Immunotherapy with DNA vaccine and live attenuated rubella/SIV gag vectors plus early ART can prevent SIVmac251 viral rebound in acutely infected rhesus macaques

Abstract

Anti-retroviral therapy (ART) has been highly successful in controlling HIV replication, reducing viral burden, and preventing both progression to AIDS and viral transmission. Yet, ART alone cannot cure the infection. Even after years of successful therapy, ART withdrawal leads inevitably to viral rebound within a few weeks or months. Our hypothesis: effective therapy must control both the replicating virus pool and the reactivatable latent viral reservoir. To do this, we have combined ART and immunotherapy to attack both viral pools simultaneously. The vaccine regimen consisted of DNA vaccine expressing SIV Gag, followed by a boost with live attenuated rubella/gag vectors. The vectors grow well in rhesus macaques, and they are potent immunogens when used in a prime and boost strategy. We infected rhesus macaques by high dose mucosal challenge with virulent SIVmac251 and waited three days to allow viral dissemination and establishment of a reactivatable viral reservoir before starting ART. While on ART, the control group received control DNA and empty rubella vaccine, while the immunotherapy group received DNA/gag prime, followed by boosts with rubella vectors expressing SIV gag over 27 weeks. Both groups had a vaccine "take" to rubella, and the vaccine group developed antibodies and T cells specific for Gag. Five weeks after the last immunization, we stopped ART and monitored virus rebound. All four control animals eventually had a viral rebound, and two were euthanized for AIDS. One control macaque did not rebound until 2 years after ART release. In contrast, there was only one viral rebound in the vaccine group. Three out of four vaccinees had no viral PLOS ONE PLOS ONE | https://doi.org/10.rebound, even after CD8 depletion, and they remain in drug-free viral remission more than 2.5 years later. The strategy of early ART combined with immunotherapy can produce a sustained SIV remission in macaques and may be relevant for immunotherapy of HIV in humans. PLOS ONE SIV remissionPLOS ONE | https://doi.org/10.Fig 1. Study plan.Stage I: high-dose mucosal challenge of rhesus macaques with SIVmac251 by the intra-rectal route. ART was delayed until day 3 to allow establishment of the latent viral reservoir. Stage II: the vaccine group was immunized with DNA/gag expression plasmid followed by rubella/gag vectors, while on ART. Controls received control DNA and empty rubella vaccine. Stage III: after 27 weeks, ART was withdrawn, and the animals were followed for viral rebound. Subsequently, CD8 + T cells were depleted to release latent virus.

Therapeutic vaccine-mediated Gag-specific CD8+ T-cell induction under anti-retroviral therapy augments anti-virus efficacy of CD8+ cells in simian immunodeficiency virus-infected macaques

“…However, CD8 + T-cell escape SIV variants are expected to appear during the 12 weeks before the ART initiation. We thus examined efficacy of CD8 + cells to suppress replication of autologous PBMC-derived SIVs as described in the Current attempts of therapeutic vaccination inducing SIV-specific T-cell responses under ART in macaques have shown promising results, delay or control of viremia rebound after ART cession 32,33 . However, our experiments did not exhibit significant effect on viremia rebound after ART.…”

Transient T cell expansion, activation, and proliferation in therapeutically vaccinated SIV+ macaques treated with N-803

“…Numerous therapeutic vaccine regimens have demonstrated the potential to elicit anti-SIV cellular immunity in macaque models, particularly both TCM and TEM responses (23)(24)(25). Transient antigen exposure provided by nonreplicating vectors favors the induction of TCM responses.…”

“…Gag, Pol, and Env) (23,29,30). High magnitude Gag-specific responses have also been detected in therapeutic vaccine strategies delivering Gag immunogens only (24,25). T cell recognition of multiple epitopes in Gag has been associated with lower viremia, suggesting Gag may be a promising immune target for vaccine strategies (24,(31)(32)(33).…”

“…High magnitude Gag-specific responses have also been detected in therapeutic vaccine strategies delivering Gag immunogens only (24,25). T cell recognition of multiple epitopes in Gag has been associated with lower viremia, suggesting Gag may be a promising immune target for vaccine strategies (24,(31)(32)(33). Some vaccine strategies have conferred improved viral control after suspending ART, but success is limited (23,24,29).…”

“…T cell recognition of multiple epitopes in Gag has been associated with lower viremia, suggesting Gag may be a promising immune target for vaccine strategies (24,(31)(32)(33). Some vaccine strategies have conferred improved viral control after suspending ART, but success is limited (23,24,29). This may be a consequence of eliciting too few functional antigen-specific T cells in the correct locations to suppress the rebounding virus when ART is interrupted.…”