Know the traits of HIV-1 strains capable of establishing new infections could be important for AIDS vaccine development.
After developing methods for their accurate identification, George Shaw, Beatrice Hahn, and Nicholas Parrish, from the Department of Microbiology at the Perelman School of Medicine, and their colleagues, generated infectious clones of transmitted founder and chronic control HIV-1 strains and compared their traits to probe the earliest stages of HIV-1 infection.
Transmitted founder (TF) viruses from acutely infected patients have all the genetic tools to start a new infection, while chronic control (CC) viruses from long-term HIV patients have the genetic tools to sustain an infection for years.
After a transmitted founder strain of HIV-1 infects mucosal tissues, it spreads to nearby and distant tissues, including the gut-associated lymphoid tissue. There, the virus expands exponentially, triggering a systemic cytokine storm, preceding peak viral load in the blood.
Transmission across mucous barriers is inherently inefficient and associated with a viral population bottleneck. Indeed, in 60 to 80 percent of mucosal infections, a single transmitted founder virus is responsible for productive clinical infection.
The Penn team, together with Los Alamos National Laboratory colleagues Elena Giorgi, James Theiler and Bette Korber, also perfected a way to infer the genetic blueprint of a transmitted founder virus as it established itself to capture its biological properties.
The team characterized the different attributes of the early transmission process and published their findings this week in the Proceedings of the National Academy of Sciences:
- Transmitted founder viruses show a greater interaction with dendritic cells, the first immune cell that picks up the virus and presents it to the CD4 immune cell, compared to chronic viruses.
- Transmitted founder viruses have more envelope glycoprotein on the surface of virion particles compared to control viruses. After HIV-1 gets past the mucosal barrier and establishes itself in other places in the body, it makes sense that it then loses some of the envelope glycoprotein to hide from host immune cells.
- The resistance of transmitted founder viruses to interferon is greater than that of chronic viruses. Release of the cytokine interferon by immune cells is the first step in the innate immune response, which sets 100-plus target genes into motion. “It’s like setting off a fire alarm,” says Hahn. Transmitted viruses have a greater resistance to this initial host defense, which means that they replicate more efficiently in the presence of this early innate immune response.
A primary goal of AIDS vaccine development is to prevent acquisition of HIV-1 at mucosal surfaces, where the virus first enters the body.
“The implications for making a better AIDS vaccine is to capitalize on the fact that HIV-1 is quite sensitive to early innate immune responses,” says Hahn. “We need to know which interferon stimulated genes are involved and learn how to replicate and potentiate their actions through a vaccine.”
This research was supported by the National Institutes of Health (R01 AI45378, R01 AI04088, P30 AI45008, and P30 AI27767), the Center for HIV/AIDS Vaccine Immunology (U19 AI067854), the Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (UM1 AI100645), and the Bill and Melinda Gates Foundation.