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DNA Immunotherapy and IL-12 Suppresses Viral Replication following the Cessation of Antiretroviral Drugs
J Boyer1, S Kumar1, R Halwani2, R Parkinson1, L Wu1, G Pavlakis3, B Felber3, M Lewis4, R P Sekaly2, and David Weiner*1
1Univ of Pennsylvania, Philadelphia, US; 2Ctr de Res du CHUM, CANVAC, Montreal, Canada; 3NCI, NIH, DHHS, Bethesda, MD, US; and 4Bioqual, Frederick, MD, US
Background: The pathogenic effects of HIV-1
can be delayed with the use of ART. However, reliance on this approach has
problems, and it would be of great benefit to have an immune therapy approach
that would allow for a decrease on the dependence on drugs.
Methods: We infected 32 macaques with
100 MID50 (50% macaque infectious dose) of SIV251 intravenously. The primates
reached a peak viral load and then set-point by week 12. Infected macaques were
treated beginning at week 14 with emtricitabine (FTC) and tenofovir (PMPA). The simian immunodeficiency virus (SIV) vaccine plasmid constructs were produced,
mixed together at 3 mg/mL of each plasmid and
immunized at weeks 26, 32, 36, and 41. An interkeukin
(IL)-12 adjuvant construct was mixed with the SIV plasmid constructs such that
3 mg IL-12 adjuvant plasmid was delivered per injection. Following each
injection the cellular immune response to pol, env, vif, nef,
and gag was measured by interferon-g (IFN-g) ELISpot.
In addition, the CD4 and CD8 memory functional subsets were characterized.
Results: There was no significant
increase in the cumulative immune response at any time during the study in all 7
animals in the control group. After the first injection 3 of 7 animals in the
DNA alone and 4 of 7 animals in the DNA + IL-12 group had an increased immune
response to SIV antigens in particular the SIV gag antigen as assessed by IFN-g production and ELISpot.
Importantly, we observed within the group that received IL-12 expressing
plasmids an increase in the level of proliferative
capacity to SIVgag antigen. Finally, we observed
differences by multicolor flow cytometry in the CD4
and CD8 effector and memory cell populations. Drug
treatment was discontinued 12 weeks after the final immunization. The viral
loads were monitored. The group that received IL-12 did not rebound until 3 weeks
after the cessation of ART. Furthermore of the animals that responded to
immunization, only 1 of 7 had a sustained viral load. All other responders,
after an initial viral peak, reached a set point below detectable limits.
Conclusions: This study demonstrates that IL-12
as an immunoadjuvant enhanced immune responses when
co-delivered with SIV DNA-expressing vaccines. In addition, an enhanced immune
response following DNA immunotherapy can affect viral replication.
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