A drug used to treat patients with multiple sclerosis and Crohn's disease has confirmed how "viral reservoirs" form in patients living with HIV and Aids and also proven effective in animal trials at blocking the pathways to those reservoirs in the brain and gut, according to new research conducted by professor of biology at Boston College, Ken Williams and colleagues from other universities. The drug, a humanised antibody called natalizumab, is prescribed to treat patients suffering relapse of multiple sclerosis and Crohn's disease.
In their experiments, Williams and his fellow researchers found the antibody effectively blocked a molecule that two types of white blood cells use to travel to the brain and the gut, where they collect in viral reserves linked to debilitating illnesses that afflict people living with HIV infection, even if they are symptom-free.
The researchers recently reported that a three-week course of natalizumab, applied four weeks after infection, reversed lesions on the central nervous system. Furthermore, the drug confirmed for the first time that the traffic of the virus – transported in disease-fighting cells known as monocytes and macrophages – to the brain could be physically blocked, said Williams, a senior author of the report.
In a parallel trial, a three-week course of treatment with natalizumab at the time of experimental infection completely blocked the traffic of the virus to the brain and the gut in animal subjects, according to the report. These tests confirmed the roles of monocytes in seeding the central nervous system with the virus and leukocytes leading to the infection of the gut, a precursor to a range of illnesses.
"We actually stopped all traffic and showed that if you physically block monocytes and macrophages, the virus does not enter the brain," said Williams, whose research focuses on the long-term impact of the immune system’s response to HIV/Aids infection. "And even if full and major lesions of the central nervous system are present, application of the antibody can heal that damage and eliminate the virus, underscoring the necessity for continued traffic of cells to the central nervous system and the gut to maintain infection and lesions."
The team – which included additional researchers from Boston College, Harvard Medical School, Cornell University and the University of Florida College of Medicine – studied the antibody based on earlier research that showed natalizumab blocked monocyte traffic in laboratory mice in trials focused on the treatment of multiple sclerosis. "So our question was if we can do that with HIV, does it stop virus replication in the brain, stop seeding and does it reverse injury?" said Williams. "The answer to each of those questions, we now know, is 'yes.'"
The findings suggest that similar treatment regimens for humans at the time of infection could include the use of the antibody in combination with antiretroviral drugs, a pairing that could serve to halt the seeding of HIV reservoirs in the brain and gut, while traditional antiretroviral therapies can target lymphoid organs to contain infection, Williams said. Human clinical trials would have to be conducted to pave the way for that potential use of the drug, he said.
The latest report is viewed as a critical step in the effort to combat illnesses tied to HIV infection, including nerve damage, cardiac disease, gut disorders and dementia, which strike patients living with HIV even though they are largely symptom free thanks to treatment from antiretroviral drugs.
Despite drug therapies that help hold HIV/Aids symptoms in check, researchers have centred on the presence of viral reservoirs that persist in the brain and the gut. Earlier research from the Williams lab has shown that cells and molecules from these stockpiles are present in illnesses such as neuropathy in the hands and feet, Aids-related dementia, "leaky gut" syndrome and heart inflammation in people living with HIV and Aids, said Williams.
As calls grow louder for a push to a "cure" for HIV/Aids, researchers have focused on monocytes and macrophages – as well as T-cells – as another route to the development of new drug therapies that can fully arrest the damaging impact of the virus. "When people talk about a 'cure' for Aids, it's really about eradicating these viral reservoirs," said Williams.
[link url="http://www.bc.edu/publications/chronicle/FeaturesNewsTopstories/2015/features/biologist-s-work-on–viral-reservoirs–may-have-impact-on-aids-h.html?cq_ck=1424294963103"]Boston College press release[/link]
[link url="http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004533"]PLOS Pathogens abstract[/link]