This story originally ran on May 13.
Aiming to gain a clearer understanding of the effects of drug abuse on the progression of HIV/AIDS, the US National Institute of Drug Abuse awarded researchers at Case Western Reserve University a three-year, $3 million grant to develop protein and epigenetic biomarkers and new technology to track progression of the disease, the school announced last week.
The award — part of an program initiated by NIDA in 2007 to learn more about how HIV/AIDS progresses in patients who use illicit drugs — will fund research at Case Western Reserve's Center for Proteomics and Bioinformatics and its Center for AIDS Research.
According to the school, the grant will allow investigators at the Center for Proteomics and Bioinformatics to expand their research activities in the disease and enable the Center for AIDS Research to "introduce advanced proteomic technology into its research portfolio."
The grant amount for the first year is $989,108. In 2010 and 2011 the amounts will increase to a little over $1 million each year. The money will be used to hire new personnel to do the research and fund three pilot projects, Mark Chance, director of the Center for Proteomics and Bioinformatics, told ProteoMonitor this week.
One will investigate changes in the immune system of patients who are current or past drug abusers and who are co-infected with hepatitis C. Another will examine how epithelial cells react to HIV/AIDS and drugs, and the third will examine the effect of the virus and drugs on T-cells.
The grant is one of five awarded by NIDA during the past year in an effort to use proteomics technology to fill in the knowledge chasm within the research community about the effects of drug abuse on the biology of HIV/AIDS.
While there are a number of theories that drug abuse hastens progression of the disease, "there isn't any proof of that. The data is a little fuzzy, shall we say," Chance said. "We wanted to ask that question [whether drug use affects disease progression] in as concrete a fashion as possible."
One area that he and his colleagues will be pursuing is whether there are cytokines and molecules in blood that tend to cause the immune system "to spin out of control," he said.
They also want to explore the role that drug abuse has on T-cells in the gut. "AIDS infects gut cells. It causes the mucosal barriers in the gut to be compromised and a lot of bacterial products get released into the serum and cause immune kind of responses," Chance said. "We talk about loss of T-cells in AIDS patients [but] most of the loss of T-cells in AIDS patients isn't in plasma, they're in the gut. And so we really don't know what effect that has."
His research will look at methadone use. The researchers also will take T-cells from patients and treat them with drugs, such as methamphetamines. T-cells are valuable for understanding the mechanics of the virus and for developing systems-biology tools to determine the regulatory pathways and networks that are activated with drug abuse, Chance said.
The research will be directed at two main areas, biomarkers and technology development.
On the biomarker front, the work will be classic analysis of what blood-based proteins are up- and/or down-regulated after drug use. Plasma biomarkers are optimal for patient monitoring and diagnostic tool development "because they're easy to read," Chance said. Blood-based proteomics is plagued by the problems presented by the fluid's high dynamic range. Along with depletion columns and antibody approaches, bioinformatics methods can be used to get at the low-abundance proteins that may be of most interest, Chance added.
"You can dig down based on the readout of the high-abundance proteins," he said. "We think that you can infer what's going on at lower abundance and then go back in with more sensitive measures and validate."
The research will be aimed at the discovery of novel biomarkers as well as the verification and validation of previously identified candidate markers.
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On the technology development front, the Case Western Reserve researchers will integrate data from plasma and T-cells with computational models "to understand how the up- or down-regulation of various molecules is driven." Gene and protein expression in T-cells will be correlated with the biomarkers they detect.
The Center for Proteomics and Bioinformatics will also be working with the university's computer science department, Chance said, to develop models based on protein-protein interaction networks to better understand cell regulation.
"So we're layering this -omics data — the genomics and proteomics data — on these topological models of the protein networks to understand the sub-network pieces that are really activated and deactivated" in HIV/AIDS and whether they are different in drug abuse response to T-cells, Chance said.
At the end of the grant, which is not renewable, Chance said he hopes to determine what kind of changes may occur on a protein level with HIV/AIDS patients who also abuse drugs.
"We think we're going to prove [that drug abuse changes how HIV/AIDS affects the immune system], but maybe we won't," he said. "Maybe we'll show that there isn't any strong correlation or that the mechanisms whereby drugs affect your immune system are really very different than the ones whereby AIDS affects your immune system."
'We Just Aren't There Yet'
The grant to the Case Western Reserve team is part NIDA's effort to both learn more about the effects of illicit drugs on HIV/AIDS and to expand its proteomics portfolio.
While there isn't a shortage of studies on either HIV/AIDS or drug abuse individually, the consequences of drug use among patients with the disease have not been well studied, and many HIV/AIDS research has purposely excluded patients who are characterized as drug abusers.
One goal of the grants such as the one given to Chance and his co-researchers is to include everyone in HIV/AIDS research, Diane Lawrence, the program official at NIDA on the Case Western Reserve grant, told ProteoMonitor.
"If we limit [the research] to the most straightforward, uncomplicated populations we may develop therapeutics that may not work for [a large portion] of the infected people out there," she said.
The award is being provided through a P20 mechanism. Unlike traditional grant mechanisms to create centers that use well-established technologies, P20 grants fund centers using newer, more experimental technologies such as proteomics.
The award, Lawrence said, was designed to bring in researchers with expertise in both proteomics and HIV/AIDS and apply that knowledge to drug abuse and treatment issues.
"The whole HIV field and NIH in general had really hoped that by now we'd have successful biomedical approaches for HIV prevention, some vaccines or microbicides. Unfortunately, we just aren't there yet," she said. "In general, the field is trying to take a step back and get a better understanding of the complex interactions between HIV and the host response, the genomics and the proteomics."
But though NIDA has the second largest budget directed at HIV/AIDS research among all National Institutes of Health institutes, it has been relatively late to the proteomics game. According to Chance, the National Cancer Institute and the National Heart, Lung and Blood Institute have numerous proteomics projects ongoing, but "then it sort of seems to trail off after that."
In late 2007, NIDA sought to address this by creating a grant program to create centers using proteomics technology to look at changes in protein levels of individuals with HIV/AIDS who use illicit drugs [see PM 01/10/08].
At the time, a NIDA official acknowledged that the use of proteomics technologies to look into how HIV/AIDS interacts with drugs was "a gap in our research portfolio."
"What we don’t yet completely understand are some of these protein changes that may be occurring [and] the mechanisms involved,” David Shurtleff, director of the division of basic neuroscience and behavioral research at NIDA, told ProteoMonitor then. “And that’s what we’re hoping proteomics may shed some light on; these mechanisms that are involved in host response, immunity, drug-drug interactions — all these things that are likely to occur in patients who abuse drugs and have the virus.”
The 2007 program originally was for $6 million covering two grants, but because of the number of quality applications NIDA received and with some newfound additional funding, it decided to expand the program and award three additional grants, including the one awarded to the Case Western Reserve researchers, Lawrence said.
She declined to name the other four recipients, but the NIH grants database lists grants under the program for Pacific Northwest National Laboratory, the University of Nebraska Medical Center, Johns Hopkins University, and Yeshiva University.
The PNNL team, led by Richard Smith, will use proteomics technologies to do a differential study on humans with and without HIV treated and untreated with opioids, as well as "well-defined non-human primate models of lentiviral pathogenesis induced by simian immunodeficiency virus," according to the grant abstract. Funding for fiscal 2008 was $871,487. The funding amount for FY '09 was not available.
The grant to the University of Nebraska will be headed by Howard Fox and includes the Scripps Research Institute and the University of California, San Diego. Broadly, the work will develop strategies to discover biomarkers "that reflect cellular responses to HIV infection and drug abuse," according to the grant abstract. "This aim drives three proposed studies focusing on the theme that methamphetamine combines with HIV to increase the damaging affect of glial activation on the brain, impairing neurocognitive functions."
It was awarded $954,827 in FY '08. The award amount for FY '09 was not available.
Robert Cotter is leading the research being done at Johns Hopkins, which will discover, identify and develop novel biomarkers of HIV-associated cognitive disorders and dementia in patients who abuse drugs. It is receiving $246,000 for the work in FY '09.
And Ruth Angeletti will direct the work at Yeshiva, which will investigate the mechanisms "by which HIV infection causes HIV-associated neurocognitive disorders," identify biomarkers for HAND, and evaluate "the potential additive impact of buprenorphine treatment on the development and progression of HAND," according to the grant abstract. Funding for FY '09 is $995,400
The grants to the five centers are meant to create a framework for continued research, Lawrence said. "Hopefully they will turn into more comprehensive programs in the future," she said.