Wyand, M. S. et al. Protection by live, attenuated simian immunodeficiency virus against heterologous challenge. J. Virol. 73, 8356-8363

Department of Surgery, Duke University, Durham, North Carolina, United States
Journal of Virology (Impact Factor: 4.44). 11/1999; 73(10):8356-63.
Source: PubMed


We examined the ability of a live, attenuated deletion mutant of simian immunodeficiency virus (SIV), SIVmac239Delta3, which is missing nef and vpr genes, to protect against challenge by heterologous strains SHIV89.6p and SIVsmE660. SHIV89.6p is a pathogenic, recombinant SIV in which the envelope gene has been replaced by a human immunodeficiency virus type 1 envelope gene; other structural genes of SHIV89.6p are derived from SIVmac239. SIVsmE660 is an uncloned, pathogenic, independent isolate from the same primate lentivirus subgrouping as SIVmac but with natural sequence variation in all structural genes. The challenge with SHIV89.6p was performed by the intravenous route 37 months after the time of vaccination. By the criteria of CD4(+) cell counts and disease, strong protection against the SHIV89.6p challenge was observed in four of four vaccinated monkeys despite the complete mismatch of env sequences. However, SHIV89.6p infection was established in all four previously vaccinated monkeys and three of the four developed fluctuating viral loads between 300 and 10,000 RNA copy equivalents per ml of plasma 30 to 72 weeks postchallenge. When other vaccinated monkeys were challenged with SIVsmE660 at 28 months after the time of vaccination, SIV loads were lower than those observed in unvaccinated controls but the level of protection was less than what was observed against SHIV89.6p in these experiments and considerably less than the level of protection against SIVmac251 observed in previous experiments. These results demonstrate a variable level of vaccine protection by live, attenuated SIVmac239Delta3 against heterologous virus challenge and suggest that even live, attenuated vaccine approaches for AIDS will face significant hurdles in providing protection against the natural variation present in field strains of virus. The results further suggest that factors other than anti-Env immune responses can be principally responsible for the vaccine protection by live, attenuated SIV.

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Available from: David C Montefiori, Jun 19, 2014
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    • "After thirty years of HIV discovery, there are still no efficient and safe enough prophylactic and/or therapeutic vaccines that can be used in humans. Live-attenuated vaccines showed promising levels of protection in NHP models [13] [15]; however, they were associated with irreversible integration in the host genome, persistence and reversion to pathogenic state in some vaccinated animals [16] [17] impelling safer strategies for clinical use. Alternatively, DNA vaccines became more attractive tools for vaccination against HIV and other pathogens, particularly with effort being made to increase their immunogenicity via optimizing vaccine design, use of adjuvants , and delivery methods [43] [44] [45] [46] [47]. "
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    Full-text · Article · Mar 2015 · Vaccine
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    • "While recent clinical HIV vaccine trials have provided mixed results (Buchbinder et al., 2008; McElrath et al., 2008; Rerks-Ngarm et al., 2009), vital details of the molecular mechanisms that collectively contribute to protective immune responses continue to be unraveled through studies of non-human primate models. Vaccination of rhesus macaques with live attenuated strains of simian immunodeficiency virus (SIV) has been shown to elicit immunity to subsequent infection by pathogenic SIV strains (Connor et al., 1998; Daniel et al., 1992; Wyand et al., 1999). Studies of cytotoxic T-cell (CTL) responses in the rhesus macaque model show that the protection conferred by attenuated SIV is associated with the establishment of a pool of antigen-specific memory cells that display rapid and vigorous ex vivo cytopathic responses (Johnson et al., 1997). "
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    ABSTRACT: a b s t r a c t Immunization of macaques with attenuated simian immunodeficiency virus (SIV) with deletions in nef (SIVΔnef) is shown to elicit protective immunity to infection by pathogenic SIV, yet the mechanisms that orchestrate protection and prevent pathogenesis remains unknown. We utilized whole-genome transcriptional profiling to reveal molecular signatures of protective immunity in circulating CD8 þ T cells of rhesus macaques vaccinated with SIVmac239Δnef and challenged with pathogenic SIVmac251. Our findings suggest that protective immunity to pathogenic SIV infection induced by SIVmac239Δnef is associated with balanced induction of T cell activation and immunoregulatory mechanisms and dampened activation of interferon-induced signaling pathways and cytolytic enzyme production as compared with pathogenic SIVmac251 infection of unvaccinated controls. We provide evidence that protective immunity to SIVmac251 correlates with induction of biomarkers of T cell activation, differentiation, signaling, and adhesion that were down regulated in unvaccinated controls. The study highlights potential immunomodulatory networks associated with protective immunity against the virus.
    Full-text · Article · Oct 2014 · Virology
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    • "However, to make a major impact on the pandemic, improved vaccine strategies that elicit durable, broadly effective, potent protection will be required. Live attenuated vaccination (LAV) with simian immunodeficiency virus (SIV) in non-human primates has provided proof of concept of highly efficacious vaccine protection [2], [3], demonstrating durable, potent resistance against detectable superinfection with wild-type SIV challenge by multiple routes and with diverse virus strains [4]–[20]. Identification of the mechanism(s) of protection has proven to be difficult, perhaps, at least in part, due to the focus on the measurement of responses in the peripheral circulation. "
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