The potential therapy combines an approach called dendritic cell-based immunotherapy with multiplex RT-PCR to create personalized antigen-presenting cells intended to kick-start an individual’s immune response against the specific HIV strain or strains they carry. A published study on the research appeared in yesterday’s issue of the journal PLoS ONE.
Dendritic cell-based immunotherapy is a method for creating specific antigen-presenting cells from a patient’s own immune cells. To do this, researchers generate mature dendritic cells in the lab from a patient’s blood. They then coax these dendritic cells to take up specific antigens — for example, viral RNAs. When the cells are injected back into the patient, they should migrate to the lymph nodes and stimulate T-cell activity targeted against the regions of the virus with which the dendritic cells were combined.
Argos is attempting to further customize this therapy for those infected with HIV by making antigens based on the patient’s own virus or viruses. Adding these to dendritic cells creates patient-specific, antigen-presenting cells derived from their own body. Also, because the dendritic cells in the lab mature in an HIV-free setting, Tcherepanova says, they may actually be more functional than those maturing in the body of an HIV-infected individual.
The problem, however, is that HIV’s notoriously high mutation rate makes it virtually impossible to define a single pair of primers for many HIV-coding regions. Consequently, conventional methods would require sequencing each patient’s virus before creating specific primer pairs.
Argos believes its multiplex RT-PCR method circumvents such variability, allowing rapid amplification of changeable viral regions without sequencing. Rather than using a pair of very specific primers, the researchers used the Los Alamos national HIV genome database to help them design groups of primers with built-in mutations.
They then amplified four different stretches of RNA from HIV — coding the HIV-1 proteins Gag, Vpr, Rev, and Nef. These regions were selected based on published work suggesting they were likely to elicit strong immune reactions. Unlike some other HIV proteins, previous research suggests that when these four proteins are expressed, they should not damage dendritic cells.
Including all four regions may be particularly potent, because the scientists predict that even if they all mutate to escape the immune system, these combined mutations will likely weaken the virus, making it unable to proliferate.
The current study, based on results from 33 subjects in pre-clinical studies, suggests that — at least in the lab — antigen-presenting cells created by these methods can stimulate CD8 T-cells. But the group still needs to test the efficacy of this approach. They are currently completing a Phase I clinical trial in collaboration with McGill University hematologist Jean-Pierre Routy in Montreal and hope to start a multi-center, Phase II clinical trial soon.
“The findings from this study support the clinical testing of what we believe may be the world’s first commercially feasible personalized immunotherapy for patients already infected with HIV,” Argos Chief Scientific Officer Charles Nicolette said in a statement.