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Prophylactic treatment with BX795 blocks activation of AKT and its downstream targets to protect vaginal keratinocytes and vaginal epithelium from HSV-2 infection.

ABSTRACT: Genital herpes infections in humans are usually caused by herpes simplex virus type-2 (HSV-2), which result in recurrent lesions in the anogenital region. Past studies have shown that a viral protein translation inhibitor, BX795 is capable of mitigating HSV-2 infection both in vitro and in vivo when dosed therapeutically. However, any preventative benefits of this compound against HSV-2 infection remain poorly understood. In this study, we show that BX795 when added prophylactically to human vaginal keratinocytes generates strong preventative effects against a future HSV-2 infection. As a possible mechanism for this action, we found that BX795 efficiently reduces phosphorylation of AKT and its downstream targets p70S6K and 4EBP1. Our in-silico protein docking studies support our immunoblotting results and provide further credence to the proposed mechanism. Using a murine model of vaginal infection, we show that prior treatment with BX795 is also protective in vivo and leads to lower viral replication in the vaginal tissue.

SUBMITTER: Madavaraju K

PROVIDER: S-EPMC8446323 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Prophylactic treatment with BX795 blocks activation of AKT and its downstream targets to protect vaginal keratinocytes and vaginal epithelium from HSV-2 infection.

Madavaraju Krishnaraju K Yadavalli Tejabhiram T Singh Sudhanshu Kumar SK Qatanani Farreh F Shukla Deepak D

Antiviral research 20210722

Genital herpes infections in humans are usually caused by herpes simplex virus type-2 (HSV-2), which result in recurrent lesions in the anogenital region. Past studies have shown that a viral protein translation inhibitor, BX795 is capable of mitigating HSV-2 infection both in vitro and in vivo when dosed therapeutically. However, any preventative benefits of this compound against HSV-2 infection remain poorly understood. In this study, we show that BX795 when added prophylactically to human vag ...[more]

PMID: 34303747

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Project description:BX795 is a TANK binding kinase-1 inhibitor that has shown excellent therapeutic activity in murine models of genital and ocular herpes infections on topical delivery. Currently, only the BX795 free base and its hydrochloride salt are available commercially. Here, we evaluate the ability of various organic acids suitable for vaginal and/or ocular delivery to form BX795 salts/cocrystals/co-amorphous systems with the aim of facilitating pharmaceutical development of BX795. We characterized BX795-organic acid coevaporates using powder X-ray diffractometry, Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, 1H-nuclear magnetic resonance spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to elucidate the interaction between BX795 and various organic acids such as taurine, maleic acid, fumaric acid, tartaric acid, and citric acid. Furthermore, using human corneal epithelial cells and HeLa cells, we evaluated BX795-organic acid coevaporates for in vitro cytocompatibility and in vitro antiviral activity against herpes simplex virus-type 1 (HSV-1) and type-2 (HSV-2). Our studies indicate that BX795 forms co-amorphous systems with tartaric acid and citric acid. Interestingly, the association of organic acids with BX795 improved its thermal stability. Our in vitro cytocompatibility and in vitro antiviral studies to screen suitable BX795-organic acid coevaporates for further development show that all BX795-organic acid systems, at a concentration equivalent to 10 µM BX795, retained antiviral activity against HSV-1 and HSV-2 but showed differential cytocompatibility. Further, dose-dependent in vitro cytocompatibility and antiviral activity studies on the BX795-fumaric acid system, BX795-tartaric acid co-amorphous system, and BX795-citric acid co-amorphous system show similar antiviral activity against HSV-1 and HSV-2 compared to BX795, whereas only the BX795-citric acid co-amorphous system showed higher in vitro cytocompatibility compared to BX795.

Project description:BACKGROUND:The American Congress of Obstetricians and Gynecologists recommends that "the surgeon and patient discuss the potential benefits of the removal of the fallopian tubes during a hysterectomy in women at population risk of ovarian cancer who are not having an oophorectomy," resulting in an increasing rate of salpingectomy at the time of hysterectomy. Rates of salpingectomy are highest for laparoscopic and lowest for vaginal hysterectomy. OBJECTIVE:The primary objective of this study was to determine the feasibility of bilateral salpingectomy at the time of vaginal hysterectomy. Secondary objectives included identification of factors associated with unsuccessful salpingectomy and assessment of its impact on operating time, blood loss, surgical complications, and menopausal symptoms. STUDY DESIGN:This was a multicenter, prospective study of patients undergoing planned vaginal hysterectomy with bilateral salpingectomy. Baseline medical data along with operative findings, operative time, and blood loss for salpingectomy were recorded. Uterine weight and pathology reports for all fallopian tubes were reviewed. Patients completed the Menopause Rating Scale at baseline and at postoperative follow-up. Descriptive analyses were performed to characterize the sample and compare those with successful and unsuccessful completion of planned salpingectomy using Student t test, and ?2 test when appropriate. Questionnaire scores were compared using paired t tests. RESULTS:Among 77 patients offered enrollment, 74 consented (96%), and complete data were available regarding primary outcome for 69 (93%). Mean age was 51 years. Median body mass index was 29.1 kg/m2; median vaginal parity was 2, and 41% were postmenopausal. The indications for hysterectomy included prolapse (78%), heavy menstrual bleeding (20%), and fibroids (11%). When excluding conversions to alternate routes, vaginal salpingectomy was successfully performed in 52/64 (81%) women. Mean operating time for bilateral salpingectomy was 11 (±5.6) minutes, with additional estimated blood loss of 6 (±16.3) mL. There were 8 surgical complications: 3 hemorrhages >500 mL and 5 conversions to alternate routes of surgery, but none of these were due to the salpingectomy. Mean uterine weight was 102 g and there were no malignancies on fallopian tube pathology. Among the 17 patients in whom planned bilateral salpingectomy was not completed, unilateral salpingectomy was performed in 7 patients. Reasons for noncompletion included: tubes high in the pelvis (8), conversion to alternate route for pathology (4), bowel or sidewall adhesions (3), tubes absent (1), and ovarian adhesions (1). Prior adnexal surgery (odds ratio, 2.9; 95% confidence interval, 1.5-5.5; P = .006) and uterine fibroids (odds ratio, 5.8; 95% confidence interval, 1.5-22.5; P = .02) were the only significant factors associated with unsuccessful bilateral salpingectomy. Mean menopause scores improved after successful salpingectomy (12.7 vs 8.6; P < .001). CONCLUSION:Vaginal salpingectomy is feasible in the majority of women undergoing vaginal hysterectomy and increases operating time by 11 minutes and blood loss by 6 mL. Women with prior adnexal surgery or uterine fibroids should be counseled about the possibility that removal may not be feasible.

Project description:BackgroundIn the HIV-1 vaccine trial RV144, ALVAC-HIV prime with an AIDSVAX® B/E boost reduced HIV-1 acquisition by 31% at 42 months post first vaccination. The bivalent AIDSVAX® B/E vaccine contains two gp120 envelope glycoproteins, one from the subtype B HIV-1 MN isolate and one from the subtype CRF01_AE A244 isolate. Each envelope glycoprotein harbors a highly conserved 27-amino acid HSV-1 glycoprotein D (gD) tag sequence that shares 93% sequence identity with the HSV-2 gD sequence. We assessed whether vaccine-induced anti-gD antibodies protected females against HSV-2 acquisition in RV144.MethodsOf the women enrolled in RV144, 777 vaccine and 807 placebo recipients were eligible and randomly selected according to their pre-vaccination HSV-1 and HSV-2 serostatus for analysis. Immunoglobulin G (IgG) and IgA responses to gD were determined by a binding antibody multiplex assay and HSV-2 serostatus was determined by Western blot analysis. Ninety-three percent and 75% of the vaccine recipients had anti-gD IgG and IgA responses two weeks post last vaccination, respectively. There was no evidence of reduction in HSV-2 infection by vaccination compared to placebo recipients over 78 weeks of follow-up. The annual incidence of HSV-2 infection in individuals who were HSV-2 negative at baseline or HSV-1 positive and HSV-2 indeterminate at baseline were 4.38/100 person-years (py) and 3.28/100 py in the vaccine and placebo groups, respectively. Baseline HSV-1 status did not affect subsequent HSV-2 acquisition. Specifically, the estimated odds ratio of HSV-2 infection by Week 78 for female placebo recipients who were baseline HSV-1 positive (n = 422) vs. negative (n = 1120) was 1.14 [95% confidence interval 0.66 to 1.94, p = 0.64)]. No evidence of reduction in the incidence of HSV-2 infection by vaccination was detected.ConclusionsAIDSVAX® B/E containing gD did not confer protection from HSV-2 acquisition in HSV-2 seronegative women, despite eliciting anti-gD serum antibodies.

Dataset Information

Prophylactic treatment with BX795 blocks activation of AKT and its downstream targets to protect vaginal keratinocytes and vaginal epithelium from HSV-2 infection.

Publications

Prophylactic treatment with BX795 blocks activation of AKT and its downstream targets to protect vaginal keratinocytes and vaginal epithelium from HSV-2 infection.

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