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February 23, 2016

Understanding HIV Genome Methylation Could Aid Drug Design

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    The HIV lifecycle. Once HIV RNA is within the nucleus (Step 4), methylation of key genes in the host and HIV genomes were found to affect viral replication. [NIH]

    Better therapies for treating individuals infected with HIV have been slow to make it out of the laboratory and deep into clinical trials. Now, a team of researchers at University of California, San Diego School of Medicine believe they have uncovered an essential piece of data that has been overlooked for decades.  

    "We and other colleagues at pharmaceutical companies have worked over the years to develop drugs targeting HIV's genetic material, its RNA, but we never made it to the clinic," remarked senior study author Tariq Rana, Ph.D., professor of pediatrics at UC San Diego School of Medicine. "Now we know why—we were developing drugs using RNA targets that didn't have these modifications when in reality the RNA was different."

    In the current study, the UCSD scientists discovered that HIV infection of human immune cells triggers a massive increase in methylation to both human and viral RNA, which ultimately aids the replication of the virus.

    The findings from this study were published recently in Nature Microbiology through an article entitled “Dynamics of the human and viral m6A RNA methylomes during HIV-1 infection of T cells.”

    In human cells, RNA shuttle genetic information from DNA in the nucleus to the protein production machinery in the cell’s cytoplasm. In contrast, the HIV is composed solely of RNA—relying on hijacking the cell’s molecular machinery to replicate and create more viral particles.     

    Methylation of RNA and DNA is one mechanism cells utilize to regulate gene expression or alter its function. One of these modifications, known as N6-methyladenosine (m6A), is common in humans and other organisms. However, little was known about the role m6A plays in the human immune system, or in the interactions between our cells and invading pathogens, such as HIV.

    The investigators discovered m6A modifications in HIV RNA for the first time. Moreover, they also examined m6A's effect on function in both HIV and human host RNA during infection of human immune cells.  

    "M6A had always been considered a steady modification of cellular RNA. Instead, it turned out to be extremely dynamic and highly responsive to external stimuli, such as viral infections," explained lead study author Gianluigi Lichinchi, a graduate student in Dr. Rana's lab. "In the future, these findings could aid in improving the design and efficacy of HIV/AIDS vaccines."

    “In HIV-1 mRNA, we identified 14 methylation peaks in coding and noncoding regions, splicing junctions and splicing regulatory sequences,” they authors wrote. “We also identified a set of 56 human gene transcripts that were uniquely methylated in HIV-1-infected T cells and were enriched for functions in viral gene expression.”

    An essential step in HIV replication is through the actions of a protein named Rev. Rev proteins are built in the human host cell's cytoplasm, yet they move back into the nucleus, where they assemble at a particular point on HIV RNA called the Rev-responsive element (RRE). There, Rev aids in transporting newly produced HIV RNA transcripts into the host cytoplasm.

    Dr. Rana and his team found that m6A modification of both human and viral RNA impacts the interaction between the HIV Rev protein and the RNA RRE. When the scientists silenced the enzyme that removes m6A from RNA, HIV replication increased. However, when they silenced the enzyme that adds m6A to RNA, HIV replication decreased—a finding the researchers say may be exploited for the development of new drug cocktails.

    "The HIV field has missed this modification in physiological RNA structure and HIV genome for more than 30 years," Dr. Rana noted. "I will not be surprised if other viruses with RNA genomes also exploit this m6A modification mechanism to evade immune surveillance and control their replication in human cells. These viruses include, for example, influenza, Hepatitis C, Ebola, and Zika, just to name a few."

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