Hopes languished last September when a promising candidate HIV vaccine failed to work. Despite this setback, many researchers still believe immunization is possible, and a new study suggests they're correct-at least at the cellular level.
Working in mice infected with HIV, a team used a method called RNA interference to knock down three genes in T cells, protecting them from the virus. This method seemed to prevent HIV from jumping between cells in the mice.
"For the first time, we've used RNAi to dramatically suppress HIV infection in an organism," says corresponding author Premlata Shankar, who conducted the work while she was a junior investigator at the Harvard Medical School-affiliated Immune Disease Institute and an assistant professor at Harvard Medical School. Shankar is now a professor at Texas Tech University Health Sciences Center in El Paso.
Although labs must verify the findings in other animal models before attempting clinical trials, this method-published online Aug. 7 in Cell - may eventually supplement or replace the harsh drug cocktails currently prescribed to patients with HIV, reducing the side effects of treatment.
When the Nobel Prize in Physiology or Medicine was awarded in 2006 for the discovery of RNAi, the judges speculated that it might "lead to novel therapies in the future." Researchers hoped to flood specific cells in patients with short interfering RNAs (siRNAs), molecules that silence genes by disrupting the protein templates they produce. But scientists weren't sure how to deliver the siRNAs exclusively into relevant cell types within an organism.
In collaboration with Sang-Kyung Lee of Hanyang University, Shankar's lab overcame this obstacle, delivering siRNAs directly into T cells, which are targeted by HIV. The team used an apparatus analogous to a truck equipped with GPS and a trailer hitch to haul the siRNAs to their destination. The truck-in this case, a single-chain antibody developed by Georg Fey of the University of Erlangen in Germany-homed to a protein found exclusively on the surface of T cells. The trailer hitch-an oligo-9-arginine-pulled siRNAs along for the ride.
This new antibody delivery vehicle lends itself to mass production in a dish. The team built thousands of these carriers for use in experiments, loading them with siRNAs targeting three key genes. One encodes a human protein called CCR5, which dots the surface of T cells and allows HIV to gain entry. The others encode proteins produced by the virus within cells upon infection.
Harvard Medical School postdoctoral researcher and first author Priti Kumar mixed the siRNAs with the antibody carriers and injected them into the veins of mice that harbor human T cells rather than their own. These mice serve as an animal model of HIV. After being infected with the virus, the mice mirror progression of the disease in humans.