BioWorld International Correspondent
LONDON - A hitherto unknown system of innate immunity against viruses appears to be present in the human genome, several teams of researchers have suggested. The discovery, identified in the course of work to establish why retroviruses like HIV infect such a narrow range of hosts, could lead to new ways of treating HIV, either by gene therapy or by drugs.
Greg Towers, principal investigator in the Division of Infection and Immunity at University College London, told BioWorld International: "We have shown that the protein encoded by a gene called TRIM5alpha and its equivalent in a range of species represents an effective block to HIV and other retroviruses. We now want to find out whether this gene is part of a broad anti-pathogenic virus shield, and we would like to know how it works and how it blocks viral infection."
The study by Towers and his colleagues is titled "The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities." The paper is one of three published this month by the Proceedings of the National Academy of Sciences, which together suggest that TRIM5alpha is an ancient component of the mammalian immune response to viral attack.
For several years, scientists have known that monkey cells appeared to make a protein that blocks HIV from infecting their cells. Towers said: "We had characterized where HIV gets blocked in its life cycle and which part of HIV is sensitive to the block, and why another virus might not be sensitive. We had also been trying to find the gene that encoded this protein."
Then, earlier this year, Joseph Sodroski of Harvard University and colleagues reported in Nature that the protein responsible for blocking HIV infection in rhesus macaques was called TRIM5alpha.
By that time, Towers' group had worked out which retroviruses could or could not infect a series of animal species. For example, while human cells could not block infection with HIV, they could block infection by an equine retrovirus, and they also were resistant to infection with a murine retrovirus. Cells from African green monkeys, similarly, were able to block infection by at least five different retroviruses, including HIV.
"When we read the Sodroski paper," Towers said, "we asked if it was the product of the TRIM5alpha gene in humans that could block the equine and murine viruses, and whether it was the same protein blocking a range of retroviruses in African green monkeys."
To test the hypothesis, they used small interfering RNAs to knock out the expression of TRIM5alpha. "When we repeated our infection experiments, we found that human cells that lacked functional TRIM5alpha now were able to become infected with equine or murine retroviruses to which they had previously been resistant, and that African green monkey cells without TRIM5alpha also became infected by viruses that previously they had blocked," Towers said.
Interestingly, they discovered, TRIM5alpha comes from a large family of genes: humans have about 50 members, and there are probably a similar number in other mammals. When they investigated what was known about the genes, they found one is linked to the cause of promyelocytic leukemia. Studies also had established that the drug arsenic trioxide, which is used to treat PML, works by disabling the TRIM-family protein involved.
Investigations showed that arsenic trioxide could knock out both TRIM5alpha and its normal target protein, and that adding the drug also made the cells susceptible to infection by equine and murine retroviruses. Furthermore, putting the human TRIM5alpha gene into cat cells - which can normally be infected by most retroviruses - conferred the ability to block equine and murine retroviruses, just like human cells.
Papers by Jonathan Stoye and colleagues at the National Institute for Medical Research in the UK, and by Paul Bieniasz and colleagues at the Aaron Diamond AIDS Research Center, in the same issue of PNAS made similar findings.
Towers suggested that it might be possible to treat HIV infection in people by taking bone marrow stem cells and engineering into them the TRIM5alpha gene from African green monkeys, which protects those primates from HIV infection. But that would work only if gene therapy techniques could be perfected.
"It might also be possible to make drugs that will modify the action of the TRIM proteins," he added. "We already have a drug that kills TRIM activity, what we want is one that makes it more effective."