Identifying drugs for maximum penetration into lymph nodes to more effectively stop HIV virus replication
Drugs used to treat HIV penetrate poorly into lymphatic tissues where most HIV replication takes place and there is persistent low-level virus replication in these tissues according to research from the University of Minnesota and University of Nebraska Medical Center.
The results appear in the latest issue of the Proceedings of the National Academy of Sciences (PNAS).
“We know the drugs we use today are effective because our patients are doing better and living longer, but these drugs cannot cure the infection,” said Timothy Schacker, M.D., director of the Program in HIV Medicine at the University of Minnesota. “We wanted to know why and thought that maybe the drugs were not getting into the tissues where most virus replication is happening.”
Schacker teamed up with Ashley Haase, M.D., Regents’ Professor and Head of Microbiology, and Courtney Fletcher, Pharm.D., dean of the College of Pharmacy at the University of Nebraska Medical Center to measure drug levels and find the impact on HIV-1 replication in those tissues.
“These are very complex questions requiring expertise from many disciplines to get the data required to understand what is going on,” said Schacker. “This is a great example of the kind of team science we need to make progress in curing this disease.”
Schacker, the principal investigator of the project, assembled a cohort of patients and started them on antiretroviral therapy. He collected lymph nodes and gut samples from these patients at frequent intervals.
Fletcher used highly specialized and sensitive methods, developed in his laboratory, for measuring drug levels inside cells obtained from lymph nodes and gut tissues.
“The common approach of looking at drug concentrations in plasma may provide misleading information. What is most important to understand is the concentration of a drug actually inside an HIV-infected cell in the compartments where most of the virus is actually produced,” said Fletcher. “What we found, in studies conducted during six months of therapy in 12 HIV-infected persons receiving combinations of five of the most commonly used drugs to treat HIV infection was that concentrations inside the cells from lymph tissues were surprisingly low compared with blood.”
Haase then used sensitive methods to precisely measure the amount and location of virus in the lymph node and gut tissues and found the virus continued to replicate in the tissues, even when it was undetectable in blood.
“Most HIV replicates in the lymph and gut tissues and that’s where we need to look to understand the efficacy of these drugs. The ongoing replication we found in the lymph and gut tissues we tested directly correlated with the drug levels found there,” said Haase. “This persistent low-level replication may be one cause of the chronic immune activation we find in these patients, and is likely an important factor in accelerated aging, increased cardiovascular events and early mortality common in these patients.”
Schacker, Fletcher, Haase and their collaborators are now working on a comprehensive survey of all available anti-retroviral drugs in an effort to identify a combination of drugs with that will provide maximum penetration into lymph nodes and more effectively stop virus replication.
“We will not cure this disease until we can completely suppress virus replication,” said Schacker.
Funding for this research project was provided in part by the National Institutes of Health grants AI074340 and AI028433.