Semen Found to Impair Microbicide Efficacy
Microbicides are a form of drug—usually in a gel or cream—that can be applied in the vagina or rectum to prevent HIV before exposure. Their development and use has been heralded as a way for women or male receptive partners to take control of their HIV risk—particularly in situations when requesting condom use, HIV testing, or HIV treatment is not desirable or possible. Yet progress towards a fully developed and marketable product has been stymied by inconsistent clinical trial results. One large-scale study halted the use of a tenofovir gel microbicide completely when early results showed its ineffectiveness in preventing HIV among women in the trial.
Other products that showed promise in the lab proved ineffective when used in the real world. Adherence may be one component of poor outcomes—pre-exposure prophylaxis treatments don’t work if they’re used inconsistently or incorrectly. But a group of virologists—in a paper published in the journal of Science Translational Medicine—point to another potential problem for microbicides: semen.
Semen is typically the fluid that carries and transmits HIV, yet is oftentimes left out of the equation when microbicides are tested against HIV in the lab. When semen is tested in the lab, it’s known to increase HIV’s infectiousness. Fragments from proteins found in semen forms amyloid fibrils which help HIV attach to host cells. In other words, HIV exposed to semen is more likely to take up residence in the host cells and become an active infection.
This is something that Nadia Roan, PhD, a researcher at the University of California, San Francisco, has been studying with investigators at the J. David Gladstone Institute and the University of Ulm, Germany. She, and the rest of her study team, wanted to determine if semen’s infection-promoting effects on HIV make microbicides less effective when they’re exposed to semen.
That’s precisely what they found.
The series of studies they conducted were a systematic analysis of how well microbicides work to decrease viral infectiousness, with and without exposure to semen. The studies were done in the lab with cell cultures, not with human participants.
Researchers tested a few different types of microbicides to determine if a calculation called the IC50, the concentration of microbicide needed to inhibit 50% of the virus, changed in the presence of semen.
The ten microbicides they tested were: SPL7013 (a microbicide candidate called VivaGel, recently terminated from development because of adverse events); polystyrene acid, polynaphthalene sulfonate, and cellulose sulfate (three compounds considered for microbicide development which all ultimately failed to prevent HIV transmission when tested in people); the neutralizing antibodies 2F5 and 2G12; tenofovir disoproxil fumarate (an HIV nucleotide reverse transcriptase inhibitor); elvitegravir (an HIV integrase inhibitor); indinavir (an HIV protease inhibitor); and maraviroc (a CCR5 antagonist).
The team tested all of the microbicides with HIV exposed to a type of cell line called TZM-bl. They then confirmed their findings by exposing HIV to human peripheral blood mononuclear cells (blood cells taken directly from the blood of a patient).
“We found that all of the microbicides that target the HIV virus became significantly less effective in the presence of semen—sometimes by greater than 20 fold,” explained Roan.
The team further demonstrated that the ability of semen to enhance HIV infection is the likely cause of their findings. They were able to demonstrate this by also testing semen from men with ejaculatory duct obstruction—which doesn’t contain the amyloid associated with HIV infection enhancement.
“These semen samples don’t enhance HIV infection. We found that when we used those, instead of regular semen, we lost this ability to counteract the anti-HIV activity those microbicides. So it’s the ability of semen to increase the infectiousness of HIV that appears to be responsible for this effect,” she explains.
One notable exception was the CCR5 antagonist maraviroc, which has been tested—but not yet fully developed—as a possible microbicide. This anti-HIV compound worked well to prevent HIV infection even when exposed to semen.
One possible reason for this exception?
Unlike the other microbicide compounds tested in this study, the drug maraviroc doesn’t prevent HIV infection by targeting the virus itself.
Maraviroc prevents HIV infection by blocking receptors on host (human) cells—rather than a component of the viral cell. Roan thinks that this difference may be key. “We’re now trying to understand whether other microbicides targeting host cell components would show such effect.”
Despite these findings, Roan recognizes the great value of the previous microbicide research that focused on compounds found to be less effective in the presence of semen, such as tenofovir. She believes that if effects reported in this study translate to real world settings, the future development of microbicides may still use drugs such as tenofovir, but in addition to other compounds used to counteract semen’s effects.
“This is a concept we’re terming ‘combination microbicide’—where there are multiple components in microbicides. One targets the HIV virus, the other targets the HIV-promoting factors in semen,” she elaborates. Work is already underway to identity compounds that limit the ability of semen to increase HIV infectivity, notes Roan, and some candidates have already been identified.
Grant, R. and others. Whither or wither microbicides? Science 321(5888), 532-534. July 25, 2008.
Münch, J. and others. Semen-derived amyloid fibrils drastically enhance HIV infection. Cell, 131(6), 1059-1071. December 14, 2007.
Olsen, J. and others. Amyloid-binding small molecules efficiently block SEVI (semen-derived enhancer of virus infection) and semen-mediated enhancement of HIV-1 infection. J Biol Chem 285(46), 35488-96. November 12, 2010.
Zirafi, O. and others. Semen enhances HIV infectivity and impairs the antiviral efficacy of microbicides. Science Translational Medicine 6(262). November 12, 2014.