Without an HIV vaccine, prevention and treatment currently focuses on giving people living with the virus daily antiretroviral medicines. These drugs keep people healthy, and prevent onward transmission. “However, finding all people with HIV can be a challenge,” says BEEHIVE project coordinator Christophe Fraser, senior group leader in pathogen dynamics at the Nuffield Department of Medicine, University of Oxford, whose team is also working on stopping the spread of COVID-19. One of the challenges of identifying people with HIV is that: “Only flu-like symptoms are experienced at the time of infection, and then typically no symptoms until progression to AIDS years later.” Understanding the biology of the virus, its evolution as well as patterns of transmission therefore remain crucially important to developing successful HIV prevention strategies, by helping health experts to focus on sections of the population most at risk.
Filling knowledge gaps
BEEHIVE sought to fill a critical knowledge gap by searching for mutations in the virus’s genetic sequence linked to virulence, i.e. the severity of infection. One way of measuring virulence is the set-point viral load (SPVL). This is the concentration of the virus in blood plasma during the chronic stage of the disease. The project was able to build on previous groundbreaking work, carried out by Fraser and his team, which found that the SPVL that most favours the virus was the one most commonly observed. “We hypothesised that SPVL was partly under the virus’s control, and not just a result of each person’s immune system in its fight with the virus,” says Fraser. “The question was whether differences in the virus’s genetic sequence could be shown to be linked to virulence.” In other words, there should be mutations that increase or decrease how severe the infection will be. To find out, the BEEHIVE project worked with patients from eight European countries and Uganda. A dataset with detailed characterisations of disease progression was assembled, and blood samples collected from which the virus was extracted and its genetic sequence determined. The data gathered was so complex that a new computational method, called shiver, had to be developed. This led to a second computational method, called phyloscanner, which is a powerful tool for inferring viral transmission from sequence data
Scaled-up HIV analysis
The project team were able to successfully identify viral mutations linked to virulence. “We were also able to confirm that approximately one third of the variation in SPVL is due to the virus,” says Fraser. “The hope for any investigation like this is that better understanding of the molecular basis of virulence will one day lead to improved ways of stopping it.” Clinical samples fed into shiver and phyloscanner also gave the team a clearer picture of transmission patterns in populations, and BEEHIVE succeeded in characterising dual infections (when one individual is infected with two distinct HIV viruses). A key legacy of the BEEHIVE project, completed in March 2019, has been to demonstrate that HIV sequencing and associated analysis can be carried out at an unprecedented scale. Fraser and his team are currently involved in translating these insights into public health interventions in sub-Saharan Africa. "We anticipate replicating our BEEHIVE analyses within the newer, larger datasets of these African projects,” he concludes.
BEEHIVE, HIV, vaccine, antiretroviral, virulence, AIDS, virus, SPVL, genetic, sequencing, COVID-19