Engineered Vaginal<i>Lactobacillus</i>Strain for Mucosal Delivery of the Human Immunodeficiency Virus Inhibitor Cyanovirin-N

Liu, Xiaowen; Lagenaur, Laurel A.; Simpson, David; Essenmacher, Kirsten; Frazier-Parker, Courtney L.; Liu, Yang; Tsai, Daniel; Rao, Srinivas S.; Hamer, Dean H.; Parks, Thomas P.; Lee, Peter P.; Xu, Qiang

doi:10.1128/aac.00493-06

Cited by 122 publications

(99 citation statements)

References 51 publications

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“…This recombinant lactobacillus bacterium has been shown to produce high levels of structurally intact r-protein, exhibiting potent antiviral activity against laboratory and primary HIV-1 isolates. For example, the 50% inhibitory concentration of this lactobacillus-derived CVN to CCR5-tropic HIV BaL is only 0.3 nM (Liu et al 2006). The development of a novel, live microbicide that employs a commensal bacteria to deliver CVN to the vaginal channel is another fascinating application of CVN (Ndesendo et al 2008).…”

Section: Expression Rcvn In E Coli and Other Commensal Bacteriamentioning

confidence: 99%

The antiviral protein cyanovirin-N: the current state of its production and applications

Xiong

Fan

Kitazato

2010

Appl Microbiol Biotechnol

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HIV/AIDS continues to spread worldwide, and most of the HIV-infected people living in developing countries have little or no access to highly active antiretroviral therapy. The development of efficient and low-cost microbicides to prevent sexual transmission of HIV should be given high priority because there is no vaccine available yet. Cyanovirin-N (CVN)is an entry inhibitor of HIV and many other viruses, and it represents a new generation of microbicide that has specific and potent activity, a different mechanism of action and unusual chemicophysical stability. In vitro and in vivo antiviral tests suggested that the anti-HIV effect of CVN is stronger than a well-known gp120-targeted antibody (2G12) and another microbicide candidate, PRO2000. CVN is a cyanobacteria-derived protein that has special structural features, making the artificial production of this protein very difficult. In order to develop an efficient and relatively low cost approach for large scale production of recombinant CVN to satisfy medical use, this protein has been expressed in many systems by trial-and-error. Here, to summarize the potential, and remaining challenges, for the development of this protein into an HIV prevention agent, the progress in the structural mechanism determination, heterologous production, and pharmacological evaluation of CVN is reviewed.

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Section: Expression Rcvn In E Coli and Other Commensal Bacteriamentioning

confidence: 99%

The antiviral protein cyanovirin-N: the current state of its production and applications

Xiong

Fan

Kitazato

2010

Appl Microbiol Biotechnol

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“…RANTES expression plasmids were constructed based on p1063, modified from Escherichia coli/Lactobacillus shuttle vector pOsel175 (16). The expression cassette contains the native ptsH promoter, the signal sequence of the Lactobacillus crispatus S-layer protein CbsA, necessary for secretion of the recombinant protein into the culture medium (4), and the RANTES variant cDNAs or their codon-optimized versions encoding amino acids (aa) 1 to 68.…”

Section: Methodsmentioning

confidence: 99%

“…This Lactobacillus strain has proven to be ideal for its efficient growth and transformation characteristics, and its genome has been fully sequenced to facilitate comprehension and exploitation of regulatory elements, such as promoters and suitable sites for chromosomal integration (16). A modified version of plasmid pOsel175 was used for the construction of wt and C1C5 RANTES expression vectors employing a strong native ptsH promoter (16).…”

Section: Engineering Of L Jensenii To Produce Rantes Variantsmentioning

confidence: 99%

“…HIV-1 entry into target cells is an important arena for inhibitors aimed at preventing virus infection, and several proteins interfering with this process have been produced by recombinant commensal bacteria (3,4,9,(15)(16)(17)(26)(27)(28). Given the dependence of most wild HIV-1 isolates on CCR5 for entry (19), RANTES has attracted particular interest in the field of live microbicides.…”

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Engineering of Lactobacillus jensenii To Secrete RANTES and a CCR5 Antagonist Analogue as Live HIV-1 Blockers

Vangelista

Secchi

Liu³

et al. 2010

Antimicrob Agents Chemother

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“…An interesting utilization of the innate microflora system with respect to microbicides is their application as a vehicle for sustained release of drug candidates. Use of genetically modified innate vaginal bacteria which secrete anti-HIV agents as microbicide drug candidates is in early development (39,40). However, their incorporation into product formulations has been challenging.…”

Section: Physiology Of the Vagina And Barriers To Drug Deliverymentioning

confidence: 99%

Vaginal Drug Delivery Systems for HIV Prevention

Rohan

Sassi

2009

AAPS J

141

130

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Abstract. Microbicides have become a principal focus for HIV prevention strategies. The successful design of drug delivery systems for vaginal microbicide drug candidates brings with it a multitude of challenges. It is imperative that the chemical and physical characteristics of the drug candidate and its mechanism of action be clearly understood and considered to successfully deliver and target drug candidates efficiently. In addition, an understanding of the dynamic nature of the vaginal environment, the tissue and innate barriers present, as well as patient preferences are critical considerations in the design of effective microbicide products. Although the majority of drug candidates clinically evaluated to date have been delivered using conventional semisolid aqueous-based gel dosage forms, drug delivery system design has recently been extended to include advanced delivery systems such as vaginal rings, quick-dissolve films, and tablets. Ultimately, it may be necessary to develop multiple dosage platforms for a single active agent to provide users with options that can be used within the constraints of their social environment, personal choice, and environmental conditions.

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Engineered VaginalLactobacillusStrain for Mucosal Delivery of the Human Immunodeficiency Virus Inhibitor Cyanovirin-N

Cited by 122 publications

References 51 publications

The antiviral protein cyanovirin-N: the current state of its production and applications

The antiviral protein cyanovirin-N: the current state of its production and applications

Engineering of Lactobacillus jensenii To Secrete RANTES and a CCR5 Antagonist Analogue as Live HIV-1 Blockers

Vaginal Drug Delivery Systems for HIV Prevention

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