Shedding light on the HIV life cycle
There is currently no cure for HIV infection. To treat this condition, the world needs new and better antiviral drugs. In their quest for new treatments, scientists supported in part by the EU-funded T-FRAME project, coordinated by Jun-Prof. Neva Caliskan at Helmholtz Centre for Infection Research, Germany (HZI), have developed a new approach that can be used to analyse and impact key stages of the virus’ life cycle. Their study was published in the journal ‘Nature Structural & Molecular Biology’. HIV has infected approximately 84 million people and killed about 40 million worldwide since the start of the HIV epidemic in the early 1980s. Forty years on, there are still around 38 million people living with HIV – including 1.7 million children under 15 years of age. This highlights the urgent need for new approaches to antiviral therapies. However, to achieve these, we need a better understanding of the molecular processes underlying key states in the virus’ life cycle. Just like in other retroviruses, each viral particle of HIV contains two copies of the RNA genome. During viral replication, two genomes are combined in a process called dimerisation that is assumed to be a prerequisite for genome packaging. In genome packaging, viruses gather their genomes into capsids whose main purpose is to protect the genomes until they can be released into a new host for further replication. Focusing on HIV-1, the variant responsible for the vast majority of HIV infections, the researchers have now developed a new technology called Functional Analysis of RNA Structure. Called FARS-seq for short, it investigates the sequences and structures in HIV-1 that play an important role in dimerisation and genome packaging.
Making molecular mechanisms clear
“The idea that dimerization is a prerequisite for packaging has long been discussed in HIV-1 research. However, the underlying molecular mechanisms remained unclear. Our study provides this information in high resolution, allowing targeted intervention,” explains study senior author Jun-Prof. Dr Redmond Smyth, initiator of the study and research group leader at HZI, in a news item posted on the website of the Centre’s Helmholtz Institute for RNA-based Infection Research (HIRI). Study first author and HIRI researcher Liqing Ye explains further: “We were able to show that the genome of HIV-1 exists in two different RNA conformations. Only one of them is involved in genome packaging. In the second conformation, the RNA remains in the host cell to be translated into new viral proteins. These two conformations therefore act like a molecular switch to direct the fate of the viral RNA, and thus viral replication.” Aided by FARS-seq, the team comprehensively identified sequences and structures within the 5′ untranslated region of HIV-1 messenger RNA that regulate the equilibrium between the two conformations. “We hope to be able to leverage these findings into RNA-based antiretroviral drugs or improved gene therapy vectors,” states Jun-Prof. Dr Smyth in the same news item. The T-FRAME (Real-time analysis of ribosomal frameshifting and its impact on immunity and disease) project ends in 2026. For more information, please see: T-FRAME project
Keywords
T-FRAME, HIV, virus, HIV-1, RNA, genome, molecular, viral, dimerisation, genome packaging