HIV roadblock in HD

NEW YORK—Researchers at NYU Langone Medical Center havereleased a new study detailing a natural mechanism by which the immune systemseeks to fight the spread of HIV, a discovery that sheds more light on theworkings of the immune system and opens up new avenues of research for slowingthe progression of HIV to AIDS. The study was published in Nature Immunology online ahead of print.

The protein responsible, SAMHD1, is found mainly in myeloidcells, either macrophages or dendritic (immune) cells. Research has shown thatdendritic cells containing SAMHD1 are resistant to infection by HIV. When avirus such as HIV infects a cell, it takes control of the cell's molecularmaterial, specifically the deoxynucleotide triphosphates (dNTPs), to replicate.When a virus replicates, the DNA molecule that results contains all of thevirus' genes, and it sets about making more copies of itself. SAMHD1, however,blocks this by destroying the pools of dNTPs, a process researchers callnucleotide pool depletion, in a move that denies a virus the tools necessaryfor replication.

Unfortunately, like most viruses, HIV has evolved, changingto replicate primarily in CD4 T-cells, which do not contain SAMHD1. Accordingto Dr. Nathaniel R. Landau, co-lead investigator for the study, the virushas likely evolved in this way in order to purposely avoid trying to infectSAMHD1-containing cells in order to avoid trigger the greater immune system toactivate an antiviral response. Some of the viruses related to HIV, such asHIV-2 and SIV, have developed a protein called viral protein X (vpX) thatdirectly attacks SAMHD1, which then allows the virus to infect dendritic cells.

"Viruses are remarkably clever about evading our immunedefenses," said Landau, who is a professor of microbiology at the Joan and JoelSmilow Research Center at NYU School of Medicine, part of NYU Langone MedicalCenter. "They can evolve quickly and have developed ways to get around thesystems we naturally have in place to protect us. It's a bit of evolutionarywarfare and the viruses, unfortunately, usually win. We want to understand howthe enemy fights so that we can outsmart it in the end."

There is more research to be done to understand the proteinand its mechanisms, says Landau, noting that that understanding could lead tonew ideas about how to slow or stop the spread of HIV. More needs to bediscovered, such as determining which immune cells contain the protein andwhich don't, and whether it protects other cells besides macrophages anddendritic cells, such as T-cells. And Landau doesn't think SAMHD1's potentialis 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," saysLandau. "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 anypotential for being developed for therapeutics, given how recently the proteinwas discovered, but he thinks it's likely that SAMHD1 might be helping to protectagainst other viruses and bacteria in addition to HIV.

"Our direction that we are interested in with HIV is to usethis information not so much for therapeutics, but for vaccine development. Sowe would like to be able to have vaccines that work in dendritic cells, and HIVdoes not infect dendritic cells very well, because of SAMHD1, and some of thefactors that are used in vaccines also are blocked of working in dendriticcells," 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 anotherviral protein called vpX. So we can use vpX in order to make vaccines that willwork in dendritic cells. Dendritic cells are very good for vaccines, becausethey are an important component of the immune system."

"Over the past few years, a number of these naturalresistance mechanisms have been identified, specifically in HIV, but some havepotential 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 arebeing revealed through molecular biology, and we're learning a tremendousamount about how our immune system works through the study of HIV."

The study, "SAMHD1 restricts the infection of myeloid cellswith human immunodeficiency virus type 1 by depleting the intracellular pool ofdeoxynucleoside triphophates," was done in collaboration with researchers atseveral institutions, including the University of Rochester Medical Center andThe Cochin Institute in Paris. The National Institutes of Health and theAmerican Foundation for AIDS Research both contributed to funding the study.