By Mili Jayadeep | Science Editor
Human immunodeficiency virus (HIV) is a commonly known virus that causes cellular damage resulting in a weakened immune system. If the HIV virus causes extensive damage, this can become acquired immunity deficiency syndrome (AIDS).
Current treatments involve managing the virus by keeping it at low levels in the body using anti-retroviral therapy. Although there is no cure for HIV, it enables HIV sufferers to live a relatively normal life by taking regular medications. Mark Painter who is graduate student in the University of Michigan Medical School at the department of microbiology and immunology says:
“If they ever stop, in short order the virus rebounds and resets at the high levels seen before starting — and that seems to be the case even after decades of therapy.”
HIV stays dormant within the human genome of the person and could re-emerge at any point if medication is stopped. Hence, curing HIV needs the ‘shock and kill’ method; The dormant virus is activated to then be destroyed completely.
Kathleen Collins, Professor of internal medicine, microbiology and immunology led a team searching for a method to clear the virus altogether. New research conducted by this team focused on a protein known as Nef. Collins, a professor of internal medicine and microbiology and immunology, determined the role of the Nef protein in HIV infection. HIV utilises Nef to take over the function of another protein(MHC-I).
The body’s immune system has checks in place to prevent infection by foreign pathogens. However, when HIV manipulates these protein molecules, inactivation of immune cells prevents the destruction of infected cells hence enabling the pathogen’s survival.
The team initially searched for a molecule that overrides Nef to outsmart HIV’s invasion mechanism. Painter said:
“We started out screening a library of 200,000 small molecules and found none inhibited Nef.”
Following this, they approached Professor David Sherman who was involved in research involving biosynthesis of natural products from microbes at the University of Michigan Life Sciences Institute (LSI). Sherman explained:
“Often synthetic molecules have quite a low molecular weight, meaning they are fairly small. And if you need to disrupt a large protein surface or interface, such as with Nef, a small molecule won’t work well or at all. A natural products library like the one at the LSI, on the other hand, is going to have molecules with a large range of weights and sizes.”
Further efforts led the team to discover pleicomacrolides, which belong to a class of antibiotics molecules that can inhibit Nef. Painter described:
“Pleicomacrolides are widely used in lab experiments when you want to shut down the lysosome. Because of this, they are considered toxic and risky to use as drugs,”
Lysosomes are a type of cell organelle crucial to cell function. The team found that a certain pleicomacrolides known as concanamycin is effective in low concentrations that is otherwise used to disable the lysosome. Painter said,
“As a lead compound for drug development, it’s fairly exciting because we can use a very low dose, and inhibit Nef without short-term toxicity to the cells,”
The team confirmed their findings by experimenting on HIV-infected cells. They found that the body’s immune system was enabled to now clear the infected cells as this pathway was no longer inhibited. Collins said,
“It’s been extremely gratifying for this project, which began in my lab over a decade ago to finally come to fruition. I had hoped we would find something that worked as well as this compound does but it was never a guarantee that we would actually be successful. This type of research is risky but extremely important because of the potential reward.”
However Collins cautions,
“More research will be needed to optimize the compound. We will need to further separate the potent Nef inhibitory activity from the more toxic effect on lysosomal function to make it a viable therapy.”
These findings show great promise for the future of HIV treatment. The team has taken one step closer to finding a cure for HIV. More research is needed before their methods can lead to a new treatment. Combined with current therapeutics including anti-retroviral therapy, the antibiotic molecule could be used to clear the virus altogether once the molecule undergoes further chemical manipulation.Science and Technology Mili Jayadeep