Early Biodistribution and Persistence of a Protective Live Attenuated SIV Vaccine Elicits Localised Innate Responses in Multiple Lymphoid Tissues

Ferguson, Deborah; Mattiuzzo, Giada; Ham, Claire; Stebbings, Richard; Li, Bo; Rose, Nicola J.; Mee, Edward T.; Smith, Deborah; Page, Mark; Cranage, Martin; Almond, Neil; Towers, Greg J.; Berry, Neil

doi:10.1371/journal.pone.0104390

Cited by 9 publications

(20 citation statements)

References 65 publications

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“…Following infection with SIV strains that are pathogenic in IO RMs, CMs have an infection course that is less consistently pathogenic, with viral load profiles that may be several logs lower and more variable [19], though, like CO RMs, it is possible that this limitation may be overcome by using viruses adapted for this species [20–22]. Despite the more limited historical use of CMs for AIDS research, CMs from the island of Mauritius, which are descended from a small number of founder animals subject to insular geographic isolation resulting in limited genetic MHC class I and class II diversity [23,24], have emerged as a valuable research tool for studies seeking to more completely control for animal MHC haplotypes than is readily feasible with other, more outbred macaque hosts and populations [25,26*,27]. …”

Section: Nhp Host Speciesmentioning

confidence: 99%

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Prete

Lifson

Keele

2016

Current Opinion in HIV and AIDS

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Purpose of review Nonhuman primate (NHP) models of AIDS are powerful systems for evaluating HIV vaccine approaches in vivo. Authentic features of HIV-1 transmission, dissemination, target cell tropism, and pathogenesis, and aspects of anti-HIV-1 immune responses, can be recapitulated in NHPs provided the appropriate specific model parameters are considered. Here, we discuss key model parameter options and their implications for HIV-1 vaccine evaluation. Recent findings With the availability of several different NHP host species/subspecies, different challenge viruses and challenge stock production methods, and various challenge routes and schema, multiple NHP models of AIDS exist for HIV vaccine evaluation. The recent development of multiple new challenge viruses, including chimeric simian-human immunodeficiency viruses (SHIVs) and simian immunodeficiency virus (SIV) clones, improved characterization of challenge stocks and production methods, and increased insight into specific challenge parameters have resulted in an increase in the number of available models and a better understanding of the implications of specific study design choices. Summary Recent progress and technical developments promise new insights into basic disease mechanisms and improved models for better preclinical evaluation of interventions to prevent HIV transmission.

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Section: Nhp Host Speciesmentioning

confidence: 99%

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Prete

Lifson

Keele

2016

Current Opinion in HIV and AIDS

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“…However, neither serological responses ( Almond et al , 1997 ), nor CD8 + T-cell-mediated immunity (Stebbings et al , 2004, 2005 ) appear to identify a central role for adaptive immune responses in this model of vaccine protection. Recent studies have identified strong innate responses to SIVmacC8, particularly localized responses in lymphoid tissues immediately following vaccine delivery, which may impact on the early protection observed in our studies ( Ferguson et al , 2014 ).…”

Section: Introductionmentioning

confidence: 87%

Live attenuated simian immunodeficiency virus vaccination confers superinfection resistance against macrophage-tropic and neurovirulent wild-type SIV challenge

Berry

Ham

Alden

et al. 2015

Journal of General Virology

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Vaccination with live attenuated simian immunodeficiency virus (SIV) in non-human primate species provides a means of characterizing the protective processes of retroviral superinfection and may lead to novel advances of human immunodeficiency virus (HIV)/AIDS vaccine design. The minimally attenuated SIVmacC8 vaccine has been demonstrated to elicit early potent protection against pathogenic rechallenge with genetically diverse viral isolates in cynomolgus macaques (Macaca fascicularis). In this study, we have characterized further the biological breadth of this vaccine protection by assessing the ability of both the nef-disrupted SIVmacC8 and its nef-intact counterpart SIVmacJ5 viruses to prevent superinfection with the macrophage/neurotropic SIVmac239/17E-Fr (SIVmac17E-Fr) isolate. Inoculation with either SIVmacC8 or SIVmacJ5 and subsequent detailed characterization of the viral replication kinetics revealed a wide range of virus–host outcomes. Both nef-disrupted and nef-intact immunizing viruses were able to prevent establishment of SIVmac17E-Fr in peripheral blood and secondary lymphoid tissues. Differences in virus kinetics, indicative of an active process, identified uncontrolled replication in one macaque which although able to prevent SIVmac17E-Fr superinfection led to extensive neuropathological complications. The ability to prevent a biologically heterologous, CD4-independent/CCR5+ viral isolate and the macrophage-tropic SIVmac316 strain from establishing infection supports the hypothesis that direct target cell blocking is unlikely to be a central feature of live lentivirus vaccination. These data provide further evidence to demonstrate that inoculation of a live retroviral vaccine can deliver broad spectrum protection against both macrophage-tropic as well as lymphocytotropic viruses. These data add to our knowledge of live attenuated SIV vaccines but further highlight potential safety concerns of vaccinating with a live retrovirus.

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“…A crucial property of minimally-attenuated SIV vaccines, which are the most effective, is the widespread distribution of the vaccine virus in multiple lymphoid tissues [22] but the role of occult replication ( i . e .…”

Section: Introductionmentioning

confidence: 99%

“…replication in lymphoid tissue when virus is no longer or only intermittently detected in the peripheral circulation) in the generation of protective immunity is not fully understood. Vaccine virus persistence may result in multiple alterations in the host innate immune system that contribute to protection, in addition to the induction of adaptive immune responses [22]. In the study reported here we have sought to influence occult phase persisting turnover of live attenuated SIV using a novel approach: the conditionally live attenuated SIVmac239Δ nef vaccine (SIVrtTA) that in vitro is absolutely dependent on the presence of doxycycline (dox) to replicate [24, 25].…”

Section: Introductionmentioning

confidence: 99%

Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

et al. 2016

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In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity.

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Early Biodistribution and Persistence of a Protective Live Attenuated SIV Vaccine Elicits Localised Innate Responses in Multiple Lymphoid Tissues

Cited by 9 publications

References 65 publications

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Live attenuated simian immunodeficiency virus vaccination confers superinfection resistance against macrophage-tropic and neurovirulent wild-type SIV challenge

Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine

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