Future VirologyVol. 6, No. 5 EditorialFree AccessAnti-HIV microbicide development: targeting the virus is the keyBarry R O’KeefeBarry R O’KeefeMolecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Building 562, Room 201, NCI-Frederick, Frederick, MD 21702-1201, USA. Search for more papers by this authorEmail the corresponding author at okeefeba@mail.nih.govPublished Online:24 May 2011https://doi.org/10.2217/fvl.11.38AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: antiviraldrug developmentHIVmicrobicidePrEPSeveral news outlets [1], US government agencies [101] and international organizations [102] have recently highlighted the rapidly developing pipeline for anti-HIV microbicides. The majority of this interest, it is pleasant to say, has been warranted by the positive clinical trial results reported for both topical [2] and oral pre-exposure prophylaxis (PrEP) [3] in 2010. These results give hope for future chemical interventions that can slow the progression of HIV and reduce the yearly figure of >2,000,000 new infections reported for 2008.The goal of an efficacious anti-HIV microbicide had seemingly been as unobtainable as an effective vaccine. Previous trials with five different agents failed to show significant efficacy in human clinical trials [4–7]. These nonspecific agents generally fell into three classes: polyanions such as cellulose sulfate and carrageenan, which prevent viral attachment; surfactants such as nonoxynol-9 and SAVVY (C31G), which destabilize membranes; and buffering agents such as BufferGel® (carbopol 974P), which maintain acidic pH in the vaginal cavity. Only one trial, with the polyanion naphthalene sulfate (PRO 2000), showed even modest evidence of efficacy in protecting women from HIV [8]. The general failure of these classes of agents in the clinic has led to a shift in strategy towards the development of agents that directly target the virus.Recent human trials have utilized antiretroviral agents (ARVs) already in clinical use as therapeutics. The justification for this has been the rapidity with which these agents could be moved toward human use, their clinical evidence of safety and their proven efficacy as therapeutics. The results of two groundbreaking studies were reported in 2010, which clearly demonstrated that both topical and oral PrEP could be effective in preventing the spread of HIV. In the first study, CAPRISA 004 in South Africa, PrEP treatment using a 1% tenofovir gel formulation both prior to and after coitus resulted in a 39% reduction in the HIV transmission rate after 30 months [2]. This was the first trial to show clear evidence of efficacy for a topical microbicide and, as such, it received significant attention [9,103]. Shortly thereafter, a second trial, the Pre-Exposure Prophylaxis Initiative (iPrEx) on men and transgender women in six countries, showed that a daily dose of the combination ARV Truvada® (tenofovir and emtricitabine; Gilead Sciences, CA, USA) resulted in a 44% decrease in HIV transmission rates after 14 months [3]. The combined effect of these two positive results has been to energize a beleaguered field of research and encourage further studies with additional agents, formulations and dosing regimens to optimize these success rates. Ongoing trials, such as VOICE (oral Truvada or tenofovir or topical 1% tenofovir gel) and FEM-PrEP (daily oral Truvada), will hopefully confirm these initial results and increase the pace of development towards broadly available PrEP.The use of current ARV therapeutics as prophylactics against HIV is not without potential pitfalls however. The possibility of the enhanced development of resistant virus, which would then also be resistant to ARVs widely used in current therapeutic regimens, although undocumented as yet, is of continuing concern [10]. This concern is especially relevant in less-adherent patient populations where regular HIV testing is not a current option. In addition, daily-dosing regimens, although potentially advantageous for adherence, could substantially drive up the cost of PrEP when compared with coitally associated dosing regimens [11]. This is a particular problem in those countries in sub-Saharan Africa where transmission rates are highest and per-capita medical spending is lowest. For example, the low-cost generic version of Truvada sold in Africa is still US$11 per month, meaning a year’s supply would exceed the yearly per-capita health spending in many sub-Saharan countries [104].To build upon these recent successes, several groups are seeking to develop additional microbicide candidates that would interdict other aspects of the preintegration virus life cycle. With the knowledge gained from both the positive and negative clinical trials, these candidates are being more stringently evaluated preclinically [12]. There is a clear need for compounds to provide alternatives with greater potency, different mechanisms of action and, hopefully, a significant fitness cost to the virus for the development of resistance. In addition, as with HAART, future PrEP might be most successful if combinations of active compounds are used rather than single agents. Several classes of ARVs are being put forward as potential oral or topical PrEP agents; these include non-nucleoside reverse transcriptase inhibitors (NNRTIs) and entry inhibitors targeting several aspects of viral attachment and fusion.With the aforementioned success of the nucleoside reverse transcriptase inhibitors tenofovir and emtricitabine in mind, several NNRTIs are being evaluated for their utility as PrEP agents. UC781 is a NNRTI that has been shown to have a long intracellular half-life (5.5 days) [13] and minimal systemic adsorption when administered topically [14]. In human explant studies, UC781 was shown to fully protect tissues at concentrations as low as 10 µM [15]. Another NNRTI that is in clinical development for PrEP is dapivirine (TMC-120), the poor oral bioavailability of which has limited its use orally as a potential therapeutic but does not preclude its topical use in anti-HIV microbicide gel formulations. Dapivirine protected cervical explants for up to 6 days at concentrations between 1 and 10 µM [16]. In a Phase I clinical study, a dapivirine gel was well tolerated by women at concentrations up to 0.02% [17]. Both of these agents are considered second-generation NNRTIs, with activity against viruses that have become resistant to first-generation NNRTIs.The second major class of PrEP candidates is the entry inhibitors that can either interact with viral components or cellular receptors such as CCR5 (the coreceptor utilized by HIV for the vast majority of sexual transmissions). With the exception of the triazole allosteric CCR5 receptor antagonist maraviroc (Celsentri®; Pfizer, NY, USA), which was approved by the US FDA for oral anti-HIV therapy in 2007, all of the lead molecules in this category are biologicals. This group includes analogs of the CCR5 ligand RANTES such as PSC-RANTES, 5P12-RANTES and 6P4-RANTES, which have shown promising activity as topical microbicides in a vaginal challenge model with rhesus macaques [18]. In addition, fully recombinant production of the PSC-RANTES analogs 5P12-RANTES and 6P4-RANTES has reduced the cost of these entry inhibitors [19], increasing their potential utility for topical PrEP. Several antiviral lectins have also been discovered and show promise as topical microbicide candidates. The protein cyanovirin-N (CV-N), originally isolated from the blue–green alga Nostoc ellipsosporum[20], binds specifically to high-mannose oligosaccharides, decorating the HIV viral envelope protein gp120 [21], as do all members of this class. CV-N has displayed excellent activity in both vaginal and rectal acute challenge models in macaques [22,23] and has recently been reported to protect macaques from repeated low-dose challenges when administered as a probiotic, via lactobacilli that are engineered to produce and excrete CV-N [24,25]. More recently, another lectin named griffithsin (GRFT) was isolated from a red alga and was reported to inhibit HIV at picomolar concentrations [26]. GRFT is more potent than CV-N, is active against a broad spectrum of HIV-1 strains and is stable in the cervico–vaginal environment [27]. GRFT has also been shown to be nonimmunogenic, nontoxic to vaginal epithelia and to protect human cervical explants from HIV infection at 10-nM concentrations [28]. The large-scale production of GRFT in Nicotiana benthamiana plants has also provided a low-cost source for this lectin [28]. Numerous additional natural product-derived lectins have been identified that have activity against HIV, and it is only a matter of time before a member of this group enters human clinical trials. Finally, several broadly neutralizing monoclonal antibodies are being developed as microbicides, including the gp120-specific antibodies 2G12 and b12 and the gp41-specific antibodies 2F5 and 4E10. Owing to the refined binding domains for these molecules, monoclonal antibodies are being evaluated in combination to offer the broadest possible activity in a Phase I clinical trial in Europe [29].The current status of drug development in both oral and topical anti-HIV PrEP is the most promising it has been over the last decade. The clinical successes of both topical tenofovir gel and oral Truvada have energized the field. With these ‘proof-of-principle’ results in hand, the pathway forward for additional PrEP candidates is more certain. The shift in strategy toward utilizing agents that directly target the virus life cycle, rather than the nonspecific agents used previously in clinical studies, appears to be validated. Now the need for additional efficacious PrEP agents, preferably those not currently used in therapeutic regimens, will drive the near-term development pipeline. Issues of cost, adherence, formulation and dosing regimen will continue to complicate future clinical trials, as will the now higher barrier for both ethical and statistically significant trials.Financial & competing interests disclosureBR O’Keefe is a listed inventor on patents for both cyanovirin and griffithsin. These patents are wholly owned by the US government, which receives royalties from licensees. BR O’Keefe has received a small percentage of these royalty payments from the US government. 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The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download