Antibiotic molecule enables immune system to kill HIV infected cells
Researchers have discovered an unexpected potential weapon against HIV
protein

Date:
September 10, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
A class of antibiotic molecules called pleicomacrolides inhibit
the Nef protein, which HIV uses to evade the body's immune system.



FULL STORY ==========================================================================
Ever since the first cases of a mysterious disease in the early 1980s
exploded into the HIV/AIDS pandemic, researchers have been searching
for ways to outsmart the deadly virus. Now thanks to anti-retroviral
therapy, people living with HIV can live relatively normal lifespans --
as long as they take their medications every day.


==========================================================================
"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," says Mark Painter, Ph.D., a graduate student
in the University of Michigan Medical School's department of microbiology
and immunology.

The reason is that HIV can hide inside the human genome, lying dormant and ready to emerge at any time. Because of this, a true cure for HIV relies
on waking the latent virus and eliminating it before it has a chance to
again take hold of the body's cells, an approach known as shock and kill.

Working with a team under the direction of Kathleen Collins, M.D.,
Ph.D., they set out to find a weapon to kill HIV by targeting a protein
called Nef. In 1998, Collins, who is a professor of internal medicine
and microbiology and immunology, discovered that HIV uses Nef to evade
the body's immune system by overriding the functioning of a protein on
a cell's surface that lets immune cells know that the cell is infected
and in need of elimination. By disabling this protein, called MHC-I,
infected cells are able to proliferate.

The research tried determine if there was an FDA-approved drug or molecule already on the market that could override Nef, restore the functioning
of MHC- I and allow the body's own immune system, specifically cells
known as cytotoxic T lymphocytes, to recognize the HIV-infected cells
and destroy them.

"We started out screening a library of 200,000 small molecules and found
none inhibited Nef," says Painter. Undeterred, they approached David
Sherman, Ph.D.

of the U-M Life Sciences Institute, whose lab studies the biosynthesis
of natural products from microbes, such as cyanobacteria.



========================================================================== "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," explains Sherman. "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." After screening approximately 30,000 molecules, they discovered that a class of antibiotic molecules called pleicomacrolides inhibited Nef.

"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," says Painter. The lysosome is an essential cell organelle used to break down worn out cell parts, viruses and bacteria.

However, the team determined that a pleicomacrolide called concanamycin
A inhibits Nef at much lower concentrations than those needed to inhibit
the lysosome. "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," said Painter.

In a proof of concept experiment, they treated HIV-infected, Nef
expressing cells with concanamycin A and found that cytotoxic T cells
were able to clear the infected T cells.

"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," says Collins. But, she adds, the molecule is not yet ready to be used as a drug
for treatment of HIV infected people. "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." Collins, Painter and their colleagues are continuing work on refining the chemistry of concanamycin A to make it
even more viable as a potential therapy.

When combined with ART and future treatments that shock latent HIV awake, Painter notes the therapy could be used to clear any remaining virus, essentially curing HIV.


========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Kelly
Malcom. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mark M. Painter, Gretchen E. Zimmerman, Madeline S. Merlino,
Andrew W.

Robertson, Valeri H. Terry, Xuefeng Ren, Megan R. McLeod,
Lyanne Gomez- Rodriguez, Kirsten A. Garcia, Jolie A. Leonard,
Kay E. Leopold, Andrew J.

Neevel, Jay Lubow, Eli Olson, Alicja Piechocka-Trocha,
David R. Collins, Ashootosh Tripathi, Malini Raghavan,
Bruce D. Walker, James H. Hurley, David H. Sherman, Kathleen
L. Collins. Concanamycin A counteracts HIV- 1 Nef to enhance
immune clearance of infected primary cells by cytotoxic T
lymphocytes. Proceedings of the National Academy of Sciences,
2020; 202008615 DOI: 10.1073/pnas.2008615117 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200910171820.htm

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