Security guard. HIV-1, shown here on a lymphocyte, may be stopped at the cell's entrance if small RNAs are used to disable a key receptor.

Interfering With HIV

Short stretches of RNA, called small RNAs, can interfere with gene function and are thought to protect the genome against harmful DNA or viruses. A new study now shows that these RNA bits can be used to make cells resist one of the deadliest viruses, HIV.

HIV enters cells through receptors studding the surface of immune system soldiers called helper T cells. To accomplish this, HIV binds to a protein called CD4 and is assisted by another protein called CCR5. Because people with a mutation in their CCR5 gene, which produces the co-receptor, are resistant to HIV infection, scientists have long suspected that disrupting the production of CCR5 might be a way to "immunize" cells against HIV.

Virologist David Baltimore of the California Institute of Technology in Pasadena, along with virologist Irvin Chen of the University of California, Los Angeles, and their colleagues, decided to see whether they could use small interfering RNAs (siRNAs), class of small RNAs, to inhibit the CCR5 gene. The team created a gene therapy by packaging the molecules inside a vector--a virus called a lentivirus, which was derived from HIV itself. According to postdoctoral researcher Xiao-Feng Qin, the study's first author, once inside the cell the DNA copy of siRNAs integrate into the cell's chromosomes, allowing that cell's offspring to inherit a largely inactive CCR5 gene. SiRNAs blocked the expression of CCR5 by up to tenfold in the daughter cells of cells with normal CCR5 expression. When challenged with HIV-1, control cells showed three to seven times higher infection rates than cells with reduced CCR5 expression, the team reports in the 23 December online issue of the Proceedings of the National Academy of Sciences.

"This is a very nice, well-controlled study, and obviously CCR5 is a target of interest in anti-HIV gene therapy," says molecular biologist John Rossi of City of Hope Cancer Center near Los Angeles. But he says that this strategy will be more effective when combined with additional viral targets--something the Baltimore group is already working to do. Others agree that more work is needed. "It is an important first step but, like all genetic therapies, the path to the clinic is still a ways off," says virologist Judy Lieberman of Harvard Medical School's Center for Blood Research in Boston.

Related sites
Baltimore's Lab
Chen's Lab
Science's Breakthrough of the Year: Small RNAs