Is Gene Therapy the Road to an HIV Cure?

Man-made Molecule Fools HIV Into Attacking Dummy Targets

International AIDS Vaccine Initiative (IAVI)

Researchers from the Harvard Medical School and Scripps Research Institute in Florida have announced that a novel gene therapy, delivered intramuscularly, has effectively blocked the transmission of HIV-1 and HIV-2 in a group of macaque monkeys repeatedly exposed to the virus. The discovery is seen as the first step toward developing a vaccine candidate that may able to provide the same protections in humans.

The Harvard and Scripps researchers were able to develop a lab-created molecule called eCD4-Ig, which mimics two types of protein receptors found on the surface of the white blood cells that HIV naturally attaches to during infection. In doing so, HIV is "fooled" into latching itself onto the genetic construct, thereby neutralizing it.

How eCD4-Ig Works

eCD4-Ig is made up a fragment of CD4 and another fragment of CCR5—two target receptors that act as entry "locks" to a cell—which together are fused onto a piece of antibody. The genetic construct is then inserted into an adenovirus (a type of non-disease-causing virus), which is delivered directly into muscle tissue. Once there, the harmless virus quickly infects cells, inserting its DNA into the nucleus, and turns them into protein factories—churning out more and more of these modified antibodies.

Previous attempts at employing "unenhanced" CD4-Ig (i.e., without the CCR5 fragment) have only been partially successful at best.

In other cases, if concentrations of the modified antibodies were too low, HIV activity would only be enhanced. This is because the HIV was able to escape neutralization just enough to mutate and bind onto receptors.

While HIV is still able to escape and mutate in the presence of eCD4-Ig, the bivalent (i.e., involving two set of chromosomes) interaction appears to impose a heavy cost on the mutated virus, dramatically reducing its ability to replicate.

In their controlled animal studies, the researchers reported that monkeys inoculated the genetically modified adenovirus were able to block all strains of HIV-1, HIV-2 and SIV (the simian form of HIV), even after being repeatedly injected with high doses of the virus for 40 weeks. Not one of the inoculated monkeys was infected, and none experience any negative effect to the eCD4-Ig (presumably because their bodies recognized the proteins as their own).

Monkeys not given the eCD4-Ig inoculate were all infected.

What Does All of This Mean?

While it's still too early to suggest that tests in humans will render the same results, the approach suggests a potentially game-changing strategy in the development of an effective neutralizing vaccine to HIV.

Some have already begun to hypothesize that the development of a successful eCD4-Ig vaccine, one that works effectively over the long term, might be effective in neutralizing viral activity in HIV-infected patients, either on its own or with other agents.

If this is, in fact, achievable, then even patients with deep, multi-drug resistance could potentially benefit.

Still, all of this remains highly speculative. Further research will likely provide greatly insights in the coming months, pointing the way to early-stage human trials in the near future.

Other Novel Approaches to Gene Therapy

In addition to the Harvard/Scripps research, other scientist are looking into other gene editing techniques to either fight or prevent HIV infections.

One such model from scientists at Temple University extracts HIV-infected T-cells from a patient's blood and uses an enzyme called Cas9  to "snip" the HIV genetic material from from the host cell's DNA. By doing so, the cells are less able to be infected by HIV.

It is theorized that by injecting these cells back into the patient's body, the ability of HIV to infect will be greatly diminished, slowing disease progression while enabling the re-engineered cells to become part of the person's genome (genetic makeup). 

Similarly, scientists at UCLA are exploring the use of an engineered molecule called CAR (chimeric antigen receptor), which is able to turn any blood cell into a disease-fighting white blood cell. By inserting CAR into blood-forming stem cells, the scientists were able to transform the cells into the specific "killer" types needed to neutralize free-circulating HIV.

While both studies are currently in the test tube stage, the discoveries are considered significant in the development of possible neutralizing HIV vaccine candidates.

Sources:

Gardner, M.; Kattenhorn, L.; Kondur, H.; et al. "AAV-express CD4-Ig provides durable protection for multiple SHIV Challenges." Nature. February 18, 2015; doi:10.1038/nature14264.

Kaminski, R; Chen, Y.; Tedaldi, E.; et al. "Elimination of HIV-1 genomes from human T-lymphoid cells by CRISPR/Cas9 gene editing." Nature. March 4, 2016; published online DOI:10.1038/srep22555.

Zhen, A.; Kamata, M.; Rezek, V. et al. "HIV-Specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells." Molecular Therapy.  August 2015; 23(80):1358-1367.

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