A follow-up study: 6-year cART-free virologic control of rhesus macaques after PD-1-based DNA vaccination against pathogenic SHIV SF162P3CN challenge

Abstract

ABSTRACT An effective vaccine for combination antiretroviral therapy (cART)-free virologic control of HIV-1 by enhancing antigen-specific effector-memory CD8 + T lymphocytes could be useful in controlling the AIDS pandemic. Previously, we demonstrated that a programmed death-1 (PD-1)-based DNA vaccine, pRhPD1-p27, was effective in inducing Gag-p27-specific effector-memory CD8 + T cells for viremia suppression in rhesus macaques infected with pathogenic SHIV SF162P3CN for 2 years. In this follow-up study, we report on two pRhPD1-p27-vaccinated and SHIV SF162P3CN -infected macaques that have remained alive to date with undetectable viremia levels and low proviral loads over 6 years in the absence of cART, achieving a state of sustained virologic control. Polyfunctional effector-memory Gag-p27-specific T cells were maintained in these macaques. Moreover, several T cell epitopes found at 6 years post-viral challenge were identical to those induced during the vaccination phase, indicating sustained vaccine-induced memory T cell responses. The viral challenge resulted in de novo Nef-specific T cell responses, which were also maintained. These Gag-p27- and Nef-specific T cell responses were stronger than those in some SHIV SF162P3CN -infected macaques that showed viremia control after experimental therapy using a tandem bispecific neutralizing antibody. Our findings indicate that the PD-1-based DNA vaccine strategy holds promise as a clinical immunotherapy for long-term HIV-1 suppression. IMPORTANCE Efficient strategies for HIV-1 cART-free virologic control are critical for ending the AIDS pandemic. The essential role of effector-memory CD8 + T cells in controlling viremia and eliminating virus-infected cells has made them a promising target for vaccine development. It has been previously reported that PD-1-based DNA vaccination was effective in inducing polyfunctional effector-memory CD8 + T cells for AIDS virus control for 2 years in rhesus monkeys. This follow-up study extends the findings and shows that a viremia-free period of over 6 years was detected in two monkeys immunized with PD-1-based DNA vaccine against pathogenic SHIV SF162P3CN infection in the absence of antiretroviral therapy. Long-term vaccine-induced memory T cell responses were detected. Our results warrant the clinical trials of PD-1-based DNA vaccines for achieving HIV-1 cART-free virologic control used either alone or in combination with other biomedical interventions.