Mutant host cell protein sequesters critical HIV-1 element

January 15, 2009

Scientists have identified a new way to inhibit a molecule that is critical for HIV pathogenesis. The research, published by Cell Press in the January 16th issue of the journal Molecular Cell, presents a target for development of antiretroviral therapeutics that are likely to complement existing therapies and provide additional protection from HIV and AIDS.

Infection of human cells with HIV-1 requires multiple events that involve complex interactions between viral elements and cellular proteins. The virus must copy key parts of its DNA as mRNA molecules through a process called transcription. The mRNA molecules must be properly "spliced", or rearranged, and then transported out of the cell nucleus and into the cytoplasm where the mRNAs can be "translated" into viral proteins.

"Although there has been a great deal of effort directed at understanding HIV-1 transcription, mRNA splicing and nuclear export, little is known about the translational control of HIV-1 RNA in the cytoplasm," says senior study author, Dr. Johnny J. He from the Center for AIDS Research at Indiana University School of Medicine.

Dr. He and colleagues examined a protein called HIV-1 Nef that is translated from completely spliced HIV-1 RNA. Nef is very important for HIV pathogenesis and AIDS disease. "It is highly conceivable that intervention with Nef expression may complement the current anti-HIV therapies that are mainly targeted at HIV-1 protease and reverse transcriptase, providing a better treatment outcome," explains Dr. He.

The researchers found that a mutant form of Src-associated protein in mitosis of 68kDa (Sam68), a host cellular protein involved in HIV-1 pathogenesis, specifically interacts with nef mRNA and directly suppresses Nef expression. This particular Sam68 mutant was previously shown to inhibit HIV-1 replication by overriding its wild-type counterpart's function in nuclear export of unspliced and incompletely spliced HIV RNA. However, the mutant Sam68 was present in the cytoplasm, suggesting that it may serve some function in the cytoplasmic stage of the HIV-1 life cycle.

The ability of the Sam68 cytoplasmic mutant to interfere with Nef correlated with its ability to induce stress granules in the cytoplasm. Stress granules regulate gene expression at the translational level in response to a variety of external stimuli. Importantly, nef mRNA was targeted to and enriched in the stress granules.

"Taken together, these results demonstrate that stress granule induction and nef mRNA sequestration account for this translational suppression of Nef expression and offers a new strategy for development of anti-HIV therapeutics to buttress our fight against HIV/AIDS," concludes Dr. He.

Source: Cell Press

Explore further: Coping mechanism suggests new way to make cancer cells more vulnerable to chemotherapies

Related Stories

ALS study reveals role of RNA-binding proteins

October 20, 2016

Although only 10 percent of amyotrophic lateral sclerosis (ALS) cases are hereditary, a significant number of them are caused by mutations that affect proteins that bind RNA, a type of genetic material. University of California ...

Study gives clues to causes of motor neurone disease

October 10, 2012

(Medical Xpress)—Scientists at the University of Bath are one step further to understanding the role of one of the proteins that causes the neurodegenerative disorder, Amyotrophic Lateral Sclerosis (ALS), also known as ...

Silent RNAs express themselves in ALS disease

December 2, 2013

RNA molecules, used by cells to make proteins, are generally thought to be "silent" when stowed in cytoplasmic granules. But a protein mutated in some ALS patients forms granules that permit translation of stored RNAs, according ...

Recommended for you

HIV hijacks common cells to spread infection

February 16, 2017

Scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), together with collaborators in Europe, discovered that a common type of cell within the human reproductive and intestinal tracts ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.