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HIV roadblock in HD
NEW YORK—Researchers at NYU Langone Medical Center have released a new study detailing a natural mechanism by which the immune system seeks to fight the spread of HIV, a discovery that sheds more light on the workings of the immune system and opens up new avenues of research for slowing the progression of HIV to AIDS. The study was published in Nature Immunology online ahead of print.
The protein responsible, SAMHD1, is found mainly in myeloid cells, either macrophages or dendritic (immune) cells. Research has shown that dendritic cells containing SAMHD1 are resistant to infection by HIV. When a virus such as HIV infects a cell, it takes control of the cell's molecular material, specifically the deoxynucleotide triphosphates (dNTPs), to replicate. When a virus replicates, the DNA molecule that results contains all of the virus' genes, and it sets about making more copies of itself. SAMHD1, however, blocks this by destroying the pools of dNTPs, a process researchers call nucleotide pool depletion, in a move that denies a virus the tools necessary for replication.
Unfortunately, like most viruses, HIV has evolved, changing to replicate primarily in CD4 T-cells, which do not contain SAMHD1. According to Dr. Nathaniel R. Landau, co-lead investigator for the study, the virus has likely evolved in this way in order to purposely avoid trying to infect SAMHD1-containing cells in order to avoid trigger the greater immune system to activate an antiviral response. Some of the viruses related to HIV, such as HIV-2 and SIV, have developed a protein called viral protein X (vpX) that directly attacks SAMHD1, which then allows the virus to infect dendritic cells.
"Viruses are remarkably clever about evading our immune defenses," said Landau, who is a professor of microbiology at the Joan and Joel Smilow Research Center at NYU School of Medicine, part of NYU Langone Medical Center. "They can evolve quickly and have developed ways to get around the systems we naturally have in place to protect us. It's a bit of evolutionary warfare and the viruses, unfortunately, usually win. We want to understand how the enemy fights so that we can outsmart it in the end."
There is more research to be done to understand the protein and its mechanisms, says Landau, noting that that understanding could lead to new ideas about how to slow or stop the spread of HIV. More needs to be discovered, such as determining which immune cells contain the protein and which don't, and whether it protects other cells besides macrophages and dendritic cells, such as T-cells. And Landau doesn't think SAMHD1's potential is limited to fighting HIV.
"I think it's very likely that it will affect other viruses, particularly retroviruses, which are the same class of virus as HIV," says Landau. "There's another human retrovirus called human T-cell leukemia virus, that could be affected by SAMHD1. And other viruses could be affected as well; any virus that uses DNA to replicate could be affected."
Landau says it's too early to know whether SAMHD1 has any potential for being developed for therapeutics, given how recently the protein was discovered, but he thinks it's likely that SAMHD1 might be helping to protect against other viruses and bacteria in addition to HIV.
"Our direction that we are interested in with HIV is to use this information not so much for therapeutics, but for vaccine development. So we would like to be able to have vaccines that work in dendritic cells, and HIV does not infect dendritic cells very well, because of SAMHD1, and some of the factors that are used in vaccines also are blocked of working in dendritic cells," says Landau. "Now that we know that SAMHD1 is blocking those vaccine vectors, now we know how to overcome the block of SAMHD1. We overcome it with another viral protein called vpX. So we can use vpX in order to make vaccines that will work in dendritic cells. Dendritic cells are very good for vaccines, because they are an important component of the immune system."
"Over the past few years, a number of these natural resistance mechanisms have been identified, specifically in HIV, but some have potential applications to other viruses, as well," he noted in a press release. "This is a very exciting time in HIV research. Many of the virus' secrets are being revealed through molecular biology, and we're learning a tremendous amount about how our immune system works through the study of HIV."
The study, "SAMHD1 restricts the infection of myeloid cells with human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphophates," was done in collaboration with researchers at several institutions, including the University of Rochester Medical Center and The Cochin Institute in Paris. The National Institutes of Health and the American Foundation for AIDS Research both contributed to funding the study.