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thiscantbe

susceptibility and number of outbreaks

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thiscantbe

Nearly the whole month of July has had me becoming way too intimately acquainted with this nasty virus. I had a nasty primary outbreak complete with the whole medley of systemic symptoms as well as lesions that took forever to heal (it's not good when you have so many lesions that the dr asks if you have had surgery to your parts because you are so disfigured). I barely felt OK and then voila! I got to enjoy another outbreak, so as you can imagine I've been frustrated with my luck; it's been way more than a "minor skin condition" for me. On the other hand, the person I caught this from had no idea he was infected (and based on his sexual history he probably caught herpes close to a decade ago), and he never has noticed any symptoms, ever. Even now that he knows - which knowing can make you feel itchy and paranoid - still nada.

While I know that stress, etc play a role, I've been looking at some research articles on susceptibility cause I just want to know why this virus varies so much in different people.

There is a lot of preliminary research showing that subtle genetic differences really matter. I'm posting an abstract from a study that looked at human variation and association with lesions and shedding, and another that looked at disease susceptibility in both mouse and humans. There was also an article looking at hormone levels and susceptibility - which I guess shouldn't be a surprise! I'm also including some titles of other articles dealing with genes and susceptibility in the mouse (you can easily look up the abstracts by going to PubMed. (I have access to most of the full articles if you are really interested.)

Abstract on human genetic variation and disease severity

Bochud PY, Magaret AS, Koelle DM, Aderem A, Wald A. J Infect Dis. 2007 Aug 15;196(4):505-9. Epub 2007 Jun 29. Polymorphisms in TLR2 Are Associated with Increased Viral Shedding and Lesional Rate in Patients with Genital Herpes Simplex Virus Type 2 Infection.

Clinical and virologic manifestations of genital herpes simplex virus type 2 (HSV-2) infection vary widely. We examined frequencies of single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) 2, 3, 4, and 9 in a prospective cohort of 128 HSV-2-infected persons whose viral shedding and lesion frequency was measured by daily sampling from genital secretions. Two TLR2 haplotypes (2 and 4) were associated with increased lesional (P=.008 and P=.03) and shedding (P=.02 and P=.001) rates. An SNP in haplotype 2 (-15607A/G) was also associated with shedding (P=.01) and lesional (P=.008) rates. Polymorphisms in TLR2 may be in part responsible for differences in the severity of HSV-2 infection.

Abstract on hormone levels and susceptibility

Gillgrass AE, Fernandez SA, Rosenthal KL, Kaushic C. J Virol. 2005 Mar;79(5):3107-16. Estradiol regulates susceptibility following primary exposure to genital herpes simplex virus type 2, while progesterone induces inflammation.

We report here that sex hormones modulate susceptibility to a sexually transmitted viral agent, herpes simplex virus type 2 (HSV-2), in a mouse model. Ovariectomized mice were administered either saline (control), estradiol (E(2)), progesterone (P(4)), or a combination of both estradiol and progesterone (E+P) and infected intravaginally with HSV-2. With an inoculation dose of 10(5) PFU, the saline- and P(4)-treated mice were found to be highly susceptible to genital HSV-2 infection. Both groups had extensive pathology and high viral titers in vaginal secretions, and 100% of mice succumbed by day 4 postinfection. E(2)-treated mice were protected from HSV-2 infection at the same dose and did not display any vaginal pathology or viral shedding. There was a slow progression of genital pathology in the combination hormone-treated group, along with prolonged viral shedding; 80% of animals succumbed by day 13. With lower inoculation doses of 10(3) and 10(2) PFU, 50 and 100%, respectively, of the combination hormone-treated mice survived. Localization of HSV-2 infection showed extensive infection in the vaginal epithelium of P(4)- and saline-treated animals within 24 h of inoculation. E(2)-treated animals were clear of infection, while the E+P-treated group had focal infection at 24 h that had progressed extensively by day 3. Infection was accompanied by persistent inflammation and infiltration of neutrophils in the P(4)-treated group. An analysis of the genes in the vaginal tissue showed that inflammation in the P(4)-treated group correlated with local induction of chemokines and chemokine receptors that were absent in the E(2)-treated mice and in uninfected P(4)-treated mice. The results show that sex hormones regulate initiation of infection and immune responses to genital HSV-2 infection.

Paper with mouse research and human data to back it up

Gadjeva M et al. Clin Exp Immunol. 2004 Nov;138(2):304-11. Mannan-binding lectin modulates the response to HSV-2 infection.

Viruses have developed numerous strategies to escape recognition by the immune system. However, some viruses such as herpes simplex virus-2 (HSV-2) are recognized by initiators of the complement system, e.g. mannan-binding lectin (MBL). To study the effects of MBL deficiency during viral infection we have chosen a model of generalized HSV-2 infection. We infected MBL-A and MBL-C double knock-out mice (DKO) with HSV-2 via the intraperitoneal (i.p.) route. DKO mice cleared HSV-2 from the liver less efficiently than the comparable wild-type animals. The impairment to effectively neutralize HSV-2 correlated with compromised liver function as measured by increased plasma levels of alanine-amino transferase. No differences in the viral burden were found in other organs such as spleen or brain. Thus, MBL-mediated protection was limited to the effects of preservation of liver homeostasis. Reconstitution with recombinant human MBL before and during the HSV-2 infection dramatically lowered the viral titres in the liver. Taken together, the data show that MBL modulates the response to HSV-2 in mice by affecting neutralization of the virus. To analyse if MBL plays a role in establishment and progression of human HSV-2 infection we analysed MBL levels in the serum samples from asymptomatic (virus-exposed people who have never displayed symptoms of HSV-2 infection) and symptomatic HSV-2 patients (people with recurrent HSV-2 infections). We found that the frequency of the MBL deficiency (<100 ng/ml) was higher in the symptomatic group and significantly different from that in the asymptomatic group (P = 0.0369). This suggests that lack of MBL-mediated complement activation increases susceptibility to viral infection.

Selected Mouse papers

Thapa M, Kuziel WA, Carr DJ. J Virol. 2007 Apr;81(8):3704-13. Epub 2007 Jan 31. Susceptibility of CCR5-deficient mice to genital herpes simplex virus type 2 is linked to NK cell mobilization.

Thackray AM, Bujdoso R.. Antivir Chem Chemother. 2006;17(1):41-52. Elevated PrPC expression predisposes to increased HSV-1 pathogenicity. (I don't have access to this article).

Carr DJ, Wuest T, Tomanek L, Silverman RH, Williams BR. Immunology. 2006 Aug;118(4):520-6.The lack of RNA-dependent protein kinase enhances susceptibility of mice to genital herpes simplex virus type 2 infection.

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23andHSV

interest in article

I'd be interested in obtaining a copy of the Bochud et al paper; could you send or post it (even if temporarily)?

Though it may not help any of us in the short term, there will probably be plenty of SNP association studies coming out on this topic over the next few years.

The key will be to get more and more people to know their own genotypes, and their outbreak triggers and frequency, and then to have forums where the information (and ideas) can be shared.

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thiscantbe

if you want a copy send me a message with an email where i can mail the .pdf document to!

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