The lone Miami monkey raises hope for gene transfer
There are a group of super-antibodies that have been developed that are highly effective when used in combination against HIV. The technical name for this group of antibodies is called broadly neutralizing antibodies (bNAbs). Several of these antibodies are in clinical trials. They are usually administered via intravenous infusion. However, researchers are testing alternative ways of getting bNAbs into people; one method under study is gene transfer.
About gene transfer
Instead of intravenous infusion of antibodies, one approach is to get a host (an animal or human) to make the antibodies themselves. This approach involves encoding the information (in genetic material, DNA or RNA) for making the antibody into a harmless virus that acts as a carrier or vector and then using this vector to infect the host’s cells with this virus. Once infection occurs, the vector releases the genetic information inside the target cell. The cell then incorporates this information and begins to make antibodies.
Scientists at the University of Miami have done this using a harmless virus called recombinant adeno-associated virus vector (rAAV). The information to make antibodies is encoded in DNA and inserted into the virus. In this case, researchers encoded the information to make three different antibodies into a strain of rAAV.
The scientists then infected four monkeys with a virus called SHIV. This is a combination of SIV (simian immunodeficiency virus), which causes an AIDS-like disease in susceptible monkeys, and HIV. The hybrid virus SHIV causes severe immune deficiency faster than SIV. It can therefore speed up the pace of experiments. Scientists allowed SHIV infection to persist for at least 80 weeks, then administered rAAV containing DNA with the instructions for making three bNAbs.
Commenting on the results of this experiment, other scientists stated:
“Strikingly, in one of the animals, there was a sharp decline in the amount of [SHIV in their blood] from approximately 10,000 copies/mL to less than 15 copies/mL within a few weeks of administration of rAAV. Further analysis revealed that only this animal had maintained robust [production] of more than one of the bNAbs.”
The Miami researchers found that three of the animals developed antibodies that attacked all three bNAbs. However, the immune system of one monkey, nicknamed “the Miami monkey,” only attacked one of the three bNAbs, leaving high levels of the other two antibodies. This monkey continues to have an undetectable viral load three years after first receiving rAAV therapy via intramuscular injection.
The researchers then attempted a similar experiment with 12 additional monkeys. However, the immune systems of these monkeys also attacked the bNAbs. The experiments in gene transfer seemed safe.
A team of researchers in New York and Surrey, UK, conducted a randomized, placebo-controlled study of rAAV that encoded instructions for making one bNAb called PC9. There were 21 participants in this study, all of whom were healthy and HIV negative and who received different doses of rAAV injected into muscle.
The gene transfer was safe and side effects were generally mild to moderate and included the following:
- pain at the injection site
- tenderness at the injection site
- general muscle pain
All side effects were temporary and resolved without treatment. No serious side effects occurred and no one died. There were no abnormal laboratory test results.
Technicians detected evidence of PG9 production from muscle cells. However, the levels of this antibody were too low to be detected in the blood.
Scientists are not certain why antibody levels were so low. They found evidence that CD8+ cells from participants who received rAAV (but not placebo) were able to recognize and attack the AAV. Some vaccine recipients developed antibodies that attacked PG9.
For the future
It may be necessary to give higher doses of rAAV that encode more potent bNAbs than PC9. Clearly, refinements to the gene transfer experiment in this study are needed to minimize the immune system’s ability to destroy bNAbs.
Different teams of researchers are trying to find ways to solve this problem of the immune system attacking bNAbs that are made via gene transfer. It is likely that there will be additional gene transfer experiments in the future.
The lone success of the Miami monkey heralds a potential approach where people could one day receive gene transfer for antibodies that attack HIV. This would be helpful both to protect HIV-negative people and also to treat HIV-positive people, perhaps freeing them from the need to take anti-HIV drugs on a regular basis.
The Canadian HIV Cure Enterprise (CanCURE)
—Sean R. Hosein
- Martinez-Navio JM, Fuchs SP, Pantry SN, et al. Adeno-associated virus delivery of anti-HIV monoclonal antibodies can drive long-term virologic suppression. Immunity. 2019 Mar 19;50(3):567-575.e5.
- Liberatore RA, Ho DD. The Miami monkey: A sunny alternative to the Berlin patient. Immunity. 2019 Mar 19;50(3):537-539.
- Priddy FH, Lewis DJM, Gelderblom HC, et al. Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial. Lancet HIV. 2019 Apr;6(4):e230-e239.
- Gardner MR, Fetzer I, Kattenhorn LM, et al. Anti-drug antibody responses impair prophylaxis mediated by AAV-delivered HIV-1 broadly neutralizing antibodies. Molecular Therapy. 2019 Mar 6;27(3):650-660.
- Julg B, Barouch DH. Neutralizing antibodies for HIV-1 prevention. Current Opinion in HIV/AIDS. 2019; in press.
- Caskey M, Klein F, Nussenzweig MC. Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic. Nature Medicine. 2019 Apr;25(4):547-553.