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Novel Enzyme Shows Potential As An Anti-HIV Target

At just 9.8 kilobases, the HIV genome pales in comparison to the 3.2 gigabases of its human and nonhuman primate targets. The compact retrovirus encodes just 14 proteins, which play different roles in promoting viral infection and virulence. As a retrovirus, HIV uses the host’s cellular machinery—including RNA polymerases, which carry out transcription—to copy its RNA genome into DNA and infiltrate human chromosomal DNA. Once the virus is integrated (now called a provirus), its genes can be transcribed.

Adept as HIV is in exploiting its host’s molecular resources, the virus can’t establish a foothold without the services of its skeleton crew. The HIV transcription factor Tat (“transactivator of transcription?, for example, is an essential regulator of HIV gene expression. Without Tat, HIV transcripts don’t reach full length and can’t effect viral replication. In a new study, Melanie Ott and colleagues identify an enzyme that regulates viral transcription by modifying Tat.

The regulation of HIV genes depends on a complex interplay between proviral DNA, cellular proteins and transcription factors, and Tat. Unlike most transcription factors, Tat activates transcription by binding to RNA, specifically to a bulging “stem-loop?structure that forms at one end of all viral transcripts called the trans-acting responsive element (TAR). Tat binding to TAR requires recruiting the enzyme cyclin-dependent kinase 9 (CDK-9) to the HIV promoter (where transcription begins). CDK-9 chemically modifies the RNA polymerase and enhances its transcribing efficiency.

The transcription process—including the labyrinthine protein–protein and protein–DNA (and in the case of Tat, protein–RNA) interactions—is highly regulated. One process that figures prominently in this regulation is acetylation, which adds an acetyl group (a molecule made of oxygen, hydrogen, and carbon) to a molecule or protein. Histone acetylation was long thought to influence transcription by regulatin
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Source:PLoS Biology


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