Study explores biological properties of transmitted founder viruses

Most sexually transmitted HIV infections are the result of just one transmitted virus, but researchers are still wondering what, if anything, makes such transmitted founder viruses so special. Now, a team led by Beatrice Hahn at the University of Pennsylvania has found that transmitted founder viruses have biological properties that give them an advantage when initiating a new infection (Proc. Natl. Acad. Sci. 2013, doi: 10.1073/pnas.1304288110). The results hold true for subtype B and C viruses, both of which were included in the study. 

The study is the first in which researchers used the complete genome of transmitted founder viruses to produce such viruses in cultured cells. This ensured that the founder viruses you studied were as close to the original ones as possible. “No one has looked at the biology of the [complete] transmitted founder virus to this point,” Hahn says, adding that previously, researchers had only been able to study so-called pseudoviruses that contain the Env protein from the transmitted founder virus, combined with a standardized set of viral proteins. 

In their study, Hahn and colleagues determined the sequence of single viruses by single genome amplification (SGA), where HIV samples are diluted so much that they likely contain just one copy of the HIV genome, which can then be amplified and sequenced. 

Using SGA, they determined the sequence of 27 transmitted founder viruses, using samples collected from HIV infected people shortly after infection, too early for the immune response to exert any pressure on the viruses that might cause them to become different from the transmitted founder virus. For comparison, they also determined the sequence of 14 viruses that were isolated later, during chronic infection. Because they studied so many different viruses in each group, they had sufficient statistical power to see even subtle differences between the groups. 

They found that transmitted founder viruses are almost twice as infectious as chronic viruses, and bind better to dendritic cells, which are among the first cells HIV encounters in the mucosa. While dendritic cells don’t get infected themselves, they catch the virus and hand it over to its main target cells, the CD4+ T cells. 

Transmitted founder viruses also carry about twice as much Env protein compared to their chronic counterparts. Calculations suggest that this translates to about 18 Env spikes per particle, while chronic virus particles only carry about seven. Transmitted founder virus are therefore more likely than their chronic counterparts to still have a functional Env spike when they reach their target cells, Hahn says. That’s because not all spikes are functional to begin with, and because viruses can lose some of their spikes as they cross physical barriers such as mucus or epithelial cell layers. 

Another biological advantage of transmitted founder viruses is that they are more resistant than their chronic counterparts to interferon α, a cytokine that is released by dendritic cells as part of the innate immune response and turns on an antiviral response. This surprised Hahn, because it suggests that the innate immune response is a more powerful hurdle to the infecting virus than she had anticipated. “What the data say is [that] the initial innate immune response is actually quite powerful,” Hahn says. “If you are a transmitted founder virus, you have to overcome that hurdle.” 

Next, Hahn wants to study how interferon α exerts its powerful antiviral effects. The cytokine is known to turn on about a hundred genes, and Hahn hopes to determine which of them are most important. “If we are lucky, [there are] a limited number of key genes that are up-regulated,” she says, adding that their identification could give vaccine developers targets to improve protection by inducing a better innate immune response.