A recent study by amfAR Krim Fellow Stylianos Bournazos and associates, working in the laboratory of Dr. Jeffrey Ravetch at The Rockefeller University in New York, utilized a broadly neutralizing anti-HIV antibody to target infected CD4+ T cells harbored by mice with a humanized immune system (i.e., mice that have been injected with human stem cells). Survival of these cells could be greatly decreased by the antibody through a process involving a special immune receptor known as Fc gamma.
This work is critical as antibodies differ from anti-HIV drugs in that they can kill cells infected with HIV and neutralize freely circulating virus. This month, writing in the prestigious journal Cell, Bournazos continues the theme of viral neutralization in support of finding an AIDS cure. Recognizing that a cocktail of anti-HIV drugs attacking different parts of the HIV life cycle was the key to dramatically reducing HIV viral loads, he and his colleagues designed and tested, in vitro and in infected, humanized mice, different antibodies capable of neutralizing divergent HIV strains. But rather than simply proposing ever bigger cocktail combinations of single antibodies, they created bispecific antibodies, so that a single molecule is capable of binding to different parts of the viral envelope.
Bournazos and colleagues also modified those bispecific antibodies, creating “hinge variants” with the flexibility to adapt to envelope structures. This led to improvement in four major factors important for HIV control: viral neutralization, viral clearance, elimination of HIV-infected cells, and stimulation of host immune responses. The latter achievement raises hope for induction of long-term immunity through this strategy of administering antibodies (passive immunization), which usually provides anti-viral activity for only a few weeks.
The researchers suggest that bispecific antibodies are not only “ideal candidate molecules for the control of HIV-1 infection” but also, in considering potential broad benefits from this aspect of AIDS research, provide “a platform technology that can also be extended to other viral and cellular targets.”
Dr. Laurence is amfAR’s senior scientific consultant.