A new agent, called surfen, can work as wonder to inhibit the infectivity of HIV, scientists from the Gladstone Institute of Virology and Immunology (GIVI) have found.
Surfen might be used to supplement current HIV microbicides to greatly reduce HIV transmission during sexual contact.
Discovered by Dr. Nadia Roan, surfen is a small molecule that inhibits the actions of certain polysaccharide molecules called heparan sulfate proteoglycans (HSPG) that are found on the surface of cells.
Importantly for HIV infection, it also interferes with the action of semen-derived enhancer of viral infection (SEVI).
"Surprisingly, although HIV readily replicates once inside the body, the virus struggles to establish a beachhead of infection during sexual transmission. We have been studying SEVI, a naturally occurring factor present in semen that can make HIV thousands of times more infectious. Knowing more about surfen, a SEVI inhibitor, might enable us to lower transmission rates of HIV," said Greene.
"Because SEVI can so greatly enhance HIV infectivity, supplementing current HIV microbicide candidates with SEVI inhibitors, such as surfen, might increase their potency and overall effectiveness," explained Greene.
The researchers hypothesized that the SEVI fibrils bind target cells by interacting with cell-surface HSPG, naturally occurring anionic carbohydrate polymers with a structure that is closely related to heparin sulfate.
"SEVI has eight basic amino acids which makes this factor very positively charged. In previous work, we showed that the ability of SEVI to enhance infection was dependent on these positive charges. We reasoned that these positive charges may be interacting with negatively charged groups on HSPG of target cells," said Roan.
The scientists looked for antagonists of HSPG that might interfere with the binding of SEVI to the virus and target cells and found that surfen inhibits enhancement of HIV-1 infection mediated by pure SEVI or semen.
They further demonstrated that surfen interferes with the binding of SEVI to both target cells and HIV-1 virions.
"Because SEVI can markedly influence HIV infectivity, it forms a rather attractive target for future therapies. For example, we might be able to create combination microbicides that include agents targeting both the virus and host factors promoting infection. Such combinations might greatly diminish the spread of HIV; it is a target we are energetically pursuing," said Greene.
The discovery was published in the current issue of the Journal of Biological Chemistry.