Researchers Examining Fibrils in Semen As A Target To Help Shut Down HIV Transmission

the Infectious Disease Advisor take:

Using a heat shock protein or a small molecule to attack fibrils in semen associated with the human immunodeficiency virus (HIV) during the initial phases of infection may be a target to fight HIV, according to research from the Perelman School of Medicine at the University of Pennsylvania.

HIV is most commonly transmitted between individuals in semen, the male reproductive fluid, which contains deposits of protein fragments called amyloid fibrils. These fibrils can increase the transmission of HIV by helping the virus attach to the membrane surrounding human cells, so reducing amyloid fibrils in semen may reduce HIV transmission.

One paper, published in Chemistry & Biology earlier this month, described how investigators repurposed a yeast heat shock protein called Hsp104 to attack amyloid fibrils. First, Hsp104 and an enhanced engineered variant directly remodeled fibrils into non-amyloid forms. They also made inactive Hsp104 scaffolds that reorganized fibrils into larger, innocuous assemblies. And finally, they modified Hsp104 to interact with a chambered enzyme to irreversibly degrade fibrils from semen.

Another paper, published in the journal eLife, described a second approach – a small molecule that also disrupts amyloids in semen that promote HIV infection. However, this molecule, called CLR01, also attacks the virus itself.

Tweezers-shaped CLR01 can both disrupt fibril formation and disassemble fibrils that have already formed. CLR01 prevents HIV particles from interacting with fibrils by disrupting the membranes that surround the virus particles and can displace the virus particles that have already bound to the fibrils. 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.

CLR01 was also effective at directly disrupting other enveloped viruses, including hepatitis C virus, human cytomegalovirus, and herpes simplex virus, but was ineffective against the non-enveloped human adenovirus type 5. CLR01 may also be effective against many other enveloped viruses including flu and Ebola.