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Generation of a Dual-Target, Safe, Inexpensive Microbicide that Protects Against HIV-1 and HSV-2 Disease.

ABSTRACT: HSV-2 infection is a significant health problem and a major co-morbidity factor for HIV-1 acquisition, increasing risk of infection 2-4 fold. Condom based prevention strategies for HSV-2 and HIV-1 have not been effective at stopping the HIV-1 pandemic, indicating that alternative prevention strategies need to be investigated. We have previously developed an inexpensive HIV-1 specific microbicide that utilizes the S-layer mediated display capabilities of Caulobacter crescentus, and have shown that recombinant C. crescentus displaying HIV entry blocking proteins are able to provide significant protection from HIV-1 infection in vitro. Here we demonstrate that recombinant C. crescentus are safe for topical application and describe 5 new recombinant C. crescentus that provide protection from HIV-1 infection in vitro. Further, we demonstrate protection from disease following intravaginal infection with HSV-2 in a murine model using C. crescentus expressing the anti-viral lectins Cyanovirin-N and Griffithsin, as well as ?-1-antitrypsin and indolicidin. Interestingly, C. crescentus alone significantly reduced HSV-2 replication in vaginal lavage fluid. Protection from HSV-2 disease was strongly associated with early cytokine production in the vaginal tract. Our data support the potential for a dual-target microbicide that can protect against both HIV-1 and HSV-2, which could have an enormous impact on public health.

SUBMITTER: Farr Zuend C

PROVIDER: S-EPMC5809452 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Generation of a Dual-Target, Safe, Inexpensive Microbicide that Protects Against HIV-1 and HSV-2 Disease.

Farr Zuend Christina C Nomellini John F JF Smit John J Horwitz Marc S MS

Scientific reports 20180212 1

HSV-2 infection is a significant health problem and a major co-morbidity factor for HIV-1 acquisition, increasing risk of infection 2-4 fold. Condom based prevention strategies for HSV-2 and HIV-1 have not been effective at stopping the HIV-1 pandemic, indicating that alternative prevention strategies need to be investigated. We have previously developed an inexpensive HIV-1 specific microbicide that utilizes the S-layer mediated display capabilities of Caulobacter crescentus, and have shown tha ...[more]

PMID: 29434285

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Project description:ObjectivesTo prepare for future HIV prevention trials, we conducted prospective cohort studies among women working in food and recreational facilities in northern Tanzania. We examined the prevalence and incidence of HIV and HSV-2, and associated risk factors.MethodsWomen aged 18-44 years working in food and recreational facilities were screened to determine their eligibility for the studies. Between 2008-2010, HIV-negative women were enrolled and followed for 12 months. At enrolment and 3-monthly, we collected socio-demographic and behavioural data, and performed clinical examinations for collection of biological specimens that were tested for reproductive tract infections. Risk factors for HIV and HSV-2 incidence were investigated using Poisson regression models.ResultsWe screened 2,229 and enrolled 1,378 women. The median age was 27 years (interquartile range, IQR 22, 33), and median duration working at current facility was 2 years. The prevalences of HIV at screening and HSV-2 at enrolment were 16% and 67%, respectively. Attendance at the 12-month visit was 86%. HIV and HSV-2 incidence rates were 3.7 (95% confidence interval, CI: 2.8,5.1) and 28.6 (95% CI: 23.5,35.0)/100 person-years, respectively. Women who were separated, divorced, or widowed were at increased risk of HIV (adjusted incidence rate ratio, aRR?=?6.63; 95% CI: 1.97,22.2) and HSV-2 (aRR?=?2.00; 95% CI: 1.15,3.47) compared with married women. Women reporting ?3 partners in the past 3 months were at higher HIV risk compared with women with 0-1 partner (aRR?=?4.75; 95% CI: 2.10,10.8), while those who had reached secondary education or above were at lower risk of HSV-2 compared with women with incomplete primary education (aRR?=?0.42; 95% CI: 0.22,0.82).ConclusionsHIV and HSV-2 rates remain substantially higher in this cohort than in the general population, indicating urgent need for effective interventions. These studies demonstrate the feasibility of conducting trials to test new interventions in this highly-mobile population.

Project description:Women need multipurpose prevention products (MPTs) that protect against sexually transmitted infections (STIs) and provide contraception. The Population Council has developed a prototype intravaginal ring (IVR) releasing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (M), zinc acetate (ZA), carrageenan (CG) and levonorgestrel (LNG) (MZCL IVR) to protect against HIV, HSV-2, HPV and unintended pregnancy. Our objective was to evaluate the anti-SHIV-RT activity of MZCL IVR in genital mucosa. First, macaque vaginal tissues were challenged with SHIV-RT in the presence of (i) MIV-150 ± LNG or (ii) vaginal fluids (VF); available from studies completed earlier) collected at various time points post insertion of MZCL and MZC IVRs. Then, (iii) MZCL IVRs (vs. LNG IVRs) were inserted in non-Depo Provera-treated macaques for 24h and VF, genital biopsies, and blood were collected and tissues were challenged with SHIV-RT. Infection was monitored with one step SIV gag qRT-PCR or p27 ELISA. MIV-150 (LCMS/MS, RIA), LNG (RIA) and CG (ELISA) were measured in different compartments. Log-normal generalized mixed linear models were used for analysis. LNG did not affect the anti-SHIV-RT activity of MIV-150 in vitro. MIV-150 in VF from MZC/MZCL IVR-treated macaques inhibited SHIV-RT in vaginal mucosa in a dose-dependent manner (p<0.05). MIV-150 in vaginal tissue from MZCL IVR-treated animals inhibited ex vivo infection relative to baseline (96%; p<0.0001) and post LNG IVR group (90%, p<0.001). No MIV-150 dose-dependent protection was observed, likely because of high MIV-150 concentrations in all vaginal tissue samples. In cervical tissue, MIV-150 inhibited infection vs. baseline (99%; p<0.05). No cervical tissue was available for MIV-150 measurement. Exposure to LNG IVR did not change tissue infection level. These observations support further development of MZCL IVR as a multipurpose prevention technology to improve women's sexual and reproductive health.

Project description:Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).

Dataset Information

Generation of a Dual-Target, Safe, Inexpensive Microbicide that Protects Against HIV-1 and HSV-2 Disease.

Publications

Generation of a Dual-Target, Safe, Inexpensive Microbicide that Protects Against HIV-1 and HSV-2 Disease.

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