Unraveling the mysteries of the HIV life cycle

Although recently overshadowed by the global epidemic of COVID-19, humanity is still facing an epidemic of another disease, HIV/AIDS, with approximately 38 million people living with HIV worldwide, according to UNAIDS. Many people have died as a result of HIV infection since the epidemic began in the 1980s.

Researchers from Germany have recently developed a new technique that may be able to analyze and influence key stages of the HIV lifecycle, with the results of the study "Short- and long-range interactions in the HIV-1 5' UTR regulate genome dimerization and packaging" published in the international journal Nature Structural & Molecular Biology.

Critical stages of the viral life cycle represent very attractive targets for drugs and therapies, making it particularly important to conduct basic research to understand and influence the underlying molecular processes. A distinctive feature of HIV-1 mutants is that they contain two copies of the viral genome, which can be brought together during viral replication by a process called dimerization, which is also a prerequisite for viral packaging and can ultimately lead to the production of novel infectious viral particles and the conduct of the complete viral replication process.

In this study, researchers described FARS-seq (functional analysis of RNA structure), a novel technique that can investigate the HIV-1 life cycle at single nucleotide resolution. This technique may help researchers identify regions of the HIV-1 genome that are important for dimerization and viral packaging. Professor Redmond Smyth, who led the study, explained that dimerization is required for viral packaging, which has long been discussed in HIV-1 research. The molecular mechanisms underlying it, which are currently unknown to researchers, are provided at high resolution in this paper's study, which may also hold promise for targeted interventions.

The results of this study show that the HIV-1 genome exists in two different RNA conformations, only one of which is involved in the genome packaging process, and the second conformation, in which the RNA stays in the host cell and is subsequently translated into new viral proteins, thus acting as a molecular switch that directs the fate of viral RNA and the replication process of the virus. Now that scientists have identified sequences that regulate the balance between the two RNA conformations, this study reveals how virulence factors bind to these regions and can be used to target or interfere with viral assembly.

The researchers hope to use their findings to develop RNA-based antiretroviral drugs or improved gene therapy vectors in the future, and in the next study, they would like to see if these findings apply to other HIV strains as well through more in-depth studies. Taken together, the findings of this paper may provide new insights into the HIV-1 life cycle as well as a mechanistic explanation for the association between RNA dimerization and packaging.