By Nikhil Swaminathan
December 14, 2007
More than 80 percent of human immunodeficiency virus (HIV) infections are transmitted via sexual intercourse. And researchers may have discovered at least one reason why. According to a new study published in Cell, a component of human semen may facilitate the spread of the virus by targeting immune system cells, in some cases making the pathogen up to 100,000 times more virulent.
The team of German scientists had initially set out to determine if semen contained factors that inhibit the HIV infection. "We were not expecting to find an enhancer, and we were even more surprised about the strength," says report co-author Frank Kirchhoff, a virologist at the University of Ulm Clinic in Germany. "Most enhancers have maybe a two- or three-fold effect, but here the effect was amazingmore than 50-fold and, under certain conditions, more than 100,000-fold."
HIV, the virus that leads to AIDS, has infected 60 million people worldwide (causing 25 million deaths) since it was discovered in humans in 1981. The transmission rate from intravaginal sexual intercourse is estimated at one in every 200 to 2,000 acts. In Africa, 60 percent of new infections are in women who have had sex with HIV-positive men.
Kirchhoff and his team screened through many of the 900 proteins found in seminal fluid in their hunt for potential inhibitors and enhancers of HIV transmission. Among the enhancing factors uncovered were fragments of a protein called prostatic acid phosphatase that is secreted by the prostate gland. An analysis of the peptide's structure in semen indicated that it hooked up with similar fragments to create amyloid fibers (clusters of protein fragments that have also been implicated in diseases such as Alzheimer's). The scientists refer to the amyloid fibers as "semen-derived enhancer of virus infection" (SEVI). If they do not link to become fibers, the researchers report, the peptide segments remain inactive and do not enhance viral transmission.
When assembled, however, these fibers then act like ferries, trapping and shuttling HIV virus particles to target cells. The researchers found that HIV spiked into semen was more successful than the virus alone at infecting T cells and macrophages (immune system cells that are believed to be the infection's initial targets in the body). They also tested the threshold of virus needed to infect human tonsil cells, noting that in the presence of semen, far fewer HIV particles were needed for transmission.
Researchers injected both the naked virus and SEVI-treated HIV into the tails of rats that had been given human immune system cells. The HIV with the semen component was five times more effective at transmitting the virus. In situations where low levels of virus are transferredas during intercourseKirchhoff says, SEVI can make HIV up to 100,000 times more likely to spread when compared with the virus alone.
In an editorial accompanying the article, postdoctoral fellow Nadia Roan, along with Warner Greene, a senior investigator at the University of California, San Francisco's Gladstone Institute of Virology and Immunology, wrote: "If SEVI truly increases the real world heterosexual spread of HIV by several orders of magnitude, then negating the activity of this factor could conceivably diminish these frequencies to levels that might virtually eliminate semen-driven HIV transmission."
But, others say more work is needed to fully comprehend the role of prostatic acid phosphatase in viral transmission. "I don't think you can really make any interpretation of that experiment other than it makes the virus more infectious if it reaches target cells which is very difficult across mucosal surfaces," says Robin Shattock, a professor of cellular and molecular infection at St George's, University of London. The sentiment is echoed by Myron Cohen, an epidemiologist at the Center for Infectious Diseases at the University of North Carolina School of Medicine in Chapel Hill: "We need to understand every detail about the biology of HIV transmission ; the [next] logical experiments are to demonstrate in rhesus macaque models that this is playing a role in transmission."