Background:  We recently demonstrated that blockade of PD-1 during chronic SIV infection in the absence of ART results in restoration of T and B cell function. The therapeutic benefits of PD-1 blockade may be improved further by combining with ART. Here, we evaluated the effect of PD-1 blockade soon after interruption of ART in chronically SIV-infected macaques.

Methods:  Ten SIV-infected rhesus macaques were treated with ART at 16 weeks post infection for 21 weeks, after which the therapy was interrupted. Four weeks post ART interruption, 6 out of the 10 macaques were treated with 6 doses of fully humanized anti-PD-1 antibody (3mg/kg) on days 0, 3, 7, 14, 21, and 28, and the remaining 4 animals were left untreated (controls). All macaques were monitored for the immune restoration and viral control.

Results:  Following ART interruption, the plasma viremia increased rapidly in all animals. Similarly, the frequency of SIV-specific CD8 T cells also increased by 2 to 4 weeks. PD-1 blockade at 4 weeks of ART interruption resulted in a rapid decline in plasma viral load (100- to 2300-fold) in 3 out of the 6 animals. PD-1 blockade did not enhance the frequency of SIV-specific CD8 T cells but rather enhanced the functional phenotype as measured by the enhanced expression of the T cell co-stimulatory marker CD28. Interestingly, PD-1 blockade was effective only in animals that had measurable cytokine positive CD8 T cells at the time of ART interruption.

Conclusions:  These results demonstrate that PD-1 blockade following ART interruption can significantly enhance the viral control, however the effect of blockade seems to be dependent on maintenance of measurable SIV-specific CD8 T cell response following ART.