Mucosal SIV Vaccines Comprising Inactivated Virus Particles and Bacterial Adjuvants Induce CD8+ T-Regulatory Cells that Suppress SIV-Positive CD4+ T-Cell Activation and Prevent SIV Infection in the Macaque Model

Andrieu, Jean‐Marie; Chen, Song; Lai, Cheng-Chou; Guo, Weizhong; Lü, Weiwei

doi:10.3389/fimmu.2014.00297

Cited by 30 publications

(32 citation statements)

References 65 publications

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“…Rhesus monkeys as a model for prion disease allowed circadian rhythm parameters to be monitored, which is not possible in human CJD cases. In parallel we proved transmission of BSE and human vCJD prions to a non-human primate species (Asante et al, 2015). This comprehensive project was funded by the EU and headed by John Collinge and Adriano Aguzzi working in London and Zurich, respectively.…”

Section: Research Activitiesmentioning

confidence: 81%

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Immunodeficiency viruses and prion disease

Bodemer

2015

Primate Biol.

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Abstract. Two threatening human diseases have emerged during the past 35 years. Human immunodeficiency virus (HIV) was transmitted from non-human primates – e.g., the chimpanzee to humans – and then spread into populations all over the world. To date, around 35 million people are infected and no vaccine is available because the virus undergoes rapid mutation, resulting in a swarm of virus strains. At best, therapeutical intervention is possible with antiviral drugs; however because of its capacity to rapidly mutate, resistant virus strains develop. Since non-human primates (NHPs) carry simian immunodeficiency virus (SIV), we could assess infection and immunity by SIV/HIV in rhesus monkeys (M. mulatta) as a model for acquired immunodeficiency syndrome (AIDS). Transmissible spongiform encephalopathy (TSE) emerged in ruminants in the 1980s and shortly thereafter appeared in humans, leading to variant Creutzfeldt–Jakob disease (vCJD). The vCJD is a terminal neurological disorder since it heavily and irreversibly damages the brain. No cure is at hand. The causative agents for TSE are prions. They are unusual pathogens and enigmatic since they lack nucleic acid as inheritable information. On the other hand, prions were suspected as infectious agents for years and suspected to be the etiological agent of scrapie in sheep. Molecular biology and medicine have clearly identified prions in recent years as the responsible agent for bovine spongiform encephalopathy in ruminants (BSE). BSE has been transmitted to humans, resulting in around 225 vCJD cases. Similar to the SIV/HIV model for Acquired Immunodeficiency Syndrome (AIDS), we could establish a prion infection model in rhesus monkeys. HIV/AIDS and vCJD are zoonoses since their original pathogens can be transmitted from animals to humans. Our experimental efforts to understand these intriguing pathogens and their corresponding diseases in rhesus monkeys as a valid model for both human diseases are summarized in this review.

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Section: Research Activitiesmentioning

confidence: 81%

“…Unfortunately, none of the cumbersome vaccine trails was successful, although partial contributions to protection could be assessed. Even in 2014, rhesus and cynomolgus monkeys served as animal models in innovative vaccination strategies like the elimination of proviral DNA (Andrieu et al, 2014).…”

Section: Research Activitiesmentioning

confidence: 99%

Immunodeficiency viruses and prion disease

Bodemer

2015

Primate Biol.

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“…Importantly, in their paper, Lu et al showed that the group of four Chinese RMs vaccinated with iSIV only had a clear anti-SIV antibody response (IgM and IgG); moreover, Chinese RMs vaccinated with iSIV-L. plantarum had a strong suppressive activity generated by major histocompatibility complex E (MHC-E)-restricted regulatory and/or suppressive CD8 ϩ T cells. These cells were measurable only in fresh cells (12,28) and were not evaluated in the current study.…”

Section: Discussionmentioning

confidence: 98%

Intragastric Administration of Lactobacillus plantarum and 2,2′-Dithiodipyridine-Inactivated Simian Immunodeficiency Virus (SIV) Does Not Protect Indian Rhesus Macaques from Intrarectal SIV Challenge or Reduce Virus Replication after Transmission

Carnathan

Mackel

Sweat

et al. 2018

J Virol

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A major obstacle to development of an effective AIDS vaccine is that along with intended beneficial responses, immunization regimen may activate CD4+ T cells that can facilitate acquisition of HIV by serving as target cells for the virus. Lu et al. reported that intra-gastric administration of chemically inactivated SIV (iSIV) and (LP) (iSIV+LP) protected 15/16 Chinese-origin rhesus macaques (RMs) from high-dose intra-rectal SIV challenge at three months post-immunization. They attributed the observed protection to induction of immune tolerance, mediated by "MHC-Ib/E-restricted CD8+ regulatory T cells that suppressed SIV-harboring CD4+ T cell activation and ex vivo SIV replication in 15/16 animals without inducing SIV-specific antibodies or cytotoxic T". Andrieu et al subsequently reported protection from infection in 23/24 RM immunized intragastrically or intravaginally with iSIV and BCG, LP or , which they ascribed to the same tolerogenic mechanism. Using vaccine materials obtained from our co-authors, we conducted an immunization and challenge experiment in 54 Indian RMs, and included control groups receiving iSIV only or LP only, as well as unvaccinated animals. Intra-rectal challenge with SIV resulted in rapid infection in all groups of vaccinated RMs as well as unvaccinated controls. iSIV+LP vaccinated animals that became SIV infected showed viral loads similar to those observed in animals receiving iSIV only, LP only, and unvaccinated controls. The protection from SIV transmission conferred by intra-gastric iSIV+LP administration reported previously for Chinese origin RMs was not observed when the same experiment was conducted in a larger cohort of Indian-origin animals. Despite increased understanding in immune responses against HIV, a safe and effective AIDS vaccine is not yet available. One obstacle is that immunization may activate CD4+ T cells that could act as target cells for acquisition of HIV. An alternative strategy could involve induction of a tolerizing response that limits the availability of activated CD4+ T cells, thus limiting the ability of virus to establish infection. In this regard, exciting results were obtained in Chinese-origin rhesus macaques by using a "tolerogenic" vaccine consisting of intra-gastric administration of Lactobacillus plantarum and AT-2-inactivated SIV (iSIV+LP) which showed highly significant protection from virus transmission. Here, we administered iSIV+LP immunizations to Indian-origin rhesus macaques, and failed to observe any protective effect from virus acquisition in this experimental setting. This work is important as it contributes to the overall assessment of the clinical potential of a new candidate AIDS vaccine platform based on the iSIV+LP.

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“…However, in contrast to all established human and veterinary vaccines, none of the protected macaques developed anti-SIV antibodies [25]. …”

Section: The Bacillus Of Calmette and Guerin A Tolerogenic Adjuvant mentioning

confidence: 99%

“…Four RMs were vaccinated intragastrically with iSIV and LR; two control RMs received LR only, and two iSIV received only [25]. …”

Section: Absence Of Immune Reactivity Of Indian Macaques To Intra-gasmentioning

confidence: 99%

A 30-year journey of trial and error towards a tolerogenic AIDS vaccine

Andrieu¹,

Lü²

2018

Arch Virol

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Since 1985, we have tested several immunological approaches to suppressing HIV replication in HIV-infected patients and to prevent HIV acquisition in uninfected people. Here, after briefly reviewing our studies on immunosuppressive treatments and therapeutic dendritic cell-based therapies, we examine in more detail our work on the tolerogenic vaccines we developed against AIDS in Chinese macaques. The vaccine consisted of inactivated SIVmac239 particles adjuvanted with the Bacillus of Calmette and Guerin (BCG), Lactobacillus plantarum (LP), or Lactobacillus rhamnosus (LR). Without adjuvant, the vaccine administered by the intragastric route induced the usual simian immunodeficiency virus (SIV)-specific humoral immune responses but no post-challenge protection. In contrast, out of 24 macaques that were immunized with the adjuvanted vaccine and challenged intrarectally with SIVmac239 or SIVB670, 23 were sterilely protected for up to 5 years, while all control macaques were infected. On the other hand, all macaques of Indian origin that were immunized with the same adjuvanted vaccine were not protected. We then discovered that vaccinated Chinese macaques developed a previously unrecognized class of non-cytolytic MHC-Ib/E-restricted CD8+ T cells (or CD8+ T-Regs) that suppressed the activation of SIV RNA-infected CD4+ T cells and thereby inhibited the (activation-dependent) reverse transcription of the virus and prevented the establishment of SIV infection. Finally, we found a similar population of HLA-E-restricted CD8+ T-Regs in human elite controllers (a small group of HIV-infected patients whose viral replication is naturally inhibited). Ex vivo, their CD8+ T-Regs suppressed viral replication in the same manner as those of vaccinated Chinese macaques. It is noteworthy that all of these elite controllers had a homo- or heterozygous HLA-Bw4-80I genotype. Taking into account the longevity and the high percentage of vaccine-protected Chinese macaques together with the concomitant identification of a robust ex vivo correlate of protection and the discovery of similar CD8+ T-Regs in human elite controllers, preventive and therapeutic HIV vaccines should be envisaged in humans.

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Mucosal SIV Vaccines Comprising Inactivated Virus Particles and Bacterial Adjuvants Induce CD8+ T-Regulatory Cells that Suppress SIV-Positive CD4+ T-Cell Activation and Prevent SIV Infection in the Macaque Model

Cited by 30 publications

References 65 publications

Immunodeficiency viruses and prion disease

Immunodeficiency viruses and prion disease

Intragastric Administration of Lactobacillus plantarum and 2,2′-Dithiodipyridine-Inactivated Simian Immunodeficiency Virus (SIV) Does Not Protect Indian Rhesus Macaques from Intrarectal SIV Challenge or Reduce Virus Replication after Transmission

A 30-year journey of trial and error towards a tolerogenic AIDS vaccine

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