Background:  ART leads to drastic reduction in viral burden, but HIV (or SIV in macaques) remaining in pharmacological sanctuaries, rebounds rapidly upon treatment interruption. Immune restoration methods are highly desirable. We explored therapeutic immunization of ART-treated SIV_mac251-infected rhesus macaques, using a new generation of DNA-based vaccine vectors that produce either secreted or intracellularly degraded antigens.

Methods:  Macaques infected for 15 to 70 weeks with SIV_mac251 were treated with a combination of PMPA, didanosine (ddI), and stavudine for 13 to 23 weeks. During this time, the animals were vaccinated intramuscularly with various optimized forms of DNA vectors expressing SIV antigens and then released from treatment. The animals were monitored for rebounding virus and changes in SIV-specific immune responses during and after termination of therapy. Statistical analyses were performed for all the animals at least partially responding to ART by reducing viremia.

Results:  The benefit of immunotherapy was determined by comparing average viremia or alternatively the area under the curve per time unit, for the periods before ART start and after ART release. We found that 6 of 12 ART-treated and vaccinated animals had substantial decreases in virus loads, some for periods up to 70 weeks, and reached levels below the detection of the virus load assay. An additional 3 animals had substantial reductions in viremia after ART and immunotherapy. Analysis of 13 animals that received only ART showed that none controlled viremia after release from ART. Macaques receiving DNA showed a significant decrease in viral load after therapy termination (p < 0.001, Wilcoxon rank sum test). Therefore, DNA vaccination, but not ART alone led to substantial decreases in viremia. In addition, measurement of cellular immune responses showed induction of SIV-specific cellular immune responses during therapy. The animals controlling viremia had persistent cellular immune responses after release from ART.

Conclusions:  The combination of novel forms of DNA vaccines administered during ART treatment induced an immune response able to control viremia after removal of ART. Importantly, animals able to control virus maintained this ability for more than a year after ART termination. Therefore, optimized DNA vectors may be beneficial either alone or in combination with other vaccine modalities as an addition to antiretroviral treatment.

Keywords: chronic infection; immunotherapy; DNA vaccination