Targeting Amyloid to Stop HIV

Amyloid protein structures are best known for the troubles they pose in the brains of Alzheimer’s patients. Now researchers are trying to exploit their presence in a very different place – in semen – to find a new way to stop HIV.

Scientists have created a substance that targets amyloid structures in semen and have used it to weaken the ability of HIV to infect the body’s immune cells in the laboratory. The experimental compound, originally designed to help Alzheimer’s patients by disrupting the actions of amyloid in the brain, make it much more likely that HIV particles will simply slide past human immune cells instead of gaining a foothold for infection during sexual intercourse

The work by scientists at the University of Rochester Medical Center, in collaboration with chemists at the University of California at San Diego, offers a new lead in the effort to develop a microbicide to prevent HIV transmission from one person to another. The findings were published online recently in the Journal of Biological Chemistry.

The focus of the work is an amyloid structure that was discovered in semen three years ago by German researchers. The structure, known as SEVI for Semen-derived Enhancer of Viral Infection, enhances infection by sticking both to HIV particles and to the immune cells that HIV infects. It’s a middle man in the infection process – one that researchers believe is a powerful driver of HIV’s ability to infect a person during heterosexual intercourse. SEVI has offered a new target to researchers trying to stop the virus.

“HIV viral particles are tiny and adrift amid a sea of semen and cervical mucus during sexual intercourse,” said Stephen Dewhurst, Ph.D., the microbiologist who heads the team. “The virus must sink quickly in this fluid to have the opportunity to contact the cells that it infects.That’s what SEVI allows it to do – to literally stick around.”

So Dewhurst teamed with Jerry Yang, Ph.D., a chemist at UCSD who previously created a compound designed to minimize the harmful interactions of amyloid with other proteins and lipids in the brain. Yang created a molecule called BTA-EG6 which fits in between the individual small proteins that cluster to form SEVI and blocks SEVI’s interactions with both the virus and the target immune cells. One key to the chemistry is the compound ethylene glycol – the central component of anti-freeze – which makes it particularly difficult for SEVI to stick to the virus or to cells.

“The compound drives a wedge between SEVI and both HIV particles and human cells, making it difficult for SEVI to interact with either. It’s like surrounding SEVI with air bags so it can’t bring HIV and the body’s cells together,” said Dewhurst. “Jerry Yang is the one who came up with this, and it’s ingenious.”

In experiments led by first author Joanna Touger Olsen, an M.D./Ph.D. student in the Dewhurst laboratory, the presence of SEVI boosted the ability of HIV to infect cells dramatically, roughly three to six times what it was without SEVI. When the non-stick compound was added, that advantage was muted, and rates of infection dropped nearly to levels when SEVI was absent. The investigators say the results must be interpreted cautiously, though, as the influence of factors such as the strain of HIV and the human cell line used in the study need to be looked at further.