MicroRNAs Help Control HIV Life Cycle
Scientists at Burnham Institute for Medical Research (Burnham) have discovered that specific microRNAs (non-coding RNAs that interfere with gene expression) reduce HIV replication and infectivity in human T-cells. In particular, miR29 plays a key role in controlling the HIV life cycle. The study suggests that HIV may have co-opted this cellular defense mechanism to help the virus hide from the immune system and antiviral drugs.
Tariq Rana, Ph.D., director of the Program for RNA Biology at Burnham, and colleagues, found that the microRNA miR29 suppresses translation of the HIV-1 genome by transporting the HIV mRNA to processing-bodies (P-bodies), where they are stored or destroyed. This results in a reduction of viral replication and infectivity. The study also showed that inhibition of miR29 enhances viral replication and infectivity. The scientists further demonstrated that strains of HIV-1 with mutations in the region of the genome that interact with miR29 are not inhibited by miR29.
“We think the virus may use this mechanism to modulate its own lifecycle, and we may be able to use this to our advantage in developing new drugs for HIV,” said Dr. Rana. “Retroviral therapies greatly reduce viral load but cannot entirely eliminate it. This interaction between HIV and miR29 may contribute to that inability. Perhaps, by targeting miR29, we can force HIV into a more active state and improve our ability to eliminate it.”
Rana’s team looked at miR29 expression levels in infected and uninfected cells and found that miR29 expression was enhanced by HIV-1 infection. Blocking the activity of miR29 with interfering RNA resulted in increased replication and infectivity of the virus. The scientists tested the association of miR29 and HIV-1 by mutating both miR29 and its target region on the HIV virus. When either was altered, miR29s suppression of HIV replication and infectivity was reduced or eliminated.
In addition, the team suppressed P-bodies in the cells and noted a similar effect. This suggests that HIV may use miRNAs to become dormant and escape immune response.
Molecular Cell, Volume 34, Issue 6, 686-695, 26 June 2009
Cellular MicroRNA and P Bodies Modulate Host-HIV-1 Interactions p696
Robin Nathans 1,Chia-ying Chu 1,2, Anna Kristina Serquina 1,Chih-Chung Lu 1,2, Hong Cao 1 and Tariq M. Rana 1,2, Corresponding Authors,
1 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA
2 Program for RNA Biology, Sanford Children’s Health Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
MicroRNAs (miRNAs), 22 nt noncoding RNAs, assemble into RNA-induced silencing complexes (RISCs) and localize to cytoplasmic substructures called P bodies. Dictated by base-pair complementarity between miRNA and a target mRNA, miRNAs specifically repress posttranscriptional expression of several mRNAs. Here we report that HIV-1 mRNA interacts with RISC proteins and that disrupting P body structures enhances viral production and infectivity. In HIV-1-infected human T lymphocytes, we identified a highly abundant miRNA, miR-29a, which specifically targets the HIV-1 3UTR region. Inhibiting miR-29a enhanced HIV-1 viral production and infectivity, whereas expressing a miR-29 mimic suppressed viral replication. We also found that specific miR-29a-HIV-1 mRNA interactions enhance viral mRNA association with RISC and P bodyproteins. Thus we provide an example of a single host miRNA regulating HIV-1 production and infectivity. These studies highlight the significance of miRNAs and P bodies in modulating host cell interactionswith HIV-1 and possibly other viruses.