Longitudinal and Spatial Analyses Reveal Distinct Immune Response Landscapes in Lung and Intestinal Tissue of SARS-CoV-2-Infected Rhesus Macaques

ABSTRACT In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8+ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8+ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4+ and CD4−CD8− T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts of SIV infection.

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Analysis and Prospects of Using Recombinant Vaccinia Virus MVA Strain as a Vector in the Development of the Vaccines against Human and Simian Immunodeficiency Virus Diseases

Problems of Particularly Dangerous Infections ◽

10.21055/0370-1069-2019-2-37-44 ◽

2019 ◽

pp. 37-44

Author(s):

L. F. Stovba ◽

V. T. Krotkov ◽

D. I. Paveli’ev ◽

S. A. Mel’nikov ◽

V. N. Lebedev ◽

...

Keyword(s):

Immune Response ◽

Simian Immunodeficiency Virus ◽

Structural Changes ◽

Rhesus Macaques ◽

Laboratory Animals ◽

Cell Immune Response ◽

Effective Vaccine ◽

Protective Efficiency ◽

Immunodeficiency Virus ◽

Immunodominant Antigens

The review presents the results of preclinical use of vector vaccines against human immunodeficiency virus (HIV) disease and simian immunodeficiency virus (SIV) disease. Application of antiretroviral therapy exclusively is insufficient for elimination of HIV from patient’s body. This dictates the need for an effective vaccine which will reduce the number of new cases of the disease and reduce the risk of virus transmission. Current practice of medicinal product development showed the effectiveness of heterologous prime-boost regimens for the induction of expressed immune response in laboratory animals. Various vector constructs were used as priming vaccines: DNA vaccines, Bacille Calmette-Guerin vaccine, chimpanzee adenovirus, vesicular stomatitis virus, alphavirus repli-clone. Booster vaccine was represented by recombinant MVA strain. In all vector vaccines, different genes of immunodominant antigens of HIV and SIV agents were inserted. On rhesus macaques, murine, rabbit models, it was demonstrated that deployed vaccination schemes were safe and induced immune response. Because membrane HIV protein is highly variable, strongly glycoziled and subjected to structural changes during receptor binding, it cannot be viewed as a target for induction of virus neutralized antibodies. Therefore, we mainly studied the cell immune response that was presented by poly-functional CD8+ T-cells. However, some recent researches are aimed at such modification of envelope HIV immunogene that would provide for virus neutralizing antibody induction. The study of protective efficiency of the induced immunity in rhesus macaques, immunized with recombinant vectors expressing SIV’ s immunodominant antigens, in case of subsequent inoculation with virulent SIV strain has revealed that all monkeys developed illness. Assuming that the constructions with SIV’ s immunodominant antigens under protective efficiency testing on rhesus macaques imitate AIDS in humans, it seems that vaccines, developed up-to-date, will not be effective for collective immunity formation against AIDS. Therefore, the search for novel combinations of expressed immunodominant antigens for the inclusion into the composition of priming and booster vaccines remains a priority area at present time.

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Potential significance of the cellular immune response against the macaque strain of simian immunodeficiency virus (SIVMAC) in immunized and infected rhesus macaques

Journal of General Virology ◽

10.1099/0022-1317-73-9-2273 ◽

1992 ◽

Vol 73 (9) ◽

pp. 2273-2281 ◽

Cited By ~ 8

Author(s):

G. Voss ◽

S. Nick ◽

C. Stahl-Hennig ◽

C. Coulibaly ◽

H. Petry ◽

...

Keyword(s):

Immune Response ◽

Simian Immunodeficiency Virus ◽

Cellular Immune Response ◽

Rhesus Macaques ◽

Potential Significance ◽

Immunodeficiency Virus ◽

Cellular Immune

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DNA Encoding an HIV-1 Gag/Human Lysosome-Associated Membrane Protein-1 Chimera Elicits a Broad Cellular and Humoral Immune Response in Rhesus Macaques

PLoS ONE ◽

10.1371/journal.pone.0000135 ◽

2006 ◽

Vol 1 (1) ◽

pp. e135 ◽

Cited By ~ 22

Author(s):

Priya Chikhlikar ◽

Luciana Barros de Arruda ◽

Milton Maciel ◽

Peter Silvera ◽

Mark G. Lewis ◽

...

Keyword(s):

Immune Response ◽

Membrane Protein ◽

Humoral Immune Response ◽

Rhesus Macaques ◽

Dna Encoding ◽

Humoral Immune ◽

Hiv 1

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2729. mRNA Vaccines Encoding Conserved Influenza Antigens Induce Robust and Durable Immunity in Rhesus Macaques

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2407 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S961-S961

Author(s):

Jessica Flynn ◽

Kara Cox ◽

Sinoeun Touch ◽

Yangsi Ou ◽

Teresa Weber ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Rhesus Macaques ◽

Vaccine Dose ◽

T Cell Responses ◽

Immune Recognition ◽

Serum Antibodies ◽

Ifn Gamma ◽

Cell Responses ◽

Lipid Nanoparticle

Abstract Background In response to immune pressure, influenza virus evolves, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response that can recognize multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the immunogenicity of mRNA vaccines encoding the stem domain of hemagglutinin (HA) or nucleoprotein (NP) in nonhuman primates (NHPs). Methods Rhesus macaques were immunized three times intramuscularly, at 28 day intervals, with lipid nanoparticle-encapsulated mRNA encoding either HA stem (Yassine et al, 2015) or NP. Serum and PBMCs were collected up to 14 or 24 weeks, respectively, after the last vaccination. The magnitude and durability of humoral and cell-mediated immunity were evaluated. ELISA, competition ELISA, an in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) reporter bioassay, and microneutralization assays were used to characterize serum immune responses. Intracellular cytokine staining (IFN-gamma and IL-2) was used to assess antigen-specific T-cell responses. Results HA stem-immunized NHPs developed a robust anti-stem binding titer after a single vaccine dose, and after two doses, serum antibodies recognized several antigenically distinct Group 1 HA proteins. This broad antibody response persisted for at least 14 weeks post-dose 3 (PD3). Serum antibodies showed ADCC activity and competed with a well-characterized broadly neutralizing antibody, CR9114, for binding to HA stem; however, the polyclonal serum had only minimal activity against a panel of H1N1 viruses in a microneutralization assay. HA-specific CD4+ T-cell responses were detectable PD3. A robust antibody binding response was also detected in NP-vaccinated NHPs, and titers remained high for at least 14 weeks PD3. Additionally, these animals developed robust NP-specific T-cell responses that persisted for at least 24 weeks PD3. On average, 0.5% of CD4+ and 4% of CD8+ T cells produced IFN-gamma in response to NP peptide stimulation at the peak of the response, 2 weeks after the last vaccine dose was administered. Conclusion Lipid nanoparticle-encapsulated mRNA vaccines encoding conserved influenza antigens induce a robust and durable immune response in NHPs. Disclosures All authors: No reported disclosures.

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Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Journal of Virology ◽

10.1128/jvi.01272-16 ◽

2016 ◽

Vol 90 (23) ◽

pp. 10823-10843 ◽

Cited By ~ 9

Author(s):

Nicole Arnold ◽

Thomas Girke ◽

Suhas Sureshchandra ◽

Ilhem Messaoudi

Keyword(s):

Gene Expression ◽

Immune Response ◽

T Cells ◽

Virus Infection ◽

Innate Immune Response ◽

Rhesus Macaques ◽

Innate Immune ◽

Sensory Ganglia ◽

Simian Varicella Virus ◽

Varicella Virus

ABSTRACTPrimary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression.IMPORTANCEMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection.

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