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OK, first, needed research and a bunch of other articles.

I've seen hundreds of cases of recurrent HV infections (labialis, zoster, etc.) uncomplicated by secondary infection, some of which looked horrific. But never, ever have I seen scarring as a result. I have never understood why other causes of dermal damage leave scars (e.g. burns and lacerations) but not HSV. I did a derm rotation with Lookingbill and Marks, and even they (back then) didn't have an answer (well, like most radiologists, they hedged.)

I've lived uneventfully without the explanation, just taking it on face value. But today is the day I tried to find an answer and could not.

Edited to add: In my reading, I came across one journal article that said shingles frequently leaves scars. This surprised me considerably. I've had shingles 3 times (yes, I know I'm one of those lucky ones... I also had chicken pox twice. No, I'm not immunocompromised. Yes, I was vaccinated.), and only my memory (and records) can attest to which dermatomes were involved. Am I mistaken? Are there no takers? C'mon... isn't the promise of a bit of schadenfreude worth it?

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  • Varicella virus infection can certainly leave scars. Human Herpes Virus (Herpes simplex) tends not to. I can't give a definitive answer, but I don't see any growth-factor genes in the viral genome, like you find in poxviruses. However, it is a large genome and it seems relatively understudied, so I would not be surprised if one of the genes turns out to have such function.
    – bob1
    Apr 13 at 21:58
  • @bob1 - Shingles is reactivated herpes zoster. I've never seen scars from it, whereas the first infection does leave scars. Have you a different experience? I wonder why that is. The growth factor genes idea is interesting, something I'll look at. Thanks! Apr 14 at 8:15
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    Herpes zoster = varicella virus. Shingles can certainly leave scars. I had a pretty good look at the literature and no identified growth factors other than an endothelial (vascular) growth factor. It seems herpes simplex can leave scars too - just relatively uncommon and usually observed after repeat occurrences. Generally the healing seems to be by conventional mechanisms. Still working on it.
    – bob1
    Apr 18 at 8:10
  • @bob1 _ Work quickly! Bounty expires is <24°! Apr 19 at 13:16

1 Answer 1

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+500

I apologize in advance, a lot of the papers referenced may be paywalled.

There's a lot of literature on the various Herpesviridae and it is a large pleotropic family, producing such viruses as Cytomegalovirus (CMV), Human alphaherpevirus-3(AKA Varicella-Zoster virus (VZV)/chickenpox/shingles), Human alphaherpesvirus (AKA Herpes simplex virus(HSV)/cold sores), Human herpevirus-6 (roseola/sixth disease). Obviously, many of these do not have any skin involvement at all, and so won't produce scarring. However, ZVZ in both its chickenpox and shingles forms does scar 1 (I can also personally attest to the chickenpox bit, no shingles yet), and HSV also scars 2, but often only after repeat occurrences at the same location and is a common cause of ocular scars with vision loss 3.

The genomes of the Herpesviridae are large and not fully studied. They are about 100,000- 250,000 base-pairs and contain quite a number of genes, generally in the 50-100 range, with a number of proteins being produced from secondary processing of the transcribed RNA (splicing etc). Not all proteins are fully characterized in any of the species that I can see. I have found a fairly complete description of the gene products and proteins for CMV in Van Damme and Van Loock4 (see supplementary PDF), and Cohen5 and Zerboni et al6 for HSV, and there are a number of immune modulators and apoptosis inhibitors that affect how the cell or body respond to infection.

Most notably is an interleukin 10 (IL10) homologue, vIL10 (protein UL111A in CMV), which is also found in a couple of other Herpesviridae members, but not in VZV or HSV as far as I can tell. IL10 is implicated in wound healing, but is also used for a bunch of immune response maturation processes. In addition, there are a number of proteins produced that may play roles in suppressing immune responses and activate growth factors, but are not easily identifiable as they lack structural and sequence homology to currently known ones. The current state of things for VZV is nicely reviewed in Zerboni6, linked above, but is more focussed on how these factors affect viral output rather than healing post-infection

Edited to add: One group of authors claim to have identified some fractions from cells infected with HSV that have growth-factor-like properties7, which have been sporadically looked at and published since the 1990s. In these it seems that the fractions probably contain several viral proteins that may contribute to the growth factor function, but as of 2016 no further work has been done on them. I had initially ignored these as they seemed to have not clarified exactly what was going on, but the research seems good.

1 Moffat J, Ku CC, Zerboni L, et al. VZV: pathogenesis and the disease consequences of primary infection. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 37. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47382/

2 LAWRENCE COREY, HARRY G. ADAMS, ZANE A. BROWN, et al; Genital Herpes Simplex Virus Infections: Clinical Manifestations, Course, and Complications. Ann Intern Med.1983;98:958-972. doi:10.7326/0003-4819-98-6-958

3 Whitley R, Kimberlin DW, Prober CG. Pathogenesis and disease. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 32. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47449/

4 Van Damme, E., & Van Loock, M. (2014). Functional annotation of human cytomegalovirus gene products: an update. Frontiers in microbiology, 5, 218. https://doi.org/10.3389/fmicb.2014.00218

5 Cohen J. I. (2010). The varicella-zoster virus genome. Current topics in microbiology and immunology, 342, 1–14. https://doi.org/10.1007/82_2010_10

6 Zerboni, L., Sen, N., Oliver, S. L., & Arvin, A. M. (2014). Molecular mechanisms of varicella zoster virus pathogenesis. Nature reviews. Microbiology, 12(3), 197–210. https://doi.org/10.1038/nrmicro3215

7 Lachová V, Svetlíková D, Golais F, Šupolíková M, Turianová L, Betáková T. Transforming Activity of Murine Herpesvirus 68 Putative Growth Factor Is Related to the Ability to Change Cytoskeletal Structure. Intervirology. 2016;59(3):137-142. doi: 10.1159/000453067. Epub 2017 Jan 5. PMID: 28052265.

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    Thanks for the answer, and I'm very happy to award you the bounty. The abstract to the paper by LAWRENCE et al. doesn't mention scarring. I considered genital herpes when I wrote the question and was unsure, but I can say that I had patients in my private practice with genital herpes, and, again, never saw scarring. Whitlow as well, and I had one patient who had a recurrent herpetic lesion on his left cheek for years which had been misdiagnosed as acne before I saw it. It cleared sans sequelae. I know I am only one person, and the number of patients I followed longitudinally is small... Apr 20 at 3:19
  • The Lawrence paper does mention it once in the body text: "Ulcerative lesions persisted between 4 and 15 days. Lesions on the penis and mons pubis became crusted before reepithelializing. Lesions on mucosal or moist cutaneous surfaces reepithelialized without crusting. Suppurative secondary infection of lesions was not seen in this population and residual scarring from lesions was uncommon." I saw reports of scarring in a number of other papers, with similar throw-away lines of "uncommon/infrequent" for both genital and oral. Ocular scarring much more commonly mentioned in the reports...cont
    – bob1
    Apr 20 at 3:30
  • ...but one of my children seems to have inherited my luck with herpesviruses. When I first contracted herpes labialis, I was an adult, and initially had about 8-10 cold sores/year. After a decade, they tapered off (by that I mean 6-8 episodes/year) for ~ a decade slowly decreasing to where I now only get them about 4x/yr. My now adult child as a toddler bit my lip and broke open the vessicles, and though I rushed to wash them well, had a horrific initial infection from nose to chin, and had monthly cold sores for about a decade, tapering now to about 6-8 times/yr in their fourth decade. Apr 20 at 3:31
  • ...particularly in congenital cases. I couldn't re-find where I saw it reported that recurrence was more likely to lead to scarring unfortunately.
    – bob1
    Apr 20 at 3:32
  • Oh dear, that does seem like bad luck. There's normally some (limited) sort of protective effect of repeat occurrence, and I suspect there's some fairly low-hanging fruit immunologically speaking for some research into recurrence and immune responses.
    – bob1
    Apr 20 at 3:34

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