In research suggesting a way to unlock the potential of AIDS vaccines, scientists at Dana-Farber 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 recent studies, 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 raised by a vaccine. The research, conducted in laboratory cell cultures and other models, indicates that a combination of CD4-mimicking compounds and 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,” says Joseph Sodroski, MD, of Immunology and Virology at Dana-Farber and associate director of the Harvard Medical School Center for AIDS Research.
The two studies 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 uses spike-shaped envelope proteins to attach to receptors called CD4 and CCR5 on immune system T cells. The binding to CD4 causes the envelope to change shape, allowing HIV-1 to infect the cell.
The prominent position of the envelope spike—situated conspicuously on the surface of HIV-1—exposes it to attack by immune system antibodies. But the virus manages to keep a low profile: because the envelope protein can change shape, cloak itself in sugar molecules, and assume different forms in different strains of the virus, HIV-1 is often able to elude those antibodies. This combination of concealment and changeability has made the development of protective vaccines extremely challenging, Sodroski remarks.
No current HIV-1 vaccine candidate effectively musters antibodies that recognize the envelope’s shape before it has bound to CD4 – a prerequisite for blocking infection. And vaccines can summon antibodies against the CD4-bound form of the envelop aren’t able to stop HIV-1 from infecting the cell.
The new research involves small compounds built to resemble key parts of CD4. They 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 shutdown the virus.
In a study earlier this year in the Journal of Infectious Diseases, researchers showed that the direct antiviral effect of these compounds can protect against vaginal exposure to HIV-1 in animal models. At lower doses, the compounds make HIV-1 vulnerable to attack from easily generated antibodies.
The more recent study, in Nature Communications, was conducted in other animal models and showed 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 time.