Multipurpose prevention technologies: the future of HIV and STI protection

Fernández-Romero, José A.; Deal, Carolyn D.; Herold, Betsy C.; Schiller, John T.; Patton, Dorothy L.; Zydowsky, Thomas M.; Romano, Joseph; Petro, Christopher D.; Narasimhan, Manjulaa

doi:10.1016/j.tim.2015.02.006

Cited by 67 publications

(60 citation statements)

References 57 publications

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“…In support of earlier data demonstrating that anti-HIV-1 (cellbased assays), anti-SHIV-RT (macaque vaginal explants), and anti-HSV-2 (murine model) activity of PC-1005 and anti-HPV activity (murine model) of CG is maintained in the presence of biological fluids (SP) (14,20,22,23;Kenney et al,unpublished), PC-1005 was active against HIV-1 BaL and HSV-2 in human ectocervical explants in the presence of vaginal fluids. Infection levels were inversely correlated with MIV-150 levels (HIV-1) and CG (HSV-2) levels in the CVLs.…”

Section: Figsupporting

confidence: 85%

“…PC-1005 is the only microbicide gel currently being tested in clinical trials that targets HIV and two other main sexually transmitted infections (STIs): HSV-2 and HPV (23). Overall, our data point to the potent anti-HIV and anti-HSV-2 activity of PC-1005 in mucosal targets and endorse the further development of PC-1005 as a broad-spectrum on-demand microbicide.…”

Section: Figmentioning

confidence: 59%

“…Kenney Zydowsky, and N. Teleshova, submitted for publication), and its activity is not affected by SP (20). Furthermore, PC-1005 gel provides CG-mediated activity against HPV, and this activity is not compromised in the presence of SP (22,23).…”

mentioning

confidence: 97%

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In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

Villegas

Calenda

Zhang

et al. 2016

Antimicrob Agents Chemother

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Our recent phase 1 trial demonstrated that PC-1005 gel containing 50 μM MIV-150, 14 mM zinc acetate dihydrate, and carrageenan (CG) applied daily vaginally for 14 days is safe and well tolerated. Importantly, cervicovaginal lavage fluid samples (CVLs) collected 4 or 24 h after the last gel application inhibited HIV-1 and human papillomavirus (HPV) in cell-based assays in a dose-dependent manner (MIV-150 for HIV-1 and CG for HPV). Herein we aimed to determine the anti-HIV and anti-herpes simplex virus 2 (anti-HSV-2) activity of PC-1005 in human cervical explants afterin vitroexposure to the gel and to CVLs from participants in the phase 1 trial. Single HIV-1BaLinfection and HIV-1BaL–HSV-2 coinfection explant models were utilized. Coinfection with HSV-2 enhanced tissue HIV-1BaLinfection.In vitroexposure to PC-1005 protected cervical mucosa against HIV-1BaL(up to a 1:300 dilution) in single-challenge and cochallenge models. CG gel (PC-525) provided some barrier effect against HIV-1BaLat the 1:100 dilution in a single-challenge model but not in the cochallenge model. Both PC-1005 and PC-525 at the 1:100 dilution inhibited HSV-2 infection, pointing to a CG-mediated protection. MIV-150 and CG in CVLs inhibited HIV (single-challenge or cochallenge models) and HSV-2 infections in explants in a dose-dependent manner (P< 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4 h after the last gel administration was observed compared to infection detected in the presence of baseline CVLs. The anti-HIV and anti-HSV-2 activity of PC-1005 gelin vitroand CVLs in human ectocervical explants supports the further development of PC-1005 gel as a broad-spectrum on-demand microbicide.

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Section: Figsupporting

confidence: 85%

Section: Figmentioning

confidence: 59%

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In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

Villegas

Calenda

Zhang

et al. 2016

Antimicrob Agents Chemother

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“…gonorrhoeae isolates were cultured from frozen stocks stored at Ϫ80°C onto gonococcal base agar solid medium (GCB 1 , Difco, Sparks, MD) containing Kellogg's supplements I (1:100) and II (1: 1000) (30). After incubation for 18 -20 h at 37°C in a humid, 5% CO 2 atmosphere, transparent colonies with piliated or nonpiliated colony morphologies were sub-cultured onto GCB plates.…”

Section: Methodsmentioning

confidence: 99%

“…Despite current prevention and management strategies, infections caused by sexually transmitted pathogens affect hundreds of millions of women and men in both resourceconstrained and developed countries (1). Gonorrhea remains a leading public health burden with an estimated 78 million new cases annually worldwide (2).…”

mentioning

confidence: 99%

Proteomics-driven Antigen Discovery for Development of Vaccines Against Gonorrhea

Zielke

Wierzbicki

Baarda

et al. 2016

Molecular & Cellular Proteomics

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Expanding efforts to develop preventive gonorrhea vaccines is critical because of the dire possibility of untreatable gonococcal infections. Reverse vaccinology, which includes genome and proteome mining, has proven very successful in the discovery of vaccine candidates against many pathogenic bacteria. However, progress with this approach for a gonorrhea vaccine remains in its infancy. Accordingly, we applied a comprehensive proteomic platform-isobaric tagging for absolute quantification coupled with two-dimensional liquid chromatography and mass spectrometry-to identify potential gonococcal vaccine antigens. Our previous analyses focused on cell envelopes and naturally released membrane vesicles derived from four different Neisseria gonorrhoeae strains. Here, we extended these studies to identify cell envelope proteins of N. gonorrhoeae that are ubiquitously expressed and specifically induced by physiologically relevant environmental stimuli: oxygen availability, iron deprivation, and the presence of human serum. Together, these studies enabled the identification of numerous potential gonorrhea vaccine targets. Initial characterization of five novel vaccine candidate antigens that were ubiquitously expressed under these different growth conditions demonstrated that homologs of BamA (NGO1801), LptD (NGO1715), and TamA (NGO1956), and two uncharacterized proteins, NGO2054 and NGO2139, were surface exposed, secreted via naturally released membrane vesicles, and elicited bactericidal antibodies that cross-reacted with a panel of temporally and geographically diverse isolates. In addition, analysis of polymorphisms at the nucleotide and amino acid levels showed that these vaccine candidates are highly conserved among N. gonorrhoeae strains. Finally, depletion of BamA caused a loss of N. gonorrhoeae viability, suggesting it may be an essential target. Together, our data strongly support the use of proteomics-driven discovery of potential vaccine targets as a sound approach for identifying promising gonococcal antigens. Molecular & Cellular

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Pharmaceutical Approaches to HIV Treatment and Prevention

Yavuz

Morgan

Showalter

et al. 2018

Advanced Therapeutics

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Human immunodeficiency virus (HIV) infection continues to pose a major infectious disease threat worldwide. It is characterized by the depletion of CD4 + T cells, persistent immune activation, and increased susceptibility to secondary infections. Advances in the development of antiretroviral drugs and combination antiretroviral therapy have resulted in a remarkable reduction in HIV-associated morbidity and mortality. Antiretroviral therapy (ART) leads to effective suppression of HIV replication with partial recovery of host immune system and has successfully transformed HIV infection from a fatal disease to a chronic condition. Additionally, antiretroviral drugs have shown promise for prevention in HIV pre-exposure prophylaxis and treatment as prevention. However, ART is unable to cure HIV. Other limitations include drug-drug interactions, drug resistance, cytotoxic side effects, cost, and adherence. Alternative treatment options are being investigated to overcome these challenges including discovery of new molecules with increased anti-viral activity and development of easily administrable drug formulations. In light of the difficulties associated with current HIV treatment measures, and in the continuing absence of a cure, the prevention of new infections has also arisen as a prominent goal among efforts to curtail the worldwide HIV pandemic. In this review, the authors summarize currently available anti-HIV drugs and their combinations for treatment, new molecules under clinical development and prevention methods, and discuss drug delivery formats as well as associated challenges and alternative approaches for the future.

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Multipurpose prevention technologies: the future of HIV and STI protection

Cited by 67 publications

References 57 publications

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

Proteomics-driven Antigen Discovery for Development of Vaccines Against Gonorrhea

Pharmaceutical Approaches to HIV Treatment and Prevention

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