT and MYPT1, have been reported as LSD1 substrates [4]. LSD1 can also interact with several transcription factors that modulate LSD1 involvement in different biological contexts [4]. LSD1 is currently studied mainly in cancer, but due to its wide biological role, its dysfunction is more and more investigated also in neurodegenerative diseases, protein conformation disorders, inflammation, adipogenesis, muscle differentiation, cardiovascular diseases and in viral infections and latency [4]. DNA viruses are encapsulated without histones, but rapidly acquire chromatin structure upon infection [5], making it feasible that a histone methyltransferase or demethylase could be involved in the regulation of DNA virus replication. In the last years, a number of studies confirmed that inhibition of LSD1 can block viral genome transcription and replication of DNA viruses. In contrast, RNA viruses do not rely on chromatin structure and histone capsid for their replication. As a result, LSD1 is believed to possess little influence on RNA virus replication via histone demethylation. Nevertheless, it cannot be ruled out that LSD1 downregulates RNA virus replication via the demethylation of other host or viral proteins [5].

https://www.tandfonline.com/doi/pdf/10.4155/fmc-2018-0065