Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

Abstract

dUsing whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIV mac251 . Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV.

Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition

“…The association of RAS with vaccine-conferred protection from SIV acquisition was observed in an independent data set 24 , in which we use a nonvectored vaccine composed of intraperitoneal inoculation of HEK293 cells that co-expressed the heat shock protein gp96-Ig chaperoning SIV gag and Env, together with intramuscular boosts with gp120 + gp96-Ig 25 . This vaccine significantly delayed SIV mac251 acquisition (vaccine efficacy = 68%; P = 0.01) in rhesus macaques 25 (Supplementary Table 7).…”

“…Genes that were positively correlated with delayed SIV acquisition 24 h after the first immunization with ALVAC–SIV (Fig. 6a) were also significantly associated with delayed acquisition induced by the SIV-gp96 + gp120 vaccine 24 (GSEA: FDR q value = 0.0435; Fig. 6b).…”

“…Importantly, we confirmed the potential importance of the RAS pathway by demonstrating its association with vaccine efficacy conferred by a mucosal SIV-vaccine regimen based on the combination of heat shock protein gp96-IgG with SIVgp120 (refs. 24, 25). The full understanding of the mechanisms that elicit protective response at mucosal sites, as induced by the SIV-vaccine modalities studied here, will potentially help to guide the design of future vaccines and the choice of adjuvant that is best able to potentiate efficacy and end the HIV epidemic.…”

“…The Selinger et al . 24 raw gene-expression data, samples annotations and features annotation were downloaded from the GEO (GSE59068). The raw probe intensities were normalized, as described in the Selinger et al .…”

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

“…An approach in which rhesus macaques are inoculated intravaginally or intrarectally at regular intervals with a relatively low dose of SIV has been shown to recapitulate the hallmark reduction in viral diversity characteristic of HIV-1 transmission (11)(12)(13)(14). As a result, the repeated, low-dose challenge method has become widely accepted and commonly utilized to model protection against mucosal SIV infection ( [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. Despite these numerous studies, the characteristics of the virus that influence intravaginal and intrarectal transmission and protection are incompletely understood.…”