New breakthroughs for viral HIV vaccine

HIV-like ‘death star’ strain defeated with gene therapy-inspired approach

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JUPITER, Fla.—A team at the Scripps Research Florida campus reported in July their triumph over a challenge that has long frustrated HIV researchers. In a paper entitled “AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges,” published in Science Translational Medicine, lead authors Drs. Michael Farzan and Mathew Gardner described their destruction of the “death star” strain and another especially hard-to-fight strain. This suggests that it may be possible to protect uninfected individuals from multiple forms of HIV.
The seemingly indestructible “death star” HIV-like strain has earned its nickname due to the strain’s reputation for killing off hopes for potential vaccines and immunotherapies that could prevent the disease.
According to Farzan, professor and co-chair, Department of Immunology and Microbiology at Scripps Research, “The real name of the ‘death star’ strain is SIVmac239. It is a rhesus-macaque-derived virus that is especially well adapted to the rhesus model used in our studies. It is considered a very high or even unreachable bar for vaccine studies.”
“We have solved two problems that have plagued HIV vaccine studies to date: namely, the absence of duration of response and the absence of breadth of response. No other vaccine, antibody or biologic protects against the two viruses for which we have demonstrated robust protection,” Farzan continues.
The nontraditional vaccine achieved another critical goal: durability. It protected the research animals from infection long-term with a single inoculation, he added.
The group’s work adds to the significant mark that Scripps Research is making in the fight against HIV. In July, the institute announced that the Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), an international collaboration led by Scripps Research, been awarded a $129-million, seven-year award from the National Institutes of Health to advance next-generation vaccines.
Conventional vaccine approaches typically use a piece of virus or other immunogen to activate an immune system response. Because HIV replicates and changes so quickly, that approach has not been successful. Farzan’s approach uses an adeno-associated virus (AAV) which carries within it a protective protein designed by Farzan and his colleagues to stop HIV infectivity.
“We essentially use a gene-therapy vector to transform some muscle cells into a factory making a very broad and potent inhibitor of HIV-1 infection,” says Farzan. “The inhibitor eCD4-Ig is very broad and potent because it mimics the receptors necessary for HIV to enter cells. This has two consequences. First, it inactivates the virus by fooling it into prematurely initiating an irreversible process necessary for the virus to enter T cells. Second, the virus cannot escape this inhibitor without also losing its ability to get into cells. We say that the virus must pay a very high fitness cost to evade the our inhibitor.”
The protein eCD4-Ig features two HIV co-receptors, CD4 and CCR5. During exposure to HIV, the HIV virus is attracted to eCD4-Ig. It binds, and then “undergoes conformational change prematurely, and it’s no longer able to infect,” according to Farzan.
There’s more work to be done, Gardner noted. The study showed that the research animals could eventually become infected when exposed to atypically large loads of HIV. It also showed that HIV is capable of developing resistance to eCD4-Ig, albeit in a much weakened state. But encouragingly, the research animals did not develop serious immune reactions to the adeno-associated viral vector or the eCD4-Ig. The researchers made concerted efforts to minimize that risk.
“We need to establish the safety of our inhibitor in humans, and then we need to show that AAV-expression of the same inhibitor is also safe. We are helped in the second effort by many parallel human clinical trials of AAV,” Farzan explains.
The use of AAV as a gene therapy tool has generated considerable excitement recently, gaining FDA approval for genetic diseases including inherited retinal disease and spinal muscular atrophy. This study shows it also has the potential to save lives when used as a protective vaccine.
“The results of our paper are encouraging for the potential of AAV as a platform for prevention of disease generally, and in concert with eCD4 as an agent for stopping HIV infection,” Farzan points out. “We hope ultimately to prove that our approach is safe for both infected and at-risk persons at a cost that makes it useable everywhere.
“We are excited by recent unpublished data that suggest AAV expressed eCD4-Ig can suppress an established infection. This is important because infected persons are more likely to assume the modest risks of this approach, and they can help develop a safety record that will allow use in a larger population of uninfected persons.”
When asked if there are any other diseases that a vaccine like this might be able to protect against, Farzan notes that “The same approach and a more conventional antibody could prevent infection by the influenza A virus and both major forms of human malaria. Of course in all cases, the risks and rewards need to be evaluated.”

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