Thwarting PAPSS1 may help investigators target HIV, says PLoS Pathogens paper.
A previously unknown regulatory step during HIV replication provides a potentially valuable new target for HIV/AIDS therapy. Researchers have described a separate function for sulfonation, a type of chemical modification that ensures viral genes can be expressed efficiently after HIV successfully integrates into a host genome.
Researchers screened mutagenized cells in an attempt to find ones with an ability to resist infection with murine leukemia virus (MLV), a virus often used as a model system for HIV. 3′-phosphoadenosine 5′-phosphosulfate synthase 1 (PAPSS1) was found to be a gene whose inactivation makes it difficult for MLV to multiply within its host cell. Since PAPSS1 can be shut down with readily available chemical inhibitors, it becomes an attractive target for potential HIV therapeutics.
The research team already knew that certain HIV co-receptors on the cell surface are sulfonated and that this was important for viral entry, but the group realized that sulfonation also played an important role during the infectious cycle within the cell.
The early steps of HIV infection are highly dependent on cellular processes and represent a time when the virus is particularly vulnerable to antivirals and host defense mechanisms. Therefore, “drugs that block the sulfonation pathway might render host cells resistant to HIV infection,” said Paul Ahlquist, Ph.D., professor at the University of Wisconsin.
The team infected cells with retroviruses that inserted themselves into the genome, disrupting the function of individual genes. Further experiments with chemical inhibitors of PAPS synthases and cellular sulfotransferases confirmed the importance of the cellular sulfonation pathway for retroviral replication.
At closer inspection, the virus had no problem getting inside the cell and setting up house. However, if sulfonation was impeded genetically or through chemical inhibitors during or shortly after MLV integration, subsequent gene expression controlled by the viral long terminal repeat (LTR) promoter was compromised. The scientists found the same level of integrated virus DNA but noticed that viral gene expression was 10 to 20 times lower.
LTRs flank the viral genome and function like sticky ends, which integrase uses to insert the HIV genome into the host DNA. But they also act as promoters—regulatory regions that interact with cellular and viral factors to trigger gene expression as well as the transcription of the whole genome into RNA copies that are packaged into the next generation of virus particles.
“Activation of the LTR is a major step in triggering HIV replication but we hadn’t realized before that it is also subject to regulation at a step that coincides with integration,” said Ahlquist.
The study, published in this week’s early online edition of PLoS Pathogens, was a collaboration of investigators at the Salk Institute for Biological Studies and the University of Wisconsin.
