UPenn researchers go one-up on animal model for studying HIV vaccine design

Rhesus monkey

Chimeric simian-human immunodeficiency viruses (SHIVs) allow researchers to study HIV vaccines in the rhesus monkey, a nonhuman primate whose immune system is closest to our own but in which HIV can’t infect or replicate. Researchers have now designed better SHIVs that may lead to the development of improved HIV vaccines.

George Shaw and Hui Li from the Perelman School of Medicine at University of Pennsylvania published their work in the journal Proceedings of the National Academy of Sciences.

Studying HIV has been made possible with animal models whose immune systems resemble that of humans, recapitulating the viral infection and allowing researchers to design drugs to target the virus. Smaller animals like mice, rabbits and guinea pigs are vastly different and can’t be used for HIV research.

HIV hides from the host’s immune system by rapidly mutating and, crucially, changing its outer coat protein known as the viral envelope. The envelope is studded with sugar molecules that make it even harder for the human immune system to recognize it as foreign.

SHIVs are required in the rhesus monkey HIV model since the virus can’t infect or replicate in these primates. However, SHIVs have major limitations in this model since they can adapt artificially to bind the rhesus CD4 molecule, the primary receptor for HIV--losing their natural defenses to antibodies.

The researchers therefore searched for a way to improve the SHIV. "We found that changing a single amino acid in the envelope coat protein of naturally occurring HIV strains led to dramatic differences in the ability of SHIVs to infect monkeys, while at the same time retaining the native-like features of the virus envelope and its interaction with the human immune system," Shaw said in a release.

"This is an enabling discovery for the HIV vaccine field because it allows scientists for the first time to study in a controlled and reproducible manner the interaction of natural HIV envelope proteins with monkey B lymphocytes, which are stimulated to make protective antibodies," Li added.

They found that mutating an amino acid in the viral envelope of the SHIVs caused the entry of SHIVs into monkey CD4 T cells to be improved by a thousand-fold. They then engineered “designer SHIVs” on the back of this finding, altering the viral envelope in each one, and in doing so reproducing closely the viral infection by HIV-1 observed in humans.

"These results have given us hope that the new SHIVs will indeed be a game-changer for HIV vaccine research," Shaw said. The SHIVs replicated persistently at concentrations comparable to HIV-1 levels in humans and elicited neutralizing antibody responses typical of HIV-1.

Using these designer SHIVs the researchers hope to use SHIV infections of rhesus monkeys as a more accurate model of HIV--bringing with it an improvement in effective HIV vaccine development.

- here’s the release
- here’s the article abstract