Therapeutic vaccination with IDLV-SIV-Gag results in durable viremia control in chronically SHIV-infected macaques

Abstract

Despite incredible scientific efforts, there is no cure for HIV infection. While antiretroviral treatment (ART) can help control the virus and prevent transmission, it cannot eradicate HIV from viral reservoirs established before the initiation of therapy. Further, HIV-infected individuals reliably exhibit viral rebound when ART is interrupted, suggesting that the host immune response fails to control viral replication in persistent reservoirs. Therapeutic vaccines are one current approach to improving antiviral host immune responses and enhance long term virus control. In the present study, we used an integrase defective lentiviral vector (IDLV) expressing SIV-Gag to boost anti-Gag specific immune responses in macaques chronically infected with the tier-2 SHIV-1157(QNE)Y173H. A single immunization with IDLV-SIV-Gag induced durable (>20 weeks) virus control in 55% of the vaccinated macaques, correlating with an increased magnitude of SIV-Gag specific CD8+ T-cell responses. IDLV-based therapeutic vaccines are therefore an effective approach to improve virus specific CD8+ T-cell responses and mediate virus control.

Keywords: HIV infections; Vaccines.

Fig. 1. SHIV-challenge outcome and viral load trends in infected macaques.

a Schematic of the preventive vaccine, SHIV-challenge and therapeutic intervention regimens. The nine macaques used in the therapeutic study reported here were previously employed in a preventive vaccine study testing the immunogenicity of an SIV-based IDLV expressing two clade C HIV-1 ENVs^,. Twelve weeks after completion of the scheduled vaccinations (week 234) the 5 macaques in the vaccine group and the 5 macaques in the control group were challenged intrarectally with the Clade C tier 2 SHIV1157(QNE)Y173H. Weeks post challenge are indicated in blue. b Kaplan–Meier plot showing the percentage of uninfected macaques after 5 weekly IR challenges. c Peak viral load of the infected macaques from the vaccine and control groups. Lines are group means and error bars indicate s.e.m. (p = 0.5952, Exact-Wilcoxon test). d Viral load tested weekly after initial infection in both groups up to 65 weeks post infection (no significant difference was observed between the two groups, p = 0.7302, Exact Wilcoxon test). Lines indicate group means and error bars indicate s.e.m. e Individual animals viral load. The one animal in the control group that resisted infection is not shown and was not included in the therapeutic study.

Fig. 2. Binding and neutralizing antibody responses in SHIV-1157QNEY173H infected macaques.

a ELISA binding of plasma antibodies to the SHIV encoded Env over the course of challenge for the vaccine and control group macaques. Binding titers measured as Log area under curve (Log AUC) starting at a 1:3000 plasma dilution. Horizontal bars are group means and error bars indicate s.e.m. Asterisks indicate p values < 0.05. b Antibody neutralization of Tier-1 viruses (MW965.26 and SHIV1157ipEL-p) and Tier-2 virus (SHIV-1157ipd3N4) measured in the TZM-bl neutralization assay as ID50. Values are the serum dilution at which relative luminescence units (RLUs) were reduced 50% compared to virus control wells (no test sample). The one animal in the control group that resisted infection (monkey ID: R522) was not included in the therapeutic study.

Fig. 3. SIV-Gag specific CD4+ and CD8+ T-cell responses in SHIV-1157(QNE)Y173H infected macaques.

The frequency of SIV-Gag-specific CD8+ (a, b) and CD4+ (c, d) T-cells expressing the cytokines IFN-γ, IL-2, and TNF-α was determined over time using cryopreserved PBMC stimulated overnight with SIV-Gag peptide pools.

Fig. 4. Viral load dynamics and SIV-Gag specific T-cell responses pre- and post-IDLV therapeutic interventions.

a Plasma viral RNA levels were assessed before and after IDLVs injection. b Serum levels of PGT121 bnAb post-IDLV-PGT121 injection. Frequency of SIV-Gag-specific CD8+ c and CD4+ d T-cells expressing the cytokines IFN-γ, IL-2, and TNF-α were measured before and after IDLV-SIV-Gag vaccination. Note the difference in scale for e and d and the plots in Fig. 3. Asterisks indicate p values <0.05. Comparison were made between week −1 and week 3 or 9.

Fig. 5. Inverse correlation between viral load and SIV-Gag specific CD8+ T-cell responses in IDLV injected macaques.

a IDLV-induced T-cell responses were measured over time by IFN-Ɣ ELISpot assay. b Magnitude of T-cell responses in high responder (HR) vs. low responders (LR) macaques before and after IDLV-SIV-Gag immunization. c Plasma viral RNA levels post-IDLV vaccination in high responder (HR) vs. low responders (LR) macaques before and after IDLV-SIV-Gag immunization. d Kendall’s tau correlation between T-cell responses and viral load at week 5 post IDLV-SIV-Gag immunization. e CD8+ cell counts before and after administration of the CD8-depleting mAb cM-T807. f Plasma viral RNA levels post CD8+ lymphocytes depletion in high responder (HR) vs. low responders (LR) macaques. Asterisks indicate p values < 0.05.