Electron microscopy reveals that buffer has no effect on amyloid fibrils in semen (top left); whereas CLR01 disrupts fibrils (top right). Scale: 500 nm. Atomic force microscopy reveals that buffer has no effect on the HIV virion (bottom left); CLR01 destroys it (bottom right). Scale: 100 nm. [James Shorter, Ph.D., University of Pennsylvania]
Electron microscopy reveals that buffer has no effect on amyloid fibrils in semen (top left); whereas CLR01 disrupts fibrils (top right). Scale: 500 nm. Atomic force microscopy reveals that buffer has no effect on the HIV virion (bottom left); CLR01 destroys it (bottom right). Scale: 100 nm. [James Shorter, Ph.D., University of Pennsylvania]

A small molecule previously investigated as a means of fighting Alzheimer’s disease and other neurodegenerative disorders is showing promise as a way to reduce HIV transmission and prevent AIDS. This molecule, called CLR01, keeps amyloid proteins from forming aggregates, or clumps. CLR01, it turns out, works not only on the amyloid proteins that can aggregate in the brain, but also on similar amyloids that can form fibrils in semen.

By using CLR01 against amyloid fibrils in semen, scientists hope to inhibit the transmission of HIV. These fibrils are known to enhance the transmission of HIV. They trap viral particles, helping the virus attach to the membranes surrounding human cells, increasing the risk of infection.

Scientists based at the University of Pennsylvania and the University of Ulm reasoned that a treatment capable of reducing the levels of amyloid fibrils in semen might also be able to reduce HIV transmission. They decided to test this approach with CLR01, which has been described as a pair of molecular tweezers.

The scientists were gratified to discover that CLR01 not only disrupts the amyloids in semen that promote HIV infection, the tweezers-shaped molecule also attacks the virus itself. These findings appeared August 18 in the journal eLife, in an article entitled, “A molecular tweezer antagonizes seminal amyloids and HIV infection.”

“[CLR01] inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils,” wrote the authors. “Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion–amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses.”

In the presence of CLR01, human cells exposed to semen that contained HIV were at least 100-fold less likely to become infected with the virus. Remarkably, CLR01 does not affect cell membranes, which suggests it could be safely incorporated into a vaginal or anal gel to prevent HIV infection—without the risk of side effects.

Unexpectedly, the scientists determined that CLR01 was also effective at directly disrupting other enveloped viruses such as hepatitis C virus, human cytomegalovirus, and herpes simplex virus. It was ineffective, however, against the non-enveloped human adenovirus type 5, reinforcing the idea that CLR01 is effective, in part, because of its ability to directly disrupt membranes that surround viruses.

“We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a nonspecific, colloidal mechanism,” the authors continued. “CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself.”

“We think that CLR01 could be more effective than other microbicides that are in development because of its dual action, its safety in terms of side effects and its potential broad application,” said Professor James Shorter from the University of Pennsylvania School of Medicine.

“The tweezer has been tested and is safe in zebrafish and mice. The next step could be to assess safety and efficacy in non-human primates,” added Professor Jan Münch from the University of Ulm.

The scientists anticipate that synthesizing CLR01 in large quantities will be straightforward, which will facilitate its development as a microbicide.








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