In research suggesting a way to unlock the potential in AIDS vaccines, scientists at Dana-Farber Cancer Institute and other institutions have shown that compounds that mimic key proteins on white blood cells can inactivate HIV-1, the virus that causes AIDS, and potentially protect against exposure to the virus.
In a pair of studies, including one published today in Nature Communications, the researchers found that small compounds designed to resemble CD4 – a receptor on immune system T cells – can cause a portion of HIV-1 to change shape, making the virus vulnerable to attack by antibodies roused to action by a vaccine. The research, conducted in laboratory cell cultures, mouse models, and monkeys, indicates that a combination of CD4-mimicking compounds and a vaccine could achieve the long-sought goal of preventing HIV-1 infection in people.
"Our studies reveal a powerful new approach to protect people from becoming infected by HIV-1, a necessary step in bringing an end to the global AIDS epidemic," said Joseph Sodroski, MD, of Dana-Farber, senior author of the new study.
The two studies – the earlier of which was published in the Journal of Infectious Diseases in March – sought to overcome a major barrier to the development of a successful HIV-1 vaccine: the shape-shifting nature of the virus's envelope protein.
In humans, HIV-1 binds to immune system T cells by engaging receptor proteins called CD4 and CCR5. Spike-shaped envelope proteins on HIV-1's surface enable the attachment to take place. Binding to the CD4 receptor changes the shape of the envelope protein, allowing the virus to infect the cell.
The envelope spike's position on the surface of HIV-1 exposes it to attack by immune system antibodies. But because the envelope protein can change shape, has a heavy coat of sugars, and takes a slightly different form in different strains of the virus, HIV-1 usually eludes these antibodies. This concealment and variability have made the development of protective vaccines extremely challenging, Sodroski remarks.
No current HIV-1 vaccine candidate can effectively muster antibodies that recognize the envelope's shape before it has bound to CD4 – a prerequisite for blocking infection. By contrast, vaccines can readily summon antibodies against the CD4-bound form of the envelope, but these types of antibodies aren't able to stop HIV-1 from infecting the cell.
The new research involves small compounds built to resemble key parts of CD4. These small compounds bind to the HIV-1 envelope protein much as CD4 itself does, and, like CD4, change the envelope protein's shape. High doses of these CD4-mimicking compounds irreversibly shut down the virus. In the Journal of Infectious Diseases study, researchers showed that the direct antiviral effect of these compounds can protect against vaginal exposure to HIV-1 in mouse models. At lower doses, the compounds make HIV-1 vulnerable to attack from easily generated antibodies.
The new study, conducted in monkeys, shows that the combination of a CD4-mimicking compound and vaccine-elicited antibodies provides a high degree of protection from infection by viruses like HIV-1.
"Our results could lead to an effective means to prevent HIV-1 infection, using currently available vaccines in combination with CD4-mimicking compounds," Sodroski says. "The CD4-mimicking compounds make HIV-1 susceptible to the antibodies elicited by the vaccine, making the combination of a CD4-mimicking compound and a vaccine very effective in preventing virus infection.
"To make this strategy work, HIV-1 must be exposed to the CD4-mimicking compound at the time of transmission," he continues. "We envision that individuals at risk for HIV-1 infection might use vaginal rings or other sustained-release formulations of CD4-mimetic compounds."
Researchers are now exploring ways to increase the potency of CD4-mimicking compounds and to sustain their delivery over a longer period of time.
The lead author of the Nature Communications study is Navid Madani of Dana-Farber. Co-authors are Amy M. Princiotto and Connie A. Zhao, of Dana-Farber; Linh Mach, Brandon P. Conn, and Sampa Santra, PhD, of Beth Israel Deaconess Medical Center; Shilei Ding, PhD, Jérémie Prevost, Jonathan Richard, PhD, and Andrés Finzi, PhD, of the University of Montreal; Bhavna Hora, PhD, Laura Sutherland, Todd Bradley, PhD, M. Anthony Moody, MD, and Barton F. Haynes, MD, of Duke University Medical Center; and Bruno Melillo, PhD, and Amos B. Smith, III, PhD, of the University of Pennsylvania.
The study was supported by the National Institutes of Health (grants AI124982, AI100645, GM56550, and AI90682) and the late William F. McCarty-Cooper; an amfAR grant (107431-45-RFNT); a Ragon Institute Innovation Award; a Canada Research Chair, a CIHR foundation grant; CIHR Fellowships; and an FRQS postdoctoral award.