Targeting semen proteins to prevent HIV infection

Research led by investigators from the Perelman School of Medicine at the University of Pennsylvania describes two novel approaches that could prevent HIV infection by targeting proteins in semen that boost transmission of the virus.

Researchers found a molecule called CLRO1 interfered with semen polymers called amyloid fibrils, reducing the likelihood of HIV transmission.
Image credit: James Shorter

HIV (human immunodeficiency virus) is commonly spread through sexual contact with an HIV-infected partner. The virus can be transmitted via infected blood, semen or vaginal secretions, with semen being the primary vector for the virus.

Semen contains proteins that form polymers called amyloid fibrils. These polymers help the HIV virus attach to the membranes of human cells, boosting transmission of the virus by up to 10,000 times.

The researchers at the Perelman School of Medicine propose that reducing amyloid fibril levels in semen could reduce HIV transmission. They reveal how this could be done in two separate studies.

The first - published in the journal Chemistry & Biology in 2012 - describes how a heat shock protein called Hsp104 attacks amyloid fibrils, converting them into non-amyloid forms.

In addition, the research team reveals how they developed inactive Hsp104 scaffolds that disrupt the organization of amyloid fibrils, leading to the assembly of non-threatening protein structures. The researchers also modified Hsp104, allowing it to team up with an enzyme to weaken amyloid fibrils in semen.

According to researchers, each of these strategies reduced amyloid fibrils' ability to boost HIV transmission, "so this approach has potential as a therapeutic."

'Tweezer-shaped' molecule reduces likelihood of HIV transmission by 100-fold

For the second study - recently published in eLife - the researchers teamed up with another team of researchers from the Ulm University Medical Center in Germany to reveal how a small molecule called CLRO1 not only interferes with amyloid fibrils' ability to enhance HIV transmission, but attacks the HIV virus itself.

The researchers describe CLRO1 as a "tweezer-shaped" molecule that impairs the formation of amyloid fibrils in semen and dismantles pre-formed fibrils.

In addition, CLRO1 interferes with membranes surrounding HIV virus particles, disarranging particles that have already attached to amyloid fibrils.

On exposing human cells to HIV-infected semen, the researchers found CLRO1 reduced the likelihood of HIV transmission by more than 100-fold.

The researchers say because CLRO1 has no negative impact on other cell membranes, it could be used to develop safer vaginal and anal gels that prevent HIV infection. 

"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."

The research team notes that CLRO1 has proven safe in zebrafish and mice, and the next step is to test the molecule in non-human primates.

References:

1.  Hsp104 drives ‘‘protein-only’’ positive selection of Sup35 prion strains encoding strong [PSI+], James Shorter et al., Chemistry & Biology, doi: http://dx.doi.org/10.1016/j.chembiol.2012.09.013, published online 25 September 2012.
2.  A molecular tweezer antagonizes seminal amyloids and HIV infection, James Shorter et al., eLife, published online 18 August 2015.
3.  University of Pennsylvania School of Medicine news release, accessed 18 August 2015 via EurekAlert.
4.  eLife news release, accessed 18 August 2015 via EurekAlert.