Untangling HIV transmission in men

Study could put scientists on the right path [bonne voie] to blocking the spread of new infections.

Erika Check Hayden

Free-floating HIV particles in semen [sperme] may transmit the virus from one man to another.BSIP, CAVALLINI JAMES / SCIENCE PHOTO LIBRARY

HIV could be transmitted between men in the form of free-floating virus particles found in seminal fluid, rather than through HIV-infected cells found in semen.

The virus is known to be transmitted during sex through semen. But it has been difficult to study whether the virus's genetic material is transmitted in the form of infectious RNA virus particles or as DNA locked within infected cells in semen. The answer could determine which strategies are most useful for blocking transmission of the virus from one partner to another.

"We're very interested in how to interrupt transmission, and this tells us we should really focus on the RNA replicating at the time of transmission in the blood and genital tract," says infectious disease physician Davey Smith of the University of California, San Diego, who led the study.

Smith and his team analysed samples taken from six pairs of men. One member of each pair, the source, had infected the recipient partner with HIV. The researchers studied the genetic makeup of a portion of the virus in both the source and recipient members of the pairs, and in the semen from each source. They found that the viruses in the recipients were most genetically related to the free viruses found in the seminal fluid from the source.

However, the study is small, and some scientists have pointed out other caveats within its methods. But Smith notes that studies such as this have never been done before because it is difficult to detect HIV quickly after infection, and even more difficult to convince newly infected people to sign up for a HIV-research study. "It's a delicate situation to talk about HIV transmission, and even more delicate to start collecting these samples when someone is newly diagnosed," Smith says.

If borne out by additional studies, the latest work could support the idea of 'test and treat', which aims to reduce or prevent HIV transmission by administering antiretroviral drugs to people who are HIV-positive — thereby lowering the amount of virus found in their blood and bodily fluids, says Martin Stürmer of the Johann Wolfgang Goethe-University Hospital in Frankfurt, Germany, who was not involved with the study.

"These findings further support the prevention strategy that a suppressive antiretroviral therapy resulting in an undetectable virus load in the seminal plasma interrupts sexual HIV transmission," Stürmer adds.

The study could also promote the development of topical microbicides — some of which are currently being tested in clinical trials — that aim to block HIV from entering cells at the surface of the skin. "One of the big distractors from the whole microbicide movement has been that you could use antiretroviral drugs as microbicides, but if the virus is hiding out in cells in the form of DNA then your microbicide isn't going to block it," Smith says.

Antiretroviral drugs that are taken orally before HIV exposure — an approach known as pre-exposure prophylaxis, or PrEP, which is also being tested in clinical trials — are likely to be equally effective against viruses transmitted through cells or bodily fluids because these drugs aim to stop transmission by stopping viral replication. And the use of condoms would prevent transmission either through cells or through free virus.

In the blood?

Still, the work by Smith and his colleagues used too few participants to definitively answer the question of exactly how transmission occurs: "The number of cases in their study is small, thus a broad generalization of their findings is difficult," says Stürmer.

The results of the study would also be more convincing if the samples had been taken closer to the exact time of the recipient becoming infected, some researchers suggest, because HIV mutates rapidly.

The recipients in the study provided blood samples an average of 72 days after they believed they were infected, and the sources provided blood and semen samples around 90 days after infecting the recipients.

"The samples are never taken close enough" to the time of infection, says Ron Swanstrom at the University of North Carolina Chapel Hill Center for AIDS Research, who is also studying HIV transmission between sexual partners. "It's an inherent problem with working in this field," he says. "You're inserting yourself into these people's private lives and you do a lot of work for not many samples."

Swanstrom adds that the work of Smith and his colleagues does not address what happens in male-to-female transmission of HIV. In addition, because some of the source partners in the current study had themselves become infected only recently, the study could not rule out the possibility that they had transmitted the virus through their blood during intercourse rather than through semen, because the virus particles in the source blood and semen samples were genetically quite similar.

Stürmer points out that studies by other research groups, including his own², indicate that viral transmission can occur between sexual partners even when the HIV-positive partner is being treated successfully with antiretroviral drugs, and no virus is detectable in his blood. So although the paper supports the idea that the "test and treat" strategy should work, it does not guarantee that it will.

Smith says that his group hopes to address some of these questions by studying other pairs, by further investigating the virus's genetics and by asking more questions of the participants. "We hope to better characterize what's going on at the time of transmission, which means asking some difficult questions, such as what were the partners doing at the time of transmission? Were they using condoms or no condoms, and if not, why not?" Smith explains.

1. Butler, D. M. et al. Science Transl. Med. 3, 18re2 (2010).
2. Stürmer, M., Doerr, H. W., Berger, A. & Gute, P. Antivir. Ther. 13, 729-732 (2008).

http://www.nature.com/news/2010/100210/full/news.2010.62.html