scholarly journals Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8+T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge

2014 ◽  
Vol 89 (1) ◽  
pp. 83-96 ◽  
Author(s):  
Nicolas Çuburu ◽  
Kening Wang ◽  
Kyle N. Goodman ◽  
Yuk Ying Pang ◽  
Cynthia D. Thompson ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Neutralizing Antibodies ◽  
Viral Shedding ◽  
Monophosphoryl Lipid A ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Genital Tissue

ABSTRACTNo herpes simplex virus 2 (HSV-2) vaccine has been licensed for use in humans. HSV-2 glycoproteins B (gB) and D (gD) are targets of neutralizing antibodies and T cells, but clinical trials involving intramuscular (i.m.) injection of HSV-2 gB and gD in adjuvants have not been effective. Here we evaluated intravaginal (ivag) genetic immunization of C57BL/6 mice with a replication-defective human papillomavirus pseudovirus (HPV PsV) expressing HSV-2 gB (HPV-gB) or gD (HPV-gD) constructs to target different subcellular compartments. HPV PsV expressing a secreted ectodomain of gB (gBsec) or gD (gDsec), but not PsV expressing a cytoplasmic or membrane-bound form, induced circulating and intravaginal-tissue-resident memory CD8+T cells that were able to secrete gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) as well as moderate levels of serum HSV neutralizing antibodies. Combined immunization with HPV-gBsec and HPV-gDsec (HPV-gBsec/gDsec) vaccines conferred longer survival after vaginal challenge with HSV-2 than immunization with HPV-gBsec or HPV-gDsec alone. HPV-gBsec/gDsec ivag vaccination was associated with a reduced severity of genital lesions and lower levels of viral shedding in the genital tract after HSV-2 challenge. In contrast, intramuscular vaccination with a soluble truncated gD protein (gD2t) in alum and monophosphoryl lipid A (MPL) elicited high neutralizing antibody titers and improved survival but did not reduce genital lesions and viral shedding. Vaccination combining ivag HPV-gBsec/gDsec and i.m. gD2t-alum-MPL improved survival and reduced genital lesions and viral shedding. Finally, high levels of circulating HSV-2-specific CD8+T cells, but not serum antibodies, correlated with reduced viral shedding. Taken together, our data underscore the potential of HPV PsV as a platform for a topical mucosal vaccine to control local manifestations of primary HSV-2 infection.IMPORTANCEGenital herpes is a highly prevalent chronic disease caused by HSV infection. To date, there is no licensed vaccine against HSV infection. This study describes intravaginal vaccination with a nonreplicating HPV-based vector expressing HSV glycoprotein antigens. The data presented in this study underscore the potential of HPV-based vectors as a platform for the induction of genital-tissue-resident memory T cell responses and the control of local manifestations of primary HSV infection.

scholarly journals Comparative Efficacy and Immunogenicity of Replication-Defective, Recombinant Glycoprotein, and DNA Vaccines for Herpes Simplex Virus 2 Infections in Mice and Guinea Pigs

2005 ◽  
Vol 79 (1) ◽  
pp. 410-418 ◽  
Author(s):  
Yo Hoshino ◽  
Sarat K. Dalai ◽  
Kening Wang ◽  
Lesley Pesnicak ◽  
Tsz Y. Lau ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Guinea Pigs ◽  
Lipid A ◽  
Neutralizing Antibody ◽  
Wild Type Virus ◽  
Monophosphoryl Lipid A ◽  
Plasmid Vaccine ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

ABSTRACT Many candidate vaccines are effective in animal models of genital herpes simplex virus type 2 (HSV-2) infection. Among them, clinical trials showed moderate protection from genital disease with recombinant HSV-2 glycoprotein D (gD2) in alum-monophosphoryl lipid A adjuvant only in HSV women seronegative for both HSV-1 and HSV-2, encouraging development of additional vaccine options. Therefore, we undertook direct comparative studies of the prophylactic and therapeutic efficacies and immunogenicities of three different classes of candidate vaccines given in four regimens to two species of animals: recombinant gD2, a plasmid expressing gD2, and dl5-29, a replication-defective strain of HSV-2 with the essential genes UL5 and UL29 deleted. Both dl5-29 and gD2 were highly effective in attenuating acute and recurrent disease and reducing latent viral load, and both were superior to the plasmid vaccine alone or the plasmid vaccine followed by one dose of dl5-29. dl5-29 was also effective in treating established infections. Moreover, latent dl5-29 virus could not be detected by PCR in sacral ganglia from guinea pigs vaccinated intravaginally. Finally, dl5-29 was superior to gD2 in inducing higher neutralizing antibody titers and the more rapid accumulation of HSV-2-specific CD8+ T cells in trigeminal ganglia after challenge with wild-type virus. Given its efficacy, its defectiveness for latency, and its ability to induce rapid, virus-specific CD8+-T-cell responses, the dl5-29 vaccine may be a good candidate for early-phase human trials.

scholarly journals Griffithsin and Carrageenan Combination To Target Herpes Simplex Virus 2 and Human Papillomavirus

2015 ◽  
Vol 59 (12) ◽  
pp. 7290-7298 ◽  
Author(s):  
Keith Levendosky ◽  
Olga Mizenina ◽  
Elena Martinelli ◽  
Ninochka Jean-Pierre ◽  
Larisa Kizima ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Broad Spectrum ◽  
Receptor Internalization ◽  
Target Cells ◽  
Combination Product ◽  
Viral Attachment ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

ABSTRACTExtensive preclinical evaluation of griffithsin (GRFT) has identified this lectin to be a promising broad-spectrum microbicide. We set out to explore the antiviral properties of a GRFT and carrageenan (CG) combination product against herpes simplex virus 2 (HSV-2) and human papillomavirus (HPV) as well as determine the mechanism of action (MOA) of GRFT against both viruses. We performed the experiments in different cell lines, using time-of-addition and temperature dependence experiments to differentiate inhibition of viral attachment from entry and viral receptor internalization. Surface plasmon resonance (SPR) was used to assess GRFT binding to viral glycoproteins, and immunoprecipitation and immunohistochemistry were used to identify the specific glycoprotein involved. We determined the antiviral activity of GRFT against HSV-2 to be a 50% effective concentration (EC50) of 230 nM and provide the first evidence that GRFT has moderate anti-HPV activity (EC50= 0.429 to 1.39 μM). GRFT blocks the entry of HSV-2 and HPV into target cells but not the adsorption of HSV-2 and HPV onto target cells. The results of the SPR, immunoprecipitation, and immunohistochemistry analyses of HSV-2 combined suggest that GRFT may block viral entry by binding to HSV-2 glycoprotein D. Cell-based assays suggest anti-HPV activity through α6integrin internalization. The GRFT-CG combination product but not GRFT or CG alone reduced HSV-2 vaginal infection in mice when given an hour before challenge (P= 0.0352). While GRFT significantly protected mice against vaginal HPV infection when dosed during and after HPV16 pseudovirus challenge (P< 0.026), greater CG-mediated protection was afforded by the GRFT-CG combination for up to 8 h (P< 0.0022). These findings support the development of the GRFT-CG combination as a broad-spectrum microbicide.

scholarly journals Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings From a Randomized Trial

2017 ◽  
Vol 215 (6) ◽  
pp. 856-864 ◽  
Author(s):  
David I. Bernstein ◽  
Anna Wald ◽  
Terri Warren ◽  
Kenneth Fife ◽  
Stephen Tyring ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Genital Herpes ◽  
Therapeutic Vaccine ◽  
Neutralizing Antibody ◽  
Serious Adverse Events ◽  
Viral Shedding ◽  
Dose Number ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

Abstract Background. Genital herpes simplex virus type 2 (HSV-2) infection causes recurrent lesions and frequent viral shedding. GEN-003 is a candidate therapeutic vaccine containing HSV-2 gD2∆TMR and ICP4.2, and Matrix-M2 adjuvant. Methods. Persons with genital herpes were randomized into 3 dose cohorts to receive 3 intramuscular doses 21 days apart of 10 µg, 30 µg, or 100 µg of GEN-003, antigens without adjuvant, or placebo. Participants obtained genital swab specimens twice daily for HSV-2 detection and monitored genital lesions for 28-day periods at baseline and at intervals after the last dose. Results. One hundred and thirty-four persons received all 3 doses. Reactogenicity was associated with adjuvant but not with antigen dose or dose number. No serious adverse events were attributed to GEN-003. Compared with baseline, genital HSV-2 shedding rates immediately after dosing were reduced with GEN-003 (from 13.4% to 6.4% for 30 μg [P &lt; .001] and from 15.0% to 10.3% for 100 µg [P &lt; .001]). Lesion rates were also significantly (P &lt; .01) reduced immediately following immunization with 30 µg or 100 µg of GEN-003. GEN-003 elicited increases in antigen binding, virus neutralizing antibody, and T-cell responses. Conclusions. GEN-003 had an acceptable safety profile and stimulated humoral and cellular immune responses. GEN-003 at doses of 30 µg and 100 µg reduced genital HSV shedding and lesion rates. Clinical Trials Registration. NCT01667341 (funded by Genocea).

scholarly journals Herpes Simplex Virus-2 Glycoprotein Interaction with HVEM Influences Virus-Specific Recall Cellular Responses at the Mucosa

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Sarah J. Kopp ◽  
Christopher S. Storti ◽  
William J. Muller
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Acute Infection ◽  
Surface Expression ◽  
Inverse Association ◽  
Wild Type ◽  
Recall Response ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2

Infection of susceptible cells by herpes simplex virus (HSV) requires the interaction of the HSV gD glycoprotein with one of two principal entry receptors, herpes virus entry mediator (HVEM) or nectins. HVEM naturally functions in immune signaling, and the gD-HVEM interaction alters innate signaling early after mucosal infection. We investigated whether the gD-HVEM interaction during priming changes lymphocyte recall responses in the murine intravaginal model. Mice were primed with attenuated HSV-2 expressing wild-type gD or mutant gD unable to engage HVEM and challenged 32 days later with virulent HSV-2 expressing wild-type gD. HSV-specific CD8+T cells were decreased at the genital mucosa during the recall response after priming with virus unable to engage HVEM but did not differ in draining lymph nodes. CD4+T cells, which are critical for entry of HSV-specific CD8+T cells into mucosa in acute infection, did not differ between the two groups in either tissue. An inverse association between Foxp3+CD4+regulatory T cells and CD8+infiltration into the mucosa was not statistically significant. CXCR3 surface expression was not significantly different among different lymphocyte subsets. We conclude that engagement of HVEM during the acute phase of HSV infection influences the antiviral CD8+recall response by an unexplained mechanism.

scholarly journals The Vaginal Acquisition and Dissemination of HIV-1 Infection in a Novel Transgenic Mouse Model Is Facilitated by Coinfection with Herpes Simplex Virus 2 and Is Inhibited by Microbicide Treatment

2015 ◽  
Vol 89 (18) ◽  
pp. 9559-9570 ◽  
Author(s):  
Kieran Seay ◽  
Nazanin Khajoueinejad ◽  
Jian Hua Zheng ◽  
Patrick Kiser ◽  
Christina Ochsenbauer ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mouse Model ◽  
Genital Tract ◽  
Epidemiological Studies ◽  
Preexposure Prophylaxis ◽  
Simplex Virus ◽  
Herpes Simplex Virus 2 ◽  
Hiv 1

ABSTRACTEpidemiological studies have demonstrated that herpes simplex virus 2 (HSV-2) infection significantly increases the risk of HIV-1 acquisition, thereby contributing to the expanding HIV-1 epidemic. To investigate whether HSV-2 infection directly facilitates mucosal HIV-1 acquisition, we used our transgenic hCD4/R5/cT1 mouse model which circumvents major entry and transcription blocks preventing murine HIV-1 infection by targeting transgenic expression of human CD4, CCR5, and cyclin T1 genes to CD4+T cells and myeloid-committed cells. Productive infection of mucosal leukocytes, predominantly CD4+T cells, was detected in all hCD4/R5/cT1 mice intravaginally challenged with an HIV-1 infectious molecular clone, HIV-Du151.2env-NLuc, which expresses anenvgene (C.Du151.2) cloned from an acute heterosexually infected woman and a NanoLuc luciferase reporter gene. Lower genital tract HIV-1 infection after HIV-Du151.2env-NLuc intravaginal challenge was increased ∼4-fold in hCD4/R5/cT1 mice coinfected with HSV-2. Furthermore, HIV-1 dissemination to draining lymph nodes was detected only in HSV-2-coinfected mice. HSV-2 infection stimulated local infiltration and activation of CD4+T cells and dendritic cells, likely contributing to the enhanced HIV-1 infection and dissemination in HSV-2-coinfected mice. We then used this model to demonstrate that a novel gel containing tenofovir disoproxil fumarate (TDF), the more potent prodrug of tenofovir (TFV), but not the TFV microbicide gel utilized in the recent CAPRISA 004, VOICE (Vaginal and Oral Interventions to Control the Epidemic), and FACTS 001 clinical trials, was effective as preexposure prophylaxis (PrEP) to completely prevent vaginal HIV-1 infection in almost half of HSV-2-coinfected mice. These results also support utilization of hCD4/R5/cT1 mice as a highly reproducible immunocompetent preclinical model to evaluate HIV-1 acquisition across the female genital tract.IMPORTANCEMultiple epidemiological studies have reported that genital herpes simplex virus 2 (HSV-2) infection increases the risk of HIV-1 sexual acquisition by severalfold. Understanding the underlying mechanisms by which HSV-2 facilitates HIV-1 infection and optimizing the efficacy of therapies to inhibit HIV-1 infection during HSV-2 coinfection should contribute to reducing HIV-1 transmission. Using our novel transgenic hCD4/R5/cT1 mouse model infectible with HIV-1, we demonstrated that HSV-2 infection enhances vaginal transmission and dissemination of HIV-1 infection while stimulating recruitment and activation of CD4+T cells and dendritic cells in the lower genital tract. HIV acquisition by hCD4/R5/cT1 mice vaginally coinfected with HSV-2 could be completely prevented in almost half the mice by preexposure prophylaxis (PrEP) with a novel gel containing tenofovir disoproxil fumarate (TDF), the tenofovir prodrug, but not with the tenofovir microbicide gel utilized in CAPRISA-004, VOICE, and FACTS-001 clinical trials. The hCD4/R5/cT1 mice represent a new preclinical mouse model to evaluate vaginal HIV-1 acquisition.

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