Sara and Paul are like countless married couples in the developingworld. While she raises children and looks after livestock on a farm inrural Zimbabwe, he works a subsistence-wage job in a distant town. Theysee each other, at best, once a month. The last time Paul came home,Sara noticed a vaginal discharge just days after he left. A localclinic confirmed her suspicion -- Paul had given her a sexuallytransmitted infection. But when she tried to get him to wear a condom,she received a severe beating.

If 20 years of AIDS have taught us anything, it's that men, straightor gay, rich or poor, would sooner chuck a condom than slip it on. Insub-Saharan African countries, condom use falls as low as 7 percent.Nearly half of gay American men in their 20s report that they recentlyhad unprotected anal sex. "I don't think it's hard to ask someone towear a condom, but guys hate them," says Dyanne Stempel, a single whitefemale living in Los Angeles. "They don't say anything and then theyeither can't perform or they get uncomfortable."

But what if Sara and Dyanne had a stealth method of protection?Something called, let's say, Coochie Cream or Booty Butter -- anodorless gel, lotion, foam or suppository that could help protect themfrom STDs, but that would also ensure the seamless intimacy cherishedin those passionate moments? "It would be a dream," Stempel says.

For 15 years, certain scientists -- gravely underfunded and mostlydismissed by the AIDS research mainstream -- have toiled to make thisdream a reality. Now the fruit of their labor is ripening, just as thecause of women enters the vanguard of AIDS consciousness. Theirinventions are called microbicides -- and while the unfortunate namesounds like a fungus-eradication product, if all goes well, thesewoman-controlled "chemical condoms" could reach the over-the-countermarket in five years and become the biggest reproductive-healthinnovation since the birth-control pill.

No longer the fantasy of womanist policy wonks and heated activists,microbicides have become a cause célèbre, splashed onto the pages ofpublications like Vogue and The Wall Street Journal.Their credibility comes not only from the most promising candidates'recent clinical trial advances but also from the stepped-up efforts ofbillionaire philanthropists Bill and Melinda Gates, who have donated atotal of $50 million to microbicide research. In February, they madetheir most recent contribution, $20 million to fund a Phase III trial-- the final, FDA-required test of efficacy in humans -- of a promisingseaweed-based product called Carraguard.

The need for such a revolutionary product has become alarminglyclear: Worldwide, 17.6 million women have HIV. A single unprotected sexact is eight times more likely to infect a woman than a man. AcrossAfrica and Asia, women in ostensibly monogamous marriages are at greatrisk of contracting HIV and STDs. In Thailand, a study in the Journal of Acquired Immune Deficiency Syndromes reported, 76 percent of HIV positive women said that their only sexual contact was with their husbands.

"The issue of women has come front and center in the AIDS epidemic,"says Helene Gayle, MD, who championed women's prevention programs as atop official at the Centers for Disease Control and Prevention and nowoversees the Gates Foundation's AIDS giving. "The reality is, we'restill many years from having a vaccine, and that's made people realizewe need to diversify research and development. We can't just focus ontreatments and vaccines -- we need to find intermediary technologies."

Carraguard is just one of nearly 60 microbicides in development inthe United States, India, Brazil, Belgium and Britain. These productscome in a wide variety of formulations. Some are contraceptive as wellas antimicrobial; others would allow for conception while nixing HIV.Because of the prevalence of anal sex, many researchers insist thatmicrobicides must work rectally as well as vaginally. This has theadded bonus of making them valuable to gay men as well as straightwomen. But each prototype aspires to a common goal: skin-to-skincontact, the ideal of intimacy across all cultures.

David Phillips, PhD, a senior scientist at the Population Council,wishes that he could say he's the genius who discovered that a simplered, seaweed-based product called carrageenan prevents viral infectionssuch as HIV. But in fact, carrageenan, a food thickener used inCampbell's soups, ice cream and baby food, has been known for itsantiviral properties since the '60s. In the '80s, scientists beganlooking at carrageenan's potential for herpes prevention. That was whenPhillips began the research that led to the formulation of Carraguardin the late '90s. "We've shown that Carraguard is effective against HIVin the test tube and against several sexually transmitted pathogens inanimals," he says. "But there's still a lot we don't know about how HIVgets into the body. [See "Enemy at the Gate"]. Now it's our job toprove it will work with people."

Carraguard is one of five microbicides set to enter advanced-stageclinical trials this year. With so much riding on the results of theresearch, scientists such as Zeda Rosenberg, the interim executivedirector of the International Partnership on Microbicides at FamilyHealth International, has a barrage of urgent questions to answer.Overseeing the Phase III tests of two other top contenders, PRO 2000and BufferGel, Rosenberg is helping to design studies with upward of8,000 women. As far as the sheer scale and ambition go, Rosenbergmaintains an upbeat attitude. "Every challenge can be overcome withcreative design and lots of resources," she says.

But the investigations are starting with a financial straitjacket.Carraguard, for instance, has only about $20 million in its researchcoffer, although conservative estimates put the cost of a trial closerto $50 million. Beyond the money, there are logistical and ethicalproblems. Scientists can't be in bed with participants when theyactually use the gel, so they must rely on self-reporting rather thanthe data-gathering methods used in laboratory-controlled settings. Thenthere's the moral dilemma that arises when Western scientists give,say, an African woman -- whose chances of contracting HIV are 20 to 30percent -- a placebo gel rather than the real thing. It's true that theresearchers will give all volunteers condoms and encourage the use ofboth latex and microbicide (or placebo gel). But even the bestintentions could result in women being -- or ultimately feeling --exploited when their risk of infection is frighteningly high. Rosenbergacknowledges the ethical implications but still defends theproceedings, arguing that the women will receive prevention and care atstandards comparable to those in the U.S. "That means condom promotionand counseling and treatment of STDs," she says.

Rosenberg and her colleagues believe that a microbicide will havedemonstrated efficacy if, over three years, there are at least 30percent fewer infections among users than in the control group. Thatmay sound far from ideal. But researchers at the London School ofHygiene and Tropical Medicine estimate that a microbicide with 60percent effectiveness could avert 2.5 million new HIV infections overthree years worldwide. On top of the obvious human benefits, thattranslates into a $2.7 billion savings in health-care costs (notincluding HIV meds) and $1 billion in productivity for developingcountries.

"This has been discussed by many experts in the field, and there issome consensus, at least for the first clinical study, that 30 percentcould potentially lead to approval," says Debra Birnkrant, MD, directorof the FDA's division of antiviral drugs, who has reviewed everymicrobicide that has entered trials. "This is being developed globally-- not just for the U.S. -- and if we could prevent 30 percent ofinfections in Africa, that would be tremendous." Still, she envisionsthe FDA recommending the products for use with condoms. "The trials arebeing conducted with them, and the labels have to reflect that," shesays.

Even with all the drum-rolling about the promise of the "fab five"microbicides, researchers have great cause for caution. Two years ago,four microbicide finalists had made it to Phase III trials, but allultimately failed because they contained Nonoxynol-9. In studies, thespermicide was found to cause vaginal abrasions, making women even moresusceptible to HIV.

The current crop works differently. Carraguard's carrageenan belongsto a family of compounds called sulfated polymers, which are believedto coat HIV and keep it from entering host cells. BufferGel, made of afoaming agent already used in many vaginal products, mixes with thevagina's natural acidity to create a pH level hostile to HIV. Thenthere are antiretroviral products like PMPA gel, which work likecurrent AIDS therapies by blocking HIV replication. Since the '80s,hundreds of compounds have been screened in test tubes for theirability to prevent pregnancy and kill pathogens, says Henry L.Gabelnick, PhD, the director of a microbicide research consortiumcalled CONRAD that in 2000 received $25 million from the GatesFoundation. After the devastating failure of Nonoxynol-9, he says,"people began looking for formulations that were less irritating andcompounds that would bind the virus."

The finalists -- most of which have passed the small Phase II testsfor safety and initial indications of effectiveness -- all offerpromising approaches. The big problem now is money. The RockefellerFoundation Microbicide Initiative, a working group of consultants,researchers and pharmaceutical analysts, estimates that totalproduct-development costs for the first generation of microbicides willrun more than $750 million (by contrast, the average drug, includingHIV medicines, costs $500 million to develop.) Sadly, the Initiativeprojects only $230 million in public funding for microbicidedevelopment through the year 2005.

One solution would be for deep-pocketed pharmaceutical giants topartner with the current loose network of academics, nonprofits andplucky, indie biotechs such as ReProtect, the Baltimore company thatdeveloped BufferGel. But prevention has never been Pharma's bread andbutter. "As a society, we talk a lot more about therapy thanprevention," says Kevin Whaley, PhD, who helped develop BufferGel."With microbicides, we're introducing a whole new category, and that'sjust stunning to some people." To make matters worse, the female condomand the Today Sponge, two products seen as business-case precursors tomicrobicides, were thought to enjoy strong market potential but turnedout to be unmitigated flops. Annual worldwide sales of the femalecondom peaked at a miserable $6 million (in comparison, "male" condomsales have reached $295 million in the U.S. alone), and the spongeraked in a paltry $20 million -- hardly the numbers to justifymicrobicides' not-insignificant development costs.

For the most part, pharmaceutical giants are watching microbicidetesting from the sidelines and withholding their wallets. JanetSkidmore, a spokesperson for Merck, explains that her company's HIVprevention commitment lies, and will remain, firmly in vaccineterritory. "Given our experience in the vaccine field, it's just themore effective approach for us," she says. She denies that thisdecision is based on economics or microbicides' early clinicalstumbles. "We feel strongly that the best way to approach this pandemicis with a vaccine."

But if Merck and its brethren were in fact to consider the "returnon investment" numbers compiled by the Rockefeller FoundationMicrobicide Initiative, they'd likely flee in horror. While the grouprates current microbicides as "promising" and predicts that theirglobal market size could reach $900 million by 2011, it places eachcandidate's statistical chances of clinical approval and market entryat only 25 percent. Even worse, projections show that any corporatebacker of a first-generation microbicide is likely to incur financiallosses in the tens of millions of dollars. For a microbicide to beeffective in the developing world, it has to be cheap -- as little as35 cents per dose -- obliterating profit margins.

Researchers and academics argue that as long as the clinical trialsare publicly and philanthropically funded, a pharmaceutical companythat owns or acquires a successful microbicide does stand a chance tomake money. "It's not going to be a billion-dollar blockbuster,"Gabelnick says. "But the market for spermicides now is only $40 to $50million, and that hasn't kept personal-product companies from sellingthem." He also envisions a two-tier pricing system to balance out thecheapness of microbicides in poor countries. "People forget that acycle of oral contraceptives sells for $30 in a pharmacy, but donoragencies probably get them for 30 cents or less," he says, adding thatin many developing nations such as Brazil, India and China, there's asizable, growing middle class that can absorb a higher price point.

That a viable, potentially lucrative microbicide market exists indeveloped countries is something that UC/Berkeley epidemiologistBethany Young Holt, PhD, is seeking to prove with asoon-to-be-published study of young American women. "Across the board,women are uncomfortable talking to their male partners about sex --whether they're rich, poor, white or black," she observes. Holt heldfocus groups to gauge women's interest in microbicides. Their responseswere encouraging and even produced sexy packaging ideas, like a sleekgel (strawberry flavored preferred) contained in a lipstick-like case-- the must-have purse item of the coming decade.

For now, all eyes are on the holy grail of FDA approval, which couldtake another five years. But the war chest for microbicide developmentremains disturbingly light, with money coming in piecemeal from thegovernment, academic grants, private foundations and small biotechfirms. According to the Washington, DC-based Global Campaign forMicrobicides, an organization that raises public awareness andpolitical and financial support, only 1 percent of the federal AIDSresearch budget -- $35 million -- is currently allocated to microbicideresearch.

For veteran activists such as Anna Forbes, the Global Campaign'sfield organizer, this is a frustrating state-of-affairs. "When we treatmicrobicides like the ill-fated, red-haired stepchild, we're justcutting off our nose to spite our face," she says. "This could berevolutionary."

If microbicides are going to take hold, there needs to be a majorpublic education push. According to the Kaiser Family Foundation, only2 percent of Americans have even heard of microbicides.

A stronger show of political force will also be necessary, which iswhy people like policy officer Lara Stemple are working on campaignslike the California Microbicides Initiative (CaMI) in Los Angeles. CaMIand other groups have secured the sponsorship of eight senators and 38house representatives for the Microbicide Development Act, which wouldappropriate money for a new microbicide program at the NationalInstitutes of Health. Given the unpredictable AIDS climate under theBush administration -- with abstinence dominating the federal HIVeducation agenda and a paltry $200 million committed to the UN globalAIDS fund -- even Forbes concedes that the chance of passage is slim.But just introducing the act will generate legislative awareness andserve as a starting point for creative funding strategies. "Global AIDSis a hot issue on Capitol Hill," she says. "And if we can positionmicrobicides as part of the issue, then it has a much better chance ofmaking it."

With the profit sector playing possum until the proof comes in,what's urgently needed is funding from public and philanthropicsources. "We're looking for our Mrs. McCormick," Stemple says, invokingthe wealthy widow who, with reproductive-rights activist MargaretSanger, unsuccessfully lobbied the pharmaceutical industry to develop asafe, effective oral contraceptive. In 1951, Katherine Dexter McCormickput her International Harvester money where her mouth was, hiring thescientists to produce the research that ultimately led to thebirth-control pill.

Before then, liberating women's sexuality from pregnancy might haveseemed like speaking over wires, flying through the air or rocketing tothe moon -- once quixotic, even foolish, then suddenly, perhapsaccidentally, attainable. When a microbicide liberates women's -- andgay men's -- sexuality from HIV, it could finally put the brakes onhistory's worst-ever public-health catastrophe. But in the absence ofsufficient dollars and awareness, the revolution in the sheets willrequire what is sometimes equally hard to come by: movement in thestreets. "It's clear microbicides are needed, and that they'reimperative," Forbes says. "Since we're not able to attract corporatesupport, we have to make it happen ourselves."

Researchers have spent 20 years and hundreds of millions of dollarstrying to figure out how to undo HIV once it's in the body. But asvirology and reproductive biology expert David Phillips, PhD, and hispeers labor to prove the anti-HIV power of microbicides, a key mysterypersists: How does the virus get into the body in the first place?

Theories of infection abound. Phillips believes that most acts ofunprotected sexual intercourse with an HIV-infected partner won'tresult in transmission without certain mechanisms to facilitate viralentry. "It's like if a bunch of people drink contaminated water," hesays. "Some will get sick. Others won't." The ideas about transmissionvary, but ultimately any could be true -- or not. "There's so much westill don't know," Phillips says bluntly.

Most experts assume that semen carries the virus into the cervix,vagina or rectum, allowing it to invade other cells, which thencirculate it bodywide. One leading theory holds that the fatal carriersare dendritic cells -- the ones that signal the immune system toproduce antibodies. According to this view, dendritic cells pick up thevirus and take it back to the lymph nodes, contaminating them.

Another top hypothesis links HIV infiltration to epithelial cells,which line the vagina, intestines and interior of the lungs. Eventhough these cells are designed precisely to protect these sensitiveorgans from infection, for some reason they are vulnerable to viralviolation, especially in the rectum.

With a number of theories in play, the ideal microbicide would coveras many bases as possible, making the virus unsavory to dendritic cellsand preventing the virus from binding to epithelial cells. But even ifa microbicide trial is successful, it will be very difficult, if notimpossible, to isolate which infection mechanisms were blocked. "It'smy job to worry about them all," Phillips says. Clearly, the mystery ofinfection is fertile ground for future research.