scholarly journals Analysis of Simian Immunodeficiency Virus-specific CD8+ T-cells in Rhesus Macaques by Peptide-MHC-I Tetramer Staining

10.3791/54881 ◽  
2016 ◽  
Author(s):  
Lucas Gonzalez-Nieto ◽  
Aline Domingues ◽  
Michael Ricciardi ◽  
Martin J. Gutman ◽  
Helen S. Maxwell ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Mhc I ◽  
Tetramer Staining ◽  
Immunodeficiency Virus

scholarly journals Perforin Expression in the Gastrointestinal Mucosa Is Limited to Acute Simian Immunodeficiency Virus Infection

2006 ◽  
Vol 80 (6) ◽  
pp. 3083-3087 ◽  
Author(s):  
Máire F. Quigley ◽  
Kristina Abel ◽  
Bartek Zuber ◽  
Christopher J. Miller ◽  
Johan K. Sandberg ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Positive Response ◽  
Rhesus Macaques ◽  
Gastrointestinal Mucosa ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Perforin Expression ◽  
Important Site

ABSTRACT Perforin-mediated cytotoxicity is a major effector function of virus-specific CD8 T cells. We have investigated the expression of perforin in the gut, an important site of simian immunodeficiency virus (SIV) pathogenesis, during experimental SIV infection of rhesus macaques. We observed significant increases in perforin protein and mRNA expression levels in the colons of SIV-infected macaques as early as 21 days after infection. However, during chronic infection, despite ongoing viral replication, perforin expression returned to levels similar to those detected in SIV-naïve animals. These findings demonstrate the presence of a robust perforin-positive response in gastrointestinal CD8 T cells during acute, but not chronic, SIV infection.

scholarly journals Mamu-B*17+Rhesus Macaques Vaccinated withenv,vif, andnefManifest Early Control of SIVmac239 Replication

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Mauricio A. Martins ◽  
Damien C. Tully ◽  
Núria Pedreño-Lopez ◽  
Benjamin von Bredow ◽  
Matthias G. Pauthner ◽  
...  
Keyword(s):  
T Cells ◽  
Rhesus Macaques ◽  
Chronic Phase ◽  
Virologic Suppression ◽  
Mhc I ◽  
Immunodeficiency Virus ◽  
Genes Encoding ◽  
Siv Infection ◽  
Group 2 ◽  
Group 1

ABSTRACTCertain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs). These cases of “elite” control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I alleleMamu-B*17. Approximately 21% ofMamu-B*17+and 50% ofMamu-B*08+RMs control chronic-phase viremia after SIVmac239 infection. Because CD8+T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression inMamu-B*08+RMs, we investigated whether this might also be true forMamu-B*17+RMs. Two groups ofMamu-B*17+RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together withenv(group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlikeMamu-B*08+RMs, preexisting SIV-specific CD8+T cells alone do not facilitate long-term virologic suppression inMamu-B*17+RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control inMamu-B*17+RMs and implicate vaccine-induced, nonneutralizing anti-Env antibodies in the containment of immunodeficiency virus infection.IMPORTANCEA better understanding of the immune correlates of protection against HIV might facilitate the development of a prophylactic vaccine. Therefore, we investigated simian immunodeficiency virus (SIV) infection outcomes in rhesus macaques expressing the major histocompatibility complex class I alleleMamu-B*17. Approximately 21% ofMamu-B*17+macaques spontaneously controlled chronic phase viremia after SIV infection, an effect that may involve CD8+T cells targeting Mamu-B*17-restricted SIV epitopes. We vaccinatedMamu-B*17+macaques with genes encoding immunodominant epitopes in Vif and Nef alone (group 1) or together withenv(group 2). Although neither vaccine regimen prevented SIV infection, 5/8 group 2 vaccinees controlled viremia to below detection limits shortly after infection. This outcome, which was not observed in group 1, was associated with vaccine-induced, nonneutralizing Env-binding antibodies. Together, these findings suggest a limited contribution of Vif- and Nef-specific CD8+T cells for virologic control inMamu-B*17+macaques and implicate anti-Env antibodies in containment of SIV infection.

scholarly journals Antiviral Antibodies and T Cells Are Present in the Foreskin of Simian Immunodeficiency Virus-Infected Rhesus Macaques

2012 ◽  
Vol 86 (13) ◽  
pp. 7098-7106 ◽  
Author(s):  
K. Rothaeusler ◽  
Z.-M. Ma ◽  
H. Qureshi ◽  
T. D. Carroll ◽  
T. Rourke ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Immunodeficiency Virus

scholarly journals With Minimal Systemic T-Cell Expansion, CD8+ T Cells Mediate Protection of Rhesus Macaques Immunized with Attenuated Simian-Human Immunodeficiency Virus SHIV89.6 from Vaginal Challenge with Simian Immunodeficiency Virus

2008 ◽  
Vol 82 (22) ◽  
pp. 11181-11196 ◽  
Author(s):  
Meritxell Genescà ◽  
Pamela J. Skinner ◽  
Jung Joo Hong ◽  
Jun Li ◽  
Ding Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
T Cell Response ◽  
Lymphoid Tissues ◽  
Vaginal Mucosa ◽  
Challenge Virus ◽  
Immunodeficiency Virus

ABSTRACT The presence, at the time of challenge, of antiviral effector T cells in the vaginal mucosa of female rhesus macaques immunized with live-attenuated simian-human immunodeficiency virus 89.6 (SHIV89.6) is associated with consistent and reproducible protection from pathogenic simian immunodeficiency virus (SIV) vaginal challenge (18). Here, we definitively demonstrate the protective role of the SIV-specific CD8+ T-cell response in SHIV-immunized monkeys by CD8+ lymphocyte depletion, an intervention that abrogated SHIV-mediated control of challenge virus replication and largely eliminated the SIV-specific T-cell responses in blood, lymph nodes, and genital mucosa. While in the T-cell-intact SHIV-immunized animals, polyfunctional and degranulating SIV-specific CD8+ T cells were present in the genital tract and lymphoid tissues from the day of challenge until day 14 postchallenge, strikingly, expansion of SIV-specific CD8+ T cells in the immunized monkeys was minimal and limited to the vagina. Thus, protection from uncontrolled SIV replication in animals immunized with attenuated SHIV89.6 is primarily mediated by CD8+ T cells that do not undergo dramatic systemic expansion after SIV challenge. These findings demonstrate that despite, and perhaps because of, minimal systemic expansion of T cells at the time of challenge, a stable population of effector-cytotoxic CD8+ T cells can provide significant protection from vaginal SIV challenge.

scholarly journals Effects of in Vivo Cd8+ T Cell Depletion on Virus Replication in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine

1999 ◽  
Vol 191 (11) ◽  
pp. 1921-1932 ◽  
Author(s):  
Karin J. Metzner ◽  
Xia Jin ◽  
Fred V. Lee ◽  
Agegnehu Gettie ◽  
Daniel E. Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Rhesus Macaques ◽  
Cd8 T Cell ◽  
T Cell Depletion ◽  
Challenge Virus ◽  
Immunodeficiency Virus

The role of CD8+ T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for &gt;2 yr with nef-deleted SIV (SIVmac239Δnef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8+ T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8+ T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8+ T cell depletion was associated with a 1–2 log increase in SIVmac239Δnef plasma viremia. Control of SIVmac239Δnef replication was temporally associated with the recovery of CD8+ T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8+ T cells. Overall, our results indicate that CD8+ T cells play an important role in controlling replication of live, attenuated SIV in vivo.

scholarly journals Reduced Protection from Simian Immunodeficiency Virus SIVmac251 Infection Afforded by Memory CD8+ T Cells Induced by Vaccination during CD4+ T-Cell Deficiency

2008 ◽  
Vol 82 (19) ◽  
pp. 9629-9638 ◽  
Author(s):  
Monica Vaccari ◽  
Joseph Mattapallil ◽  
Kaimei Song ◽  
Wen-Po Tsai ◽  
Anna Hryniewicz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Memory Cd8 T Cells ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus

ABSTRACT Adaptive CD4+ and CD8+ T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4+ T-cell deficiency. Depletion of CD4+ cells was performed in the immunized macaques at the peak of SIV-specific CD4+ T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8+ T cells prior to challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine-induced CD8+ T cells demonstrated that SIV-specific CD8+ T cells generated under conditions of CD4+ T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8+ T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4+ T cells are critical for the generation of effective CD8+ T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4+ and CD8+ T-cell responses and protect against early depletion of CD4+ T cells postinfection.

scholarly journals Comprehensive Analysis of Nef Functions Selected in Simian Immunodeficiency Virus-Infected Macaques

2004 ◽  
Vol 78 (19) ◽  
pp. 10588-10597 ◽  
Author(s):  
Michael Schindler ◽  
Jan Münch ◽  
Matthias Brenner ◽  
Christiane Stahl-Hennig ◽  
Jacek Skowronski ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Surface Expression ◽  
Viral Fitness ◽  
Cell Surface Expression ◽  
Mhc I ◽  
Mhc Ii ◽  
Immunodeficiency Virus

ABSTRACT A variety of simian immunodeficiency virus (SIVmac) nef mutants have been investigated to clarify which in vitro Nef functions contribute to efficient viral replication and pathogenicity in rhesus macaques. Most of these nef alleles, however, were only functionally characterized for their ability to down-modulate CD4 and class I major histocompatibility complex (MHC-I) cell surface expression and to enhance SIV replication and infectivity. To obtain information on the in vivo relevance of more recently established Nef functions, we examined the ability of a large panel of constructed SIVmac Nef mutants and of variants that emerged in infected macaques to down-regulate CD3, CD28, and MHC-II and to up-regulate the MHC-II-associated invariant chain (Ii). We found that all these four Nef functions were restored in SIV-infected macaques. In most cases, however, the initial mutations and the changes selected in vivo affected several in vitro Nef functions. For example, truncated Nef proteins that emerged in animals infected with SIVmac239 containing a 152-bp deletion in nef efficiently modulated both CD3 and Ii surface expression. Overall, our results suggest that the effect of Nef on each of the six cellular receptors investigated contributes to viral fitness in the infected host but also indicate that modulation of CD3, MHC-I, MHC-II, or Ii surface expression alone is insufficient for SIV virulence.

scholarly journals Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8+T Cell Killing

2015 ◽  
Vol 89 (20) ◽  
pp. 10625-10636 ◽  
Author(s):  
Jennifer N. Rainho ◽  
Mauricio A. Martins ◽  
Francesc Cunyat ◽  
Ian T. Watkins ◽  
David I. Watkins ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Viral Persistence ◽  
Cell Killing ◽  
Mhc I ◽  
Degree Of Protection ◽  
Immunodeficiency Virus

ABSTRACTSimian immunodeficiency virus (SIV)-specific CD8+T cells kill SIV-infected CD4+T cells in an major histocompatibility complex class I (MHC-I)-dependent manner. However, they are reportedly less efficient at killing SIV-infected macrophages. Since the viral accessory protein Nef has been shown to downregulate MHC-I molecules and enhance cytotoxic T lymphocyte (CTL) evasion in human immunodeficiency virus type 1 (HIV-1)-infected CD4+T cells, we examined whether Nef played a role in protecting SIV-infected macrophages from killing by SIV-specific CD8+T cells. To explore the role of Nef in CD8+T cell evasion, we compared the ability of freshly sorted SIV-specific CD8+T cells to readily suppress viral replication or eliminate CD4+T cells or monocyte-derived macrophages infected with SIV variants containing wild-type (WT) or mutatednefgenes. As expected, SIV-specific CD8+T cells suppressed viral replication and eliminated the majority of SIV-infected CD4+T cells, and this killing was enhanced in CD4+T cells infected with thenefvariants. However, macrophages infected withnefvariants that disrupt MHC-I downregulation did not promote rapid killing by freshly isolated CD8+T cells. These results suggest that mechanisms other than Nef-mediated MHC-I downregulation govern the resistance of SIV-infected macrophages to CD8+T cell-mediated killing. This study has implications for viral persistence and suggests that macrophages may afford primate lentiviruses some degree of protection from immune surveillance.IMPORTANCEMyeloid cells are permissive for HIV/SIV replicationin vitroand may contribute to viral persistencein vivo. While many studies have been geared to understanding how CD8+T cells control viral replication in CD4+T cells, the role of these cells in controlling viral replication in macrophages is less clear. Primary, unstimulated CD8+T cells insignificantly suppress viral replication or eliminate SIV-infected macrophages. Since the viral Nef protein downregulates MHC-I and provides infected cells some degree of protection from CD8+T cell-mediated effector functions, we evaluated whether Nef may be contributing to the resistance of macrophages to CD8+T cell suppression. Our results suggest that Nef is not involved in protecting infected macrophages from CD8+T cell killing and suggest that other mechanisms are involved in macrophage evasion from CD8 surveillance.

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