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Understanding the Transmitted Virus

What are researchers learning about the enemy that a preventive AIDS vaccine would need to block—the virus that is transmitted and establishes infection? 
While many factors have hindered the development of an AIDS vaccine, HIV’s astonishing degree of diversity remains one of the biggest obstacles. To put HIV’s diversity in perspective, consider this: The global diversity of influenza A, the virus that causes the flu, each year is roughly equivalent to the diversity of HIV in a single individual after six years of being infected. With 33 million people around the world currently infected with HIV, it makes for a mind-boggling degree of diversity.

Designing and developing an AIDS vaccine to tackle that degree of viral diversity can seem an overwhelming prospect, so researchers have turned their attention to studying the enemy that a preventive AIDS vaccine would need to block—the virus that is transmitted and establishes infection.

Early detection

But nailing down the earliest events of HIV infection is a tricky proposition. For one, HIV is most often a sexually transmitted infection, making it impossible for scientists to study the actual infectious event. Also, since most individuals do not recognize or learn of their HIV infection immediately, it is difficult for researchers to obtain samples from individuals very soon after they become infected.

To overcome this hurdle, scientists have been collecting samples with greater frequency from cohorts of uninfected individuals who are at risk of acquiring HIV. Discordant couples, in which one partner is HIV infected and the other is not, are one group that is particularly useful to study. Discordant couples are uniquely valuable because they allow scientists to study both the virus that establishes infection in the newly infected partner, as well as the virus population that is circulating in the transmitting partner.

Large cohorts of discordant couples have been established in Rwanda and Zambia and frequent sampling—every month instead of every three months—of uninfected partners in these cohorts has helped researchers identify new HIV infections much closer to the point of transmission. The more frequent testing and sampling also helps reinforce risk-reduction counseling messages and promotes condom use among couples.

Technical insights are also helping researchers collect information about HIV transmission. Researchers are now able to analyze historical blood samples that were collected from a single individual and work back in time, using models that predict virus evolution, to determine with a high degree of certainty the genetic characteristics of the virus that initially established infection.

As a better picture emerges of the virus that is transmitted from person to person, there is some welcome news for vaccine researchers. Evidence now suggests that the virus that is transmitted and establishes a new infection is not nearly as diverse as HIV in an individual that has been infected for some time.

When researchers analyzed samples from just under 200 individuals who were newly infected with HIV, they found that in the majority (81%) of these individuals, a single virus led to infection. This observation was later confirmed in a group of discordant couples—in 20 discordant couples studied, 90% of infections were initiated by a single virus, despite the fact that the transmitting partner had multiple HIV variants circulating in their bodies.

This has led researchers to propose that there is a bottleneck in HIV transmission—even though many variants of HIV are in an infected individual, only certain ones are capable of getting through and establishing an infection. This transmission bottleneck effectively limits the number of HIV variants in a newly infected individual.

These observations may have important implications for AIDS vaccine design since it could indicate that a preventive vaccine would only have to contend with a very small number of viral variants to block an infection from ever occurring. However, since the virus that establishes an infection quickly mutates and varies, there is still a very short period of time in which a preventive vaccine would have to act before diversity of the virus becomes a problem.

Some exceptions

Despite the bottleneck that appears to ensue during sexual transmission, researchers believe that a quarter of the time, two or more viruses succeed in establishing infection in a newly infected individual. In studying these cases, researchers have found an association between the presence of genital infections and the number of transmitted viruses that establish infection in a single individual, suggesting that other sexually transmitted infections may alter the transmission bottleneck.

New data also suggest that the number of viral variants that are transmitted and establish infection may vary greatly depending on the mode of transmission. For example, in cohorts of injection-drug users or men who have sex with men, researchers have observed that on average, a much higher number of viral variants are responsible for establishing infection than are seen in heterosexual transmission.

Researchers are now genetically analyzing the properties of the virus that gets transmitted and establishes infection to look for additional clues that may inform vaccine design.