Resistance to superinfection by a vigorously replicating, uncloned stock of simian immunodeficiency virus (SIVmac251) stimulates replication of a live attenuated virus vaccine (SIVmacC8)

Abstract

Vaccination with live attenuated simian immunodeficiency virus (SIVmacC8) confers potent, reproducible protection against homologous wild-type virus challenge (SIVmacJ5). The ability of SIVmacC8 to confer resistance to superinfection with an uncloned ex vivo derivative of SIVmac251 (SIVmac32H/L28) was investigated. In naïve, Mauritian-derived cynomolgus macaques (Macaca fascicularis), SIVmac32H/L28 replicated to high peak titres (.10 8 SIV RNA copies ml), persisted at high levels and induced distinctive pathology in lymphoid tissues. In cynomolgus macaques vaccinated with SIVmacC8, no evidence of detectable superinfection was observed in 3/8 vaccinates following challenge 3 or 20 weeks later with SIVmac32H/L28. Analyses after SIVmac32H/L28 challenge revealed a significant reduction in viral RNA (P,0.001) and DNA levels between 20 week vaccinates and challenge controls. Amongst 3 week vaccinates, less potent protection was observed. However, analysis of env from breakthrough virus indicated .99 % sequence similarity with the vaccine virus. Highly sensitive PCR assays that distinguish vaccine and challenge virus stocks demonstrated restimulation of replication of the vaccine virus SIVmacC8 in the face of potent protection against a vigorous, homologous challenge virus. Vaccine-induced antiviral neutralizing antibodies and anti-Nef CD8 + cytotoxic T cell responses did not correlate with the outcome of the challenge. Defining the mechanism of vaccine protection will need to account for the effective control of a genetically closely related challenge virus whilst remaining unable to suppress replication of the pre-existing vaccine virus. The role of innate and intrinsic anti-retroviral immunity in the protection conferred by live attenuated SIV vaccines warrants careful study.

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

“…Just as the correlates of protective immunity have not yet been defined for the protection observed in monkeys that have received a live attenuated SIV vaccine (1,3,11,44,45,54,55), the mechanisms accounting for the partial protection observed against superinfection in our study are not clear. We used pooled peptides corresponding to SIVmac239 Gag to evaluate virus-specific cellular immune responses because the crossreactive responses are likely the most germane to controlling the replication of the heterologous virus.…”

Extralymphoid CD8 + T Cells Resident in Tissue from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Suppress SIVmac239 Replication Ex Vivo

“…While previous studies have included considerable heterogeneity in the strain of attenuated SIV, challenge strain, and macaque species used, they demonstrate collectively the broad spectrum of attenuated SIVs that effectively protect macaques against pathogenic challenge. Several studies have also shown that attenuated SIV effectively protects cynomolgus macaques against pathogenic challenge using an SIVmac239C8 virus (1)(2)(3). Like SIVmac239⌬nef, this virus has a deletion in the nef gene, but this deletion is a considerably smaller 12-bp deletion than the 182-bp deletion in SIVmac239⌬nef (24).…”

International Multicenter Study To Assess a Panel of Reference Materials for Quantification of Simian Immunodeficiency Virus RNA in Plasma

“…The SIV/ simian-human immunodeficiency virus (SHIV) macaque model supports (pre)clinical evaluations of candidate HIV vaccines to provide a scientific framework for rational vaccine design and evaluation (11,15). Different candidate vaccine strategies may be investigated and viral pathogenesis elucidated (1,2,7,18,20,24,27). However, due to costs of undertaking biomedical research using macaque models and potentially conflicting issues of intellectual property, contemporaneous comparative vaccine efficacy studies at a single center are not feasible.…”

“…The biological properties of this virus stock have been described previously (1). SIV RNA levels initially determined for each macaque (W341 and W342) by quantitative reverse transcriptase PCR (RT-PCR) (2) were subsequently analyzed using real-time PCR (1). From an initial 1/100 dilution of plasma from W342, five 10-fold dilution steps were performed in SIV-negative macaque plasma to provide an estimated (nominal) concentration range of 2 ϫ 10 6 to 2 ϫ 10 2 SIV RNA copies/ml.…”

“…The biological properties of this virus stock have been described previously (1). SIV RNA levels initially determined for each macaque (W341 and W342) by quantitative reverse transcriptase PCR (RT-PCR) (2) were subsequently analyzed using real-time PCR (1).…”