How Do Certain HIV-1 Strains Get Past Our Innate Protective Barriers?

With over 36.7 million individuals across the world living with HIV/AIDS, new, effective preventive strategies are needed in order to reduce the numbers and control the spread of infection. In order to develop new methods, researchers need more information about the virus that has caused over 35 million deaths worldwide.

Researchers from the University of Pennsylvania decided to take a closer look at the AIDS virus and the innate barriers that it needs to overcome in order to infect someone. In this analysis, they managed to identify characteristics of HIV-1 strains—the strain that accounts for the majority of infections—that mediate sexual transmission.

In order for the HIV to be transmitted through sexual intercourse, it must overcome a number of hurdles. First, the virus needs to travel through the genital mucosa—a membrane that works to protect the body from harmful infections—and then it needs to get through epithelial cells that are packed tightly together as a means to “keep invaders out,” according to the press release. If HIV manages to get through those defenses, it also needs to “thwart the initial immune-system alarm bell in the form of type 1 interferons,” aptly named cytokines that work to “interfere” with viral replication.

In the press release, study author Beatrice Hahn, MD, professor of Medicine and Microbiology in the Perelman School of Medicine at the University of Pennsylvania asked the question that the researchers sought to answer: “What is unique about these transmitted viruses that make it this far?” She continued, “The human body has considerable innate barriers that effectively combat virus infections.”

Therefore, the researchers decided to conduct a study that would allow them to examine the HIV-1 strains that were able to make it through all of the innate barriers and identify characteristics of these strains. Taking viral isolates from either plasma or genital secretions “of eight chronically HIV-1 infected donors and their matched recipients,” they found a sub-population consisting of HIV-1 strains that were able to create infections “more effectively” than others. How? They found that these particular strains were predisposed to do so via biological properties.

The team was able to create 300 virus isolates from “individual HIV-particles” that had infected “both the donors and their matched recipients.” When comparing the recipient (transmitted) viruses with the donor virus isolates, the researchers found that the recipient viruses were actually more infectious by threefold. In addition, their ability to replicate was 1.4 times higher than donor virus isolates.

The researchers also found that when it comes to IFN-alpha2 and IFN-beta—the two type 1 interferons—recipient viruses were found to be “significantly more resistant to the antiviral effects.” Furthermore, to successfully reduce replication by 50%, recipient viruses needed eight times higher concentration of IFN-alpha2 and 39 times more concentrations of IFN-beta than the donor isolates. In addition, the researchers found that the “odds of the interferon-resistant strains replicating in CD4 immune cells [the target cells for HIV]” at the “highest” doses of the two type 1 interferons were 35-fold greater for IFN-alpha2 and 250-fold greater for IFN-beta.

In the press release, co-first author of the study Shipla Iyer, a doctoral student in the Hahn lab, explained, “This means that rapidly multiplying strains of HIV-1 that are interferon resistant have increased transmission fitness.” She continued, “We confirmed this by pretreating CD4 immune cells with interferon prior to virus isolation. In doing this, we were able to select donor isolates that had a transmitted virus-like phenotype.”

Another finding pertaining to the recipient isolates provided the researchers with additional insight into the transmission process. They found that, compared with the donor isolates, infected CD4 immune cells were able to release the recipient isolates more efficiently than their donor counterparts, which suggests that “the production of cell-free particles is important” in the transmission process.

The big takeaway of this study is what the study authors refer to as the “mucosal bottleneck” which “selects for” certain HIV-1 strains that, despite the innate barriers that combat the virus, are still able to successfully and effectively replicate and spread. According to Dr. Hahn, “Knowing the viral properties that confer the ability to transmit [the virus] despite all of the human body’s barriers to infection, might aid the development of vaccines against HIV-1. But we still don’t know which viral gene products render HIV-1 resistant to interferon and how they function. The next steps will be to dissect these mechanisms to define possible new targets for AIDS prevention and therapy.”