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HIV Vaccine Progress in Animal Studies

Scientists designed a protein nanoparticle called “eOD-GT8 60mer” that binds and activates B cells needed to fight HIV.The Scripps Research Institute

HIV, the virus that causes AIDS, attacks and destroys immune cells. For those infected with HIV, antiretroviral therapy helps to prevent the virus from multiplying. But scientists haven’t yet been able to design a vaccine that protects people from HIV.

Most vaccines work by triggering the immune system to produce antibodies that help beat back infections. The HIV surface protein known as Env is a major target for potential HIV vaccines. One challenge in developing a vaccine is that Env can mutate rapidly. These changes to the protein’s surface help it to evade the immune system. The surface of the Env protein is also protected by a coat of sugar molecules that helps shield it from the immune system. Env is a “trimeric” spike-shaped protein, with 3 identical molecules, each with a cap-like region called glycoprotein 120 (gp120) atop a stem.

Researchers have identified human antibodies that can neutralize multiple strains of HIV by binding to a small portion of gp120. The antibodies fail to control the virus in the people who make them, but they can prevent infection in animal models.  Researchers have been studying these antibodies in the hope of designing a vaccine that prompts the human immune system to mount an effective defense against HIV.

Antibodies are made by B cells in response to infectious agents. Precursor B cells “mature” to better recognize foreign molecules through a process of multiple rounds of mutation and competitive selection over generations of cells. Past studies have found that the type of precursor B cells that later evolve to produce broadly neutralizing antibodies aren’t activated by native HIV glycoproteins. Three studies published on June 18, 2015, in Science and Cell described advances in understanding how to coax these cells into B cells capable of producing antibodies to neutralize HIV. The studies were funded in part by NIH’s �����鶹��Ƶ Institute of Allergy and Infectious Diseases (NIAID).

Scientists from Scripps Research Institute engineered a nanoparticle, called eOD-GT8 60mer, specifically designed to initiate the process of B cell maturation. They tested this nanoparticle alongside a native form of the HIV envelope protein in mice that were genetically modified to produce precursors of the VRC01 antibody. This antibody, , neutralizes a wide range of HIV strains by binding to a small portion of gp120. As reported in Science, the researchers found that the nanoparticle, but not the native protein, prompted a robust response from precursor B cells, beginning the process of producing broadly neutralizing antibodies.

In a second study, published in Cell, scientists at Rockefeller University, along with Scripps and Weill Medical College of Cornell teams, tested the same proteins in 2 other genetically modified mice, one engineered to produce precursors of an antibody similar to VRC01 (called 3BNC60) and another to produce a more mature version of that antibody. These investigators also found that the eOD-GT8 nanoparticle could activate precursor B cells while the native protein could not. In the more mature B cell mouse, however, the nanoparticle didn’t activate the B cells to further mature whereas the native protein did.

In the third article, published in Science, a team led by researchers at Weill Medical College of Cornell tested the same native envelope protein studied in the other 2 studies. The protein, called BG505 SOSIP, was designed to retain a structure similar to the native trimer on the virus surface. In both rabbits and rhesus macaques, immunization induced antibodies that could neutralize a relatively neutralization-resistant HIV strain. However, the breadth of this reactivity was limited. These results show that native Env proteins have the potential to induce HIV neutralizing antibodies, but more research will be needed to identify how to use native-like proteins to induce broadly neutralizing antibodies.

Taken together, these findings suggest that to produce broadly neutralizing antibodies, an HIV vaccine regimen would likely require one type of protein to prompt precursor B cells to produce antibodies with the potential to be broadly neutralizing and then another, native-like protein to coax development of more mature, neutralizing forms of the antibodies.

“While our results suggest sequential immunizations may make it possible to vaccinate against HIV, we have only just begun to understand how this sequence would work,” says Rockefeller’s Dr. Pia Dosenovic, a co-first author of the Cell paper. “We know the beginning and the end, but we don’t know what should happen in the middle.”

—by Harrison Wein, Ph.D.