Dataset Information

Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions.

ABSTRACT: Live attenuated SIV induces potent protection against superinfection with virulent virus; however the mechanism of this vaccine effect is poorly understood. Such knowledge is important for the development of clinically acceptable vaccine modalities against HIV.Using a novel, doxycycline dependent, replication-competent live-attenuated SIVmac239?nef (SIV-rtTA?nef), we show that under replication-permissive conditions SIV-rtTA?nef is fully viable. Twelve rhesus macaques were infected with a peak plasma vRNA on average two log10 lower than in 6 macaques infected with unconditionally replication-competent SIV?nef. Consistent with the attenuated phenotype of the viruses the majority of animals displayed low or undetectable levels of viraemia by 42-84 days after infection. Next, comparison of circulating T cells before and after chronic infection with parental SIV?nef revealed a profound global polarisation toward CD28-CCR7- T-effector memory 2 (TEM2) cells within CD95+CD4+ and CD95+CD8+ populations. Critically, a similar effect was seen in the CD95+ CD4+ population and to somewhat lesser extent in the CD95+ CD8+ population of SIV-rtTA?nef chronically infected macaques that were maintained on doxycycline, but was not seen in animals from which doxycycline had been withdrawn. The proportions of gut-homing T-central memory (TCM) and TEM defined by the expression of ?4?7 and CD95 and differential expression of CD28 were increased in CD4 and CD8 cells under replication competent conditions and gut-homing CD4 TCM were also significantly increased under non-permissive conditions. TEM2 polarisation was seen in the small intestines of animals under replication permissive conditions but the effect was less pronounced than in the circulation. Intracellular cytokine staining of circulating SIV-specific T cells for IL-2, IFN-?, TNF-? and IL-17 showed that the extent of polyfunctionality in CD4 and CD8 T cells was associated with replication permissivity; however, signature patterns of cytokine combinations were not distinguishable between groups of macaques.Taken together our results show that the global T memory cell compartment is profoundly skewed towards a mature effector phenotype by attenuated SIV. Results with the replication-conditional mutant suggest that maintenance of this effect, that may be important in vaccine design, might require persistence of replicating virus.

SUBMITTER: Manoussaka MS

PROVIDER: S-EPMC3706341 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions.

Manoussaka Maria S MS Berry Neil N Ferguson Deborah D Stebbings Richard R Robinson Mark M Ham Claire C Page Mark M Li Bo B Das Atze T AT Berkhout Ben B Almond Neil N Cranage Martin P MP

Retrovirology 20130605

<h4>Background</h4>Live attenuated SIV induces potent protection against superinfection with virulent virus; however the mechanism of this vaccine effect is poorly understood. Such knowledge is important for the development of clinically acceptable vaccine modalities against HIV.<h4>Results</h4>Using a novel, doxycycline dependent, replication-competent live-attenuated SIVmac239Δnef (SIV-rtTAΔnef), we show that under replication-permissive conditions SIV-rtTAΔnef is fully viable. Twelve rhesus m ...[more]

PMID: 23738926

Similar Datasets

Project description:HIV vaccine development has been hampered by issues such as undefined correlates of protection and extensive diversity of HIV. We addressed these issues using a previously established SIV-macaque model in which SIV mutants with deletions of multiple gp120 N-glycans function as potent live attenuated vaccines to induce near-sterile immunity against the parental pathogenic SIVmac239. In this study, we investigated the protective efficacy of these mutants against a highly pathogenic heterologous SIVsmE543-3 delivered intravenously to rhesus macaques with diverse MHC genotypes. All 11 vaccinated macaques contained the acute-phase infection with blood viral loads below the level of detection between 4 and 10 weeks postchallenge (pc), following a transient but marginal peak of viral replication at 2 weeks in only half of the challenged animals. In the chronic phase, seven vaccinees contained viral replication for over 80 weeks pc, while four did not. Neutralizing antibodies against challenge virus were not detected. Although overall levels of SIV specific T cell responses did not correlate with containment of acute and chronic viral replication, a critical role of cellular responses in the containment of viral replication was suggested. Emergence of viruses with altered fitness due to recombination between the vaccine and challenge viruses and increased gp120 glycosylation was linked to the failure to control SIV. These results demonstrate the induction of effective protective immune responses in a significant number of animals against heterologous virus by infection with deglycosylated attenuated SIV mutants in macaques with highly diverse MHC background. These findings suggest that broad HIV cross clade protection is possible, even in hosts with diverse genetic backgrounds. In summary, results of this study indicate that deglycosylated live-attenuated vaccines may provide a platform for the elucidation of correlates of protection needed for a successful HIV vaccine against diverse isolates.

Project description:BackgroundSome studies have found a higher frequency of fever with trivalent live attenuated influenza vaccine (LAIV) than with inactivated influenza vaccine (IIV), but quadrivalent LAIV has not been assessed. Understanding fever is important for safety reviews and for parents and providers. In addition, there have been only a limited number of studies in which text messaging was used for vaccine adverse-event (AE) surveillance.MethodsWe conducted a prospective observational study in 3 community clinics in New York City to assess post-influenza vaccination fever in 24- to 59-month-olds during the 2013-2014 season. Enrolled families of children who received quadrivalent LAIV (LAIV4) or IIV (trivalent IIV3 or quadrivalent IIV4) replied to text messages that assessed their temperature on vaccination night and the next 10 nights (days 0 to 10); missing data were collected via telephone and a diary. We compared frequencies of fever (temperature ≥ 100.4°F) according to vaccine group on days 0 to 2 and 3 to 10 by using χ2 and multivariate log-binomial regression adjusted for age, previous influenza vaccination, and vaccine coadministration. We also assessed outcomes using all sources versus only text messages.ResultsMost (84.1% [n = 540]) eligible parents enrolled. Fever frequencies on days 0 to 2 did not differ between LAIV4 and any IIV (3.8% vs 5.7%, respectively; adjusted relative risk [aRR] [95% confidence interval], 0.60 [0.25-1.46]), between LAIV4 and IIV4 (4.2% vs 7.1%, respectively; aRR, 0.58 [0.19-1.72]), or between IIV4 and IIV3 (7.1% vs 6.0%, respectively; aRR, 1.02 [0.30-3.46]). The findings were similar when all data sources versus text-message data alone were used. There were no significant differences on days 3 to 10.ConclusionsPostvaccination fever frequencies were low overall and did not differ according to influenza vaccine type during the 2013-2014 influenza season. The similarity of results when data were limited to text messages lends support to its use for surveillance of vaccine adverse events.

Dataset Information

Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions.

Publications

Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets