Ancient immune defense mechanism is no match for HIV-1

Researchers have discovered that mammalian cells infected with HIV-1 engage a primitive defense mechanism that was previously observed only in plants and invertebrates. The research also reveals exactly how HIV-1 successfully thwarts this rare form of immunity in vertebrate cells. However, elucidation of the mechanism HIV-1 uses to protect itself provides some critical insight into a potential vulnerability within the HIV-1 molecule. Identification of what might be a long sought after weakness in the virus may have application for rational design of future anti-HIV-1 therapies. The study is published in the May issue of Immunity.

RNA silencing is a type of natural immune defense in which sequence-specific RNA degradation follows the recognition of double-stranded RNA (dsRNA). The dsRNA is processed by a protein called Dicer, which chops the long strands of RNA into smaller pieces, resulting in the production of an RNA-induced silencing complex (RISC). RISC can specifically identify and degrade complementary target RNA. This process is known as RNA interference (RNAi) and can silence the ability of a virus to successfully reproduce itself. Although this mechanism has been artificially manipulated to selectively inhibit specific genes in mammalian cells, it was not known whether mammalian viruses naturally elicit this type of immunity in vertebrate cells.

Drs. Yamina Bennasser and Kuan-Teh Jeang from the Molecular Virology Section at the National Institute of Allergy and Infectious Disease and colleagues found that infection with HIV-1 induces RNAi in human cells. However, the researchers discovered that HIV-1 has an intriguing strategy to combat this cellular defense. The HIV-1 protein Tat, well known as a transcriptional activator, also can function as a suppressor of RNA silencing (SRS). Tat helps HIV-1 to elude the cell's natural RNAi defense by interfering with the ability of Dicer to process dsRNAs.

"Our results suggest that the dynamic interplay between RNAi and SRS remains physiologically conserved from plants and invertebrates to higher vertebrate animals," explains Dr. Jeang. "Our finding that Tat is an SRS also helps explain the long-standing biological observation that when HIV-1 is engineered to be lacking Tat but contains alternative transcriptional activators, it fails to spread productively in human cells." The researchers also suggest that their findings raise a challenge to proposed therapeutic strategies making use of RNAi. "Because HIV-1 evades all other RNAi by point mutations, we reason that its requirement for an SRS is solely to shield this last 'Achilles' heel that we think HIV-1 cannot alter for functional reasons. The sequence we describe may represent a viable target for RNAi that HIV-1 cannot elude by using the point mutation mechanism, " explains Dr. Jeang.

The researchers include Yamina Bennasser and Kuan-Teh Jeang of the National Institute of Allergy and Infectious Diseases; Shu-Yun Le of the National Cancer Institute; and Monsef Benkirane of the Institut de Genetique Humaine, CNRS.

Bennasser, Y., Le, S.-Y., Benkirane, M., and Jeang, K.-T. (2005). Evidence that HIV-1 Encodes an siRNA and a Suppressor of RNA Silencing. Immunity, 22, 607-619. http://www.immunity.com

Source : Cell Press