Skip Navigation LinksHome > September 2008 - Volume 3 - Issue 5 > Microbicides: chemistry, structure, and strategy
Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e32830ab9dd
Microbicides: Edited by John Kaldor and Melissa Robbiani

Microbicides: chemistry, structure, and strategy

Zydowsky, Thomas M

Free Access
Article Outline
Collapse Box

Author Information

Population Council, HIV/AIDS Program, New York, New York, USA

Correspondence to Thomas M. Zydowsky, Population Council, 1230 York Avenue, New York, NY, 10065-6307, USA Tel: +1 212 327-8746; e-mail: tzydowsky@popcouncil.org

Collapse Box

Abstract

Purpose of review: To highlight promising areas of research and preview future generations of microbicides, this review will focus on reports that described new cellular or viral targets, drug substances, or strategies that are specifically intended for topical microbicides. Those reports that dealt with the design, discovery, and synthesis of anti-HIV agents for use in oral or parenteral formulations, while important for the microbicide field, are beyond the scope of this review.

Recent findings: Drug substances intended for topical microbicides are becoming increasingly target specific and, structurally, more complex. New production methods might reduce the cost of microbicides that contain these complex molecules. Genetically engineered probiotic vaginal bacteria express an even wider range of antiviral compounds, perhaps resulting in uninterrupted, coitally independent protection. Combination microbicides that contain two or more drug substances frequently act synergistically. The discovery of new cellular targets such as syndecan-3 might lead to more effective microbicides.

Summary: Future generations of microbicides will likely contain one or more complex or highly specific drug substances, resulting in safer and more effective products. Since compliance issues continue to confound HIV and herpes simplex virus trials, efforts to bring practical, coitally independent microbicides to developing countries will become a top priority.

Back to Top | Article Outline

Introduction

From estimates of new cases of HIV infections in 2007, it appears that significant numbers of men and women in developing countries practice unprotected anal or vaginal intercourse. An estimated 1 700 000 people in sub-Saharan Africa (68% of all cases worldwide) were newly infected; an estimated 440 000 people in Asia (18% of all cases worldwide) were newly infected [1].

Condoms are readily available and effectively block the transmission of HIV, yet they are used inconsistently, if at all. Sometimes couples agree to have unprotected intercourse; more often they do not. Unable or unwilling to force the issue and left to suffer the deadly consequences of unprotected sex with an infected partner, women in developing countries desperately need a safe and effective product of their own: a microbicide.

Unfortunately for these women no approved microbicide is currently available. But the pipeline is full of interesting candidates, and perhaps an approved microbicide will be based on a finding described in this review.

Back to Top | Article Outline

Microbicide classes

Microbicides fall into one of three general classes: nonspecific, moderately specific, and HIV-specific [2•]. Nonspecific microbicides contain detergents or buffering agents; moderately specific microbicides contain anionic polymers, dendrimers, or small polyanionic molecules. Both frequently target more than one pathogen. The HIV-specific microbicides contain entry, fusion, integrase, or reverse transcriptase inhibitors, targeting only HIV. Irrespective of its class, a microbicide must not only be safe and effective, but also affordable to citizens or governments of developing nations.

Back to Top | Article Outline

Moderately specific microbicides

Polysulfonated porphyrins and phthalocyanines were previously shown to have anti-HIV activity, inhibiting cell fusion and blocking gp120 binding to CD4 [3]. At microgram per milliliter concentrations, selected analogs were recently shown to inhibit transmission of cell-associated HIV, to inactivate a range of R5 and X4 tropic viruses, and to inhibit a dextran sulfate-resistant virus [4•]. They also remained active over a range of pH values, lacked activity against probiotic vaginal bacteria, and blocked infection when target cells were pretreated with compound. The inhibitors are either commercially available or readily synthesized from commercially available precursors, and merit further investigation.

The persulfated molecular umbrella, Spm8CHAS, was previously shown to inhibit HIV and herpes simplex virus (HSV) infections [5]. In a follow-up report, microgram per milliliter concentrations of Spm8CHAS were shown to inhibit lab and clinical R5 and X4 HIV strains in cell-culture, to protect ectocervical tissue explants exposed to HIV-1, and to abolish transfer of virus to target T cells [6•]. If present throughout the infection, it inhibited HSV-2 infection of epithelial cells, retaining significant activity when administered following HSV entry. When co-administered with HIV-specific reverse transcriptase inhibitors in vitro, Spm8CHAS exhibited enhanced activity against HIV-1 and retained activity against HSV-2. It showed no toxicity to cells or explants when tested alone or in combination with reverse transcriptase inhibitors. A labeled analog of Spm8CHAS crossed the plasma cell membrane, concentrating in the nucleus. Given its interesting biological properties and ease of synthesis, Spm8CHAS warrants testing in a microbicide formulation.

Another persulfated compound with anti-HIV activity was further characterized [7•]. At low micromolar concentrations, sodium rutin sulfate (SRS) was active against a range of X4 and R5 isolates of HIV; at 10-fold higher concentrations, it was active against HSV. Adorned with 10 sulfate groups, SRS presumably mimics the anionic polymers, blocking viral entry by binding to an HIV-1 envelope glycoprotein. At low millimolar concentrations, SRS showed no adverse effects on three cultured human cell lines or on vaginal lactobacilli. SRS is available in one step from commercially available rutin, so a topical microbicide containing SRS can be evaluated easily. Moreover, many rutin analogs are available, so a persulfated compound with even better properties than SRS might be discovered.

Combination microbicides comprising the anionic polymers dextran sulfate or PRO2000 (Indevus Pharmaceuticals, Lexington, Massachusetts, USA) and IgG1b12, T20, TAK779, or cyanovirin-N (CV-N) were evaluated in U87.CD4.CCR5/CXCR4 cells and peripheral blood mononuclear cells (PBMCs) [8]. Both polymers showed inhibitor and dose-dependent synergy with most of the inhibitors tested. These results provide additional support for the notion that combination microbicides may be superior to single agent formulations.

Back to Top | Article Outline

Classes of entry (adsorption/fusion) inhibitors

Entry inhibitors can be divided into two classes: those that block viral structures (e.g., gp120 and gp41) and those that block target cell structures (e.g., CXCR4 and CCR5) [9•].

Back to Top | Article Outline

Small molecule entry inhibitors that block viral structures

The inhibitory mechanism of DCM205, a geminal disulfone previously shown to have potent and selective anti-HIV-1 activity, was elucidated [10•]. Competition studies showed that DCM205 inactivated HIV-1 in the absence of a cellular target, binding at or near the V3 loop of gp120. Given its ease of synthesis and potent activity (nanomolar to low micromolar) against a range of X4, R5, and dual-tropic lab-adapted and primary strains of HIV-1, DCM205 is an interesting candidate for a topical microbicide.

Back to Top | Article Outline

Peptide entry inhibitors that block viral structures

A series of potent D-peptide inhibitors that specifically target the highly conserved gp41 N-trimer pocket have been reported [11•]. Modified mirror-image phage display and structure-assisted design were used to discover inhibitors that were up to 40 000 times more potent than previously reported D-peptide HIV-1 inhibitors. The most potent analog, a trimeric D-peptide crosslinked with polyethylene glycol (PEG), had an IC50 value of 250 pM against the HXB2 strain of HIV. Some analogs were also active against primary HIV-1 strains such as BaL and JRFL. D-peptides are stable in vivo, so they might have therapeutically useful half-lives in the vagina or rectum; however, they might also be absorbed there, so problems associated with circulating drug are a potential liability.

By binding to the HR2 region of gp41, the modified retrocyclin analog, RC-101, inhibits HIV infection [12•,13•]. RC-101 has useful properties for a drug substance in a topical microbicide, preventing HIV-1 infection in a cervicovaginal tissue model and remaining in the tissues throughout the nine-day incubation period. In addition, RC-101 neither adversely affected tissue viability nor induced the release of inflammatory cytokines. The potential for HIV-1 to develop resistant mutants to RC-101 was investigated [14•]. Crucial RC-101 binding residues in HR2 were identified using in-silico docking methods. These residues were then mutagenized to form a series of single-site mutants of HIV-1, and the susceptibility of the mutant HIV-1 strains to RC-101 was measured. One mutant was partially resistant to RC-101, while the remaining mutants either retained wild-type susceptibility to RC-101 or were less able or unable to infect cells in a single-round replication assay.

Synthetic C-peptides such as C34 and T-20 inhibit HIV-1 infection and fusion by interfering with formation of the gp41 six-helix bundle. C-peptides that adopt a preformed α-helical conformation are more potent than their random-coil analogs [15]. Now a series of recombinant peptides that contain short coiled-coil segments fused to the C terminus of the gp41 C-peptide have been expressed in bacteria [16•]. One peptide, C52L, inhibited diverse HIV-1 strains in vitro at nanomolar concentrations, inhibiting T-20 resistant strains in a single-cycle infectivity assay. In addition, all peptides were noncytotoxic up to 1 μM in an MTT assay in PBMCs. C52L might be a cost-effective alternative to synthetic C-peptides.

Another C-peptide, C34, has been shown to block HIV infection of Langerhans cells in isolated epidermal explants [17•]. Consistent with its mechanism of action, C34 blocked HIV infection only when it was present during and after viral exposure. Experiments also showed that C34 blocked infection of Langerhans cells before reverse transcription and inhibited Langerhans cell-mediated viral transmission to T cells.

Back to Top | Article Outline

Carbohydrate binding agents

Carbohydrate binding agents (CBAs) have been shown to block HIV-1 infection by selectively binding mannose-rich regions in gp120 and gp41, efficiently preventing the dendritic-cell specific ICAM-3 grabbing integrin (DC-SIGN)-mediated transfer of HIV-1 to T cells [18•]. In B-lymphoblast Raji cells expressing DC-SIGN, a short preexposure of HIV-1 to CBAs blocked the binding of virus to cell surfaces. Subsequent co-cultivation of virus particles with C8166 cells resulted in no syncytia formation. Other classes of HIV-1 inhibitors are less effective or completely ineffective. CBAs have also been shown to prevent R5 HIV-1 infection of cultured primary human monocyte-derived macrophages (MDMs) [19•]. R5 and X4 HIV-1 strains that were exposed to CBAs and subsequently co-cultivated with uninfected CD4+ T-lymphocytes showed no syncytia formation.

Another CBA, CV-N, has been shown to potently inhibit HIV-1 and other viruses [20]. A protein isolated from cyanobacteria, CV-N is likely to have stability and immunogenicity issues that could limit its use in a microbicide. To overcome these problems, CV-N and several site-specific mutants were covalently bound to PEG [21•]. One analog, PEGylated [CV-N(Q62C)], retained significant anti-HIV activity in vitro and was less toxic to mice than CV-N.

The antiviral spectrum of griffithsin (GRFT), a CBA previously shown to have potent antiviral activity against lab strains and primary isolates of HIV-1 and low toxicity in cell culture, was further evaluated [22]. GRFT was shown to block rapidly X4 and R5 tropic HIV and HIV–simian immunodeficiency virus chimera (SHIV) strains at subnanomolar concentrations, remaining stable and highly active in cervical/vaginal lavage.

The plant-derived CBAs Galanthus nivalis agglutin (GNA) and Hippeastrum hybrid agglutin (HHA) were previously shown to inhibit HIV infection of T lymphocytes and PBMCs by binding to gp120 [23]. As a follow-up to that study, the effect of GNA and HHA on cellular targets such as epithelial cells and monocyte-derived dendritic cells (MDDCs) was determined [24•]. Both compounds inhibited attachment of HIV-1 BaL; HHA, but not GNA, inhibited transcytosis of HIV-1 JR-CSF in a dose-dependent manner, and only HHA was adsorbed at the epithelial cell surface. The data suggest that HHA interacts with receptors that mediate HIV-1 transcytosis. GNA and HHA partially inhibited the attachment of HIV to MDCC, and HHA inhibited more efficiently the transfer of HIV from MDDCs to T cells. In addition, both compounds were nontoxic at concentrations under 200 μg/ml and did not disrupt the epithelial cell surface monolayer.

Back to Top | Article Outline

Entry inhibitors that block target cell structures

A patent application [25] disclosed compounds that blocked the DC-SIGN mediated transmission of HIV-1 virus from mucosal sites of infection to T-lymphocytes. The compounds were shown to bind to DC-SIGN, preventing the interactions that allow HIV-1 attachment and subsequent infection to proceed. The inhibitors comprise high-mannose oligosaccharides assembled either on a scaffolding framework or on a polyacrylamide polymer backbone.

PSC-RANTES is a synthetic chemokine analog of RANTES that has shown promising activity as a topical microbicide [26]. Potentially less expensive, semi-synthetic analogs of PSC-RANTES were prepared and evaluated for anti-HIV activity [27•]. Two analogs were especially interesting; [Arg24,25,56,57]PSC-RANTES had comparable potency to PSC-RANTES, and the oxime analog, 4L-57, was five time less active. A potentially cheaper fermentation product, 5P12-RANTES, was reported to be as active as PSC-RANTES in vitro [28]. When dosed vaginally at 1 μM, it protected five of six macaques from SHIV infection.

Back to Top | Article Outline

Combinations of entry inhibitors

To define the activity of viral entry inhibitors against HIV-1, BMS-C (targets gp120), CMPD167 (targets CCR5), C52L (a peptide fusion inhibitor), and AMD3465 (X4 ligand) were tested alone, and in combination, against 41 R5, X4, and R5X4 HIV isolates in human PBMCs [29•]. For all isolates, the activity of combinations of two or three inhibitors at lower concentrations surpassed activity of a single inhibitor at higher concentrations, supporting the notion that combination microbicides provide expanded efficacy and spectrum compared to single drug substance formulations.

Back to Top | Article Outline

Inhibitors of herpes simplex virus

Since a strong link exists between infection with HSV-2 and the likelihood of acquiring or transmitting HIV, microbicides that target both HIV and HSV have been investigated [30].

Epigallocatechin gallate (EGCG) was previously shown to inhibit the binding of HIV gp120 to the CD4 receptor. Recently it was shown that EGCG also inactivates multiple clinical isolates of HSV-1 and HSV-2, directly affecting virions by interacting with one or more envelope glycoproteins [31•]. It has poor systemic absorption and is stable at vaginal pH, both useful properties for a drug substance in a topical microbicide. Moreover, EGCG is isolated from green tea, so perhaps the cost of drug substance will not be an issue.

Amphipathic DNA polymers, a class of compounds previously shown to inhibit HIV entry and binding, also have activity against HSV [32•]. One analog, REP9, is a synthetic 40mer that strongly inhibited HSV infection in vitro. REP9 and the related polyC analog, REP9C, have multiple mechanisms of action: they blocked HSV-2 binding and entry, remained active when added after entry, inhibited viral gene expression, blocked HSV-induced apoptosis, and embedded into human epithelial cells. Moreover, REP9 remained active in the presence of cervicovaginal secretions and seminal plasma, showing no cytoxicity to human cells.

Back to Top | Article Outline

Miscellaneous topics

Although receptors on DC-SIGN were known to capture HIV-1 and mediate transmission of the virus to T cells, studies had suggested that another receptor on DCs also captured virus. The other receptor was recently identified as syndecan-3, a DC-specific heparin sulfate proteoglycan that binds to gp120 [33••]. To completely inhibit HIV-1 capture and subsequent transmission of virus, both DC-SIGN and syndecan-3 must be neutralized. Therefore, a microbicide that targets both receptors might show improved efficacy over one that targets only a single receptor.

The cost to produce HIV-specific monoclonal antibodies in Chinese hamster ovary cells has limited the use of this class of inhibitors. To remove this obstacle, an alternative, potentially cheaper manufacturing platform for the anti-HIV antibody 2G12 was developed [34••]. Expressed in maize endosperm at 75 μg/g of dry seed weight, 90% pure 2G12 could be recovered after a two-step process. With the exception of its glycan structure, the maize-derived product was identical to 2G12 produced in Chinese hamster ovary cells. Moreover, it showed identical antigen-binding activity and nearly three times the efficacy in HIV-neutralization assays.

To reduce costs and maintain a continuous supply of antiviral compounds in the vagina, researchers have engineered probiotic lactobacilli to produce CV-N, three CD4D1D2-antibody-like fusion proteins, and RANTES [35,36••,37]. The lactobacilli that produced CV-N colonized macaque vaginas for over 2 months; the fusion proteins were functionally active viral inhibitors. Both discoveries bring the prospect for a living microbicide a little closer to reality.

Contraceptive microbicides that block HIV infection and prevent unwanted pregnancy have a place in developing nations [38]. The small molecule deoxycholyltyosine (DCT) was shown to possess both activities [39]. It blocks HIV-1 replication but not HIV-1 entry (IC50 = 21.5 μg/ml), inhibits sperm motility (0.12–1.0 mg/ml), and is spermicidal in the Sander–Cramer assay (MEC = 1 mg/ml). In addition, DCT showed low toxicity on the vaginal epithelium cell line VK2/E6E7.

Oligodeoxynucleotides (ODNs) and oligoribonucleotides (ORNs) or ODN/ORN chimeras that bind to the polypurine tract (PPT) of HIV and effect premature termination of cDNA were previously designed as an antiviral therapy for HIV-infected individuals [40]. Related compounds that can be used prophylactically to inactivate viruses before they infect target cells have now been disclosed [41•]. HIV pretreated with the compounds for 4 h lost its ability to infect target cells; viral RNA was destroyed and no p24 viral protein produced. The compounds target reverse transcriptase and ribonuclease H inside the virus, leading to premature cleavage of viral RNA.

Back to Top | Article Outline

Conclusion

Imaginative researchers continue to discover novel targets and drug substances, as well as cost effective methods to produce complex molecules, so future generations of microbicides will likely contain complex and highly specific drug substances. Safety and efficacy will be improved, but no microbicide can block HIV if women fail to use it consistently. Compliance can mean the difference between life and death for millions of people, so efforts to bring practical, coitally independent microbicides to the clinic must become a top priority.

Back to Top | Article Outline

References and recommended reading

Back to Top | Article Outline

Papers of particular interest, published within the annual period of review, have been highlighted as:

Back to Top | Article Outline

• of special interest

Back to Top | Article Outline

•• of outstanding interest

Back to Top | Article Outline

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 600–601).

1 2007 AIDS Epidemic Update. December 2007. UNAIDS/WHO. http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf. [Accessed 20 March 2008]

2• Balzarini J, Van Damme L. Microbicide drug candidates to prevent HIV infection. Lancet 2007; 369:787–797.

3 Dixon DW, Gill AF, Giribabu L, et al. Sulfonated naphthyl porphyrins as agents against HIV-1. J Inorg Biochem 2005; 99:813–821.

4• Vzorov AN, Bozja J, Dixon DW, et al. Parameters of inhibition of HIV-1 infection by small anionic microbicides. Antiviral Res 2007; 73:60–68.

5 Jing B, Janout V, Herold BC, et al. Persulfated molecular umbrellas as anti-HIV and anti-HSV agents. J Am Chem Soc 2004; 126:15930–15931.

6• Madan RP, Mesquita PM, Cheshenko N, et al. Molecular umbrellas: a novel class of candidate topical microbicides to prevent human immunodeficiency virus and herpes simplex virus infections. J Virol 2007; 81:7636–7646.

7• Tao J, Hu Q, Yang J, et al. In vitro anti-HIV and -HSV activity and safety of sodium rutin sulfate as a microbicide candidate. Antiviral Res 2007; 75:227–233.

8 Gantlett KE, Weber JN, Sattentau QJ. Synergistic inhibition of HIV-1 infection by combinations of soluble polyanions with other potential microbicides. Antiviral Res 2007; 75:188–197.

9• Nuttall J, Romano J, Douville K, et al. The future of HIV prevention: prospects for an effective anti-HIV microbicide. Infect Dis Clin North Am 2007; 21:219–239. This comprehensive review provides a current look at microbicide research and development.

10• Duong YT, Meadows DC, Srivastava IK, et al. Direct inactivation of human immunodeficiency virus type 1 by a novel small-molecule entry inhibitor, DCM205. Antimicrob Agents Chemother 2007; 51:1780–1786.

11• Welch BD, VanDemark AP, Heroux A, et al. Potent D-peptide inhibitors of HIV-1 entry. Proc Natl Acad Sci U S A 2007; 104:16828–16833.

12• Cole AM, Cole AL. Antimicrobial polypeptides are key anti-HIV-1 effector molecules of cervicovaginal host defense. Am J Reprod Immunol 2008; 59:27–34.

13• Cole AL, Herasimtschuk A, Gupta P, et al. The retrocyclin analogue RC-101 prevents human immunodeficiency virus type 1 infection of a model human cervicovaginal tissue construct. Immunology 2007; 121:140–145.

14• Fuhrman CA, Warren AD, Waring AJ, et al. Retrocyclin RC-101 overcomes cationic mutations on the heptad repeat 2 region of HIV-1 gp41. FEBS J 2007; 274:6477–6487.

15 Sia SK, Carr PA, Cochran AG, et al. Short constrained peptides that inhibit HIV-1 entry. Proc Natl Acad Sci U S A 2002; 99:14664–14669.

16• Deng Y, Zheng Q, Ketas TJ, et al. Protein design of a bacterially expressed HIV-1 gp41 fusion inhibitor. Biochemistry 2007; 46:4360–4369.

17• Sugaya M, Hartley O, Root MJ, Blauvelt A. C34, a membrane fusion inhibitor, blocks HIV infection of langerhans cells and viral transmission to T cells. J Invest Dermatol 2007; 127:1436–1443.

18• Pollicita M, Schols D, Aquaro S, et al. Carbohydrate-binding agents (CBAs) inhibit HIV-1 infection in human primary monocyte-derived macrophages (MDMs) and efficiently prevent MDM-directed viral capture and subsequent transmission to CD4+ T lymphocytes. Virology 2008; 370:382–391.

19• Balzarini J, Van Herrewege Y, Vermeire K, et al. Carbohydrate-binding agents efficiently prevent dendritic cell-specificintercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-directed HIV-1transmission to T lymphocytes. Mol Pharmacol 2007; 71:3–11. Ability of CBAs to block DC-SIGN-mediated transmission of HIV to lymphocytes distinguishes CBAs from polyanions and other classes of entry inhibitors. This might be a useful property to have in a microbicide and to screen for.

20 Boyd MR, Gustafson KR, McMahon JB, et al. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob Agents Chemother 1997; 41:1521–1530.

21• Zappe H, Snell ME, Bossard MJ. PEGylation of cyanovirin-N, an entry inhibitor of HIV. Adv Drug Deliv Rev 2008; 60:79–87.

22 Emau P, Tian B, O'keefe BR, et al. Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide. J Med Primatol 2007; 36:244–253.

23 Balzarini J, Hatse S, Vermeire K, et al. Mannose-specific plant lectins from the Amaryllidaceae family qualify as efficient microbicides for prevention of human immunodeficiency virus infection. Antimicrob Agents Chemother 2004; 48:3858–3870.

24• Saïdi H, Nasreddine N, Jenabian MA, et al. Differential in vitro inhibitory activity against HIV-1 of alpha-(1-3)- and alpha-(1-6)-D-mannose specific plant lectins: implication for microbicide development. J Transl Med 2007; 5:28. A CBA that is active in epithelial cells and dendritic cells uses multiple mechanisms.

25 Wang L-X, Wang J, Fouts T. Synthetic polyvalent carbohydrates as components of microbicides. World Patent Publication WO 2007/033329 A1; 2007.

26 Hartley O, Gaertner H, Wilken J, et al. Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors. Proc Natl Acad Sci U S A 2004; 101:16460–16465.

27• Gaertner H, Offord R, Botti P, et al. Semisynthetic analogues of PSC-RANTES, a potent anti-HIV protein. Bioconjug Chem 2008; 19:480–489.

28 Hartley O. Fully recombinant chemokine analogues provide complete protection in the macaque vaginal challenge model [abstract]. In: Microbicides 2008; 24–27 February 2008; New Delhi. New Delhi: Plan it!; 2008. Abstract AO21-286.

29• Ketas TJ, Schader SM, Zurita J, et al. Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes. Virology 2007; 364:431–440.

30 Freeman EE, Weiss HA, Glynn JR, et al. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006; 20:73–83.

31• Isaacs CE, Wen GY, Xu W, et al. Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus. Antimicrob Agents Chemother 2008; 52:962–970.

32• Guzman EM, Cheshenko N, Shende V, et al. Amphipathic DNA polymers are candidate vaginal microbicides and block herpes simplex virus binding, entry and viral gene expression. Antivir Ther 2007; 12:1147–1156. Erratum in: Antivir Ther 2008; 13:335. Amphipathic DNA polymers target both HIV and HSV, acting by multiple mechanisms. A dual inhibitor might effectively reduce transmission of HIV.

33•• de Witte L, Bobardt M, Chatterji U, et al. Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1. Proc Natl Acad Sci U S A 2007; 104:19464–19469.

34•• Ramessar K, Rademacher T, Sack M, et al. Cost-effective production of a vaginal protein microbicide to prevent HIV transmission. Proc Natl Acad Sci U S A 2008; 105:3727–3732.

35 Xu Q. Development of a live topical microbicide for women [abstract]. In: Microbicides 2008; 24–27 February 2008; New Delhi. New Delhi: Plan it!; 2008. Abstract AO17-221.

36•• Liu JJ, Reid G, Jiang Y, et al. Activity of HIV entry and fusion inhibitors expressed by the human vaginal colonizing probiotic Lactobacillus reuteri RC-14. Cell Microbiol 2007; 9:120–130.

37 Vangelista L. Expression of RANTES derivatives in Lactobacilli: a novel strategy for the development of vaginal microbicides [abstract]. In: Microbicides 2008; 24–27 February 2008; New Delhi. New Delhi: Plan it!; 2008. Abstract AO18-235.

38 The Rockefeller Foundation Microbicide Initiative. The economics of microbicide development. http://www.bvgh.org/resources/market/documents/economics.pdf. [Accessed 8 April 2008]

39 Li W-H, Liu S-W, Ying L, et al. In vitro spermicidal and anti-HIV effects of deoxycholyltyosine. Shengzhi Yu Biyun 2007; 27:661–666.

40 Moelling K. Inhibition of viruses by antisense oligomers capable of binding to polypurine rich tract of single-stranded RNA or RNA-DNA hybrids. US Patent 5,849,900; 1998.

41• Molling K. Prevention of viral infectivity. World Patent Publication WO 2007/048644 A2; 2007. It now seems possible to induce HIV to commit suicide before it infects cells. Perhaps other classes of compounds can do the same thing.

Keywords:

AIDS; HIV; microbicide; rectum; vagina

© 2008 Lippincott Williams & Wilkins, Inc.

Login

Article Level Metrics

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.