More than three-quarters of new HIV infections worldwide are acquired through sexual contact, nearly all of which involve at least one male. As researchers have been uncovering a growing number of differences between the semen-based virus and blood-borne populations—and the number of people with the virus continues to rise rapidly—the race to piece together a better understanding of the virus's makeup and behavior in the male genital tract has grown ever more urgent.

Upon infection, the virus in the blood and semen are often nearly identical, but over time, previous studies have shown, the different populations become varied, making it "clear that the virus in the blood does not always represent the virus at the site of the transmission," Jeffrey Anderson and Li-Hua Ping, both of the Center for AIDS Research at the University of North Carolina, noted in an e-mail to Scientific American.

A new series of studies reveals three distinct ways in which virus populations in the male genital tract can arise, paving the way for more refined research into virus dynamics at this crucial transmission site. The work is described in a new paper published online August 19 in PLoS Pathogens.

"These studies are rather illuminating because they provide new insights into the population of HIV virons that spreads horizontally from men," Warner Greene, director of the Gladstone Institute of Virology and Immunology at the University of California, San Francisco (UCSF), who was not involved in the new work, noted in an e-mail.

To assess these various HIV populations, the researchers, led by Anderson and Ping, sampled blood and semen from 16 men with chronic HIV-1 infections (four of whom had U.S.-based subtype B and 12 of whom had subtype C and were from Malawi). These were compared against 18 HIV- and sexually transmitted infection–negative men. The research team used single-gene amplification to study the gene responsible for HIV's major surface protein, env.

The virus is constantly changing throughout the body—in both blood and genital sites—due to both host immune-system pressures and virus copy errors. But the researchers found distinct differences in the semen-based HIV.

"In some men, the virus population was very similar to that in the blood, suggesting that the virus was being imported from the blood to the genital tract," Anderson and Ping explained. But many men had virus populations in their genital tract that looked quite different from those in their blood.

"We found two mechanisms that significantly altered the virus population in the semen," the lead researchers noted, which suggests that the "virus can grow in the seminal tract in two different ways."

In the first scenario, the virus can multiply rapidly, creating a population that "is relatively homogeneous" over the course of days or weeks. In the other process, the virus replicates in immune T cells in the genital tract over months or years, "creating a separate population of virus that is both complex and distinct from the virus in the blood," Anderson and Ping explained.

The three origins of semen-based HIV populations were not present in all men. Nadia Roan, a research scientist who works with Greene at UCSF and was also not involved in the new work, noted that "it would be very interesting to further decipher what conditions favor one mechanism over the other."

To further assess the differences in these various populations within individuals, Anderson, Ping and their team found that chemical messengers called cytokines and chemokines "can be concentrated in semen by several orders of magnitude" over those in the blood. That shift can lead to "an environment that is conducive to T-cell replication that results in amplification of subsets of viral populations and creation of genetically distinct, compartmentalized viral populations," they explained.

These chemical communicators can also make for increased inflammation, Roan noted, adding that "the inflammatory effects of semen in the context of HIV infection is an interesting area of investigation that we are also pursuing."

Previous research had found that a protein found in the male genital tract (prostatic acid phosphatase) can boost HIV's infectiousness by 50 to 100,000 times.

"We do not yet know how these differences change the biology of the virus or if these changes are important for the transmission process," Anderson and Ping noted. And as they took samples from the volunteers only once, the analysis does not compare these changes over time (but rather uses the differences in the genetic profiles to trace virus development backward).

At the very least, the researchers noted in their paper, the additional evidence of various origins and populations of HIV in semen could mean that determining the source of a sexually transmitted infection based on blood testing alone would provide "suboptimal" results.

More research remains to be done to determine how these various virus populations might play a role in sexually based infections. But, Anderson and Ping noted, "if we can find that these differences in the virus populations are important in transmission…then we can begin to apply this knowledge to vaccine and prevention strategies."