scholarly journals A Truncated Form of Nef Selected during Pathogenic Reversion of Simian Immunodeficiency Virus SIVmac239Δnef Increases Viral Replication

2003 ◽  
Vol 77 (2) ◽  
pp. 1245-1256 ◽  
Author(s):  
Lisa A. Chakrabarti ◽  
Karin J. Metzner ◽  
Tijana Ivanovic ◽  
Hua Cheng ◽  
Jean Louis-Virelizier ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Premature Stop Codon ◽  
Cell Depletion ◽  
Partial Recovery ◽  
Wild Type ◽  
T Cell Depletion ◽  
Immunodeficiency Virus

ABSTRACT The live, attenuated vaccine simian immunodeficiency virus SIVmac239Δnef efficiently protects rhesus macaques against infection with wild-type SIVmac but occasionally causes CD4+ T-cell depletion and progression to simian AIDS (SAIDS). Virus recovered from a vaccinated macaque (Rh1490) that progressed to SAIDS had acquired an additional deletion in the nef gene, resulting in a frameshift that restored the original nef open reading frame (R. I. Connor, D. C. Montefiori, J. M. Binley, J. P. Moore, S. Bonhoeffer, A. Gettie, E. A. Fenamore, K. E. Sheridan, D. D. Ho, P. J. Dailey, and P. A. Marx, J. Virol. 72:7501-7509, 1998). Intravenous inoculation of the Rh1490 viral isolate into four naive rhesus macaques induced CD4+ T-cell depletion and disease in three out of four animals within 2 years, indicating a restoration of virulence. A DNA fragment encompassing the truncated nef gene amplified from the Rh1490 isolate was inserted into the genetic backbone of SIVmac239. The resulting clone, SIVmac239-Δ2nef, expressed a Nef protein of approximately 23 kDa, while the original SIVmac239Δnef clone expressed a shorter protein of 8 kDa. The revertant form of Nef did not cause downregulation of CD4, CD3, or major histocompatibility complex class I. The infectivity of SIVmac239-Δ2nef was similar to that of SIVmac239Δnef in single-cycle assays using indicator cell lines. In contrast, SIVmac239-Δ2nef replicated more efficiently than SIVmac239Δnef in peripheral blood mononuclear cell (PBMC) cultures infected under unstimulated conditions. The p27 Gag antigen levels in SIVmac239-Δ2nef-infected cultures were still lower than those obtained with wild-type SIVmac239, consistent with a partial recovery of Nef function. The transcriptional activity of long terminal repeat (LTR)-luciferase constructs containing the nef deletions did not differ markedly from that of wild-type LTR. Introduction of a premature stop codon within Nef-Δ2 abolished the replicative advantage in PBMCs, demonstrating that the Nef-Δ2 protein, rather than the structure of the U3 region of the LTR, was responsible for the increase in viral replication. Taken together, these results show that SIV with a deletion in the nef gene can revert to virulence and that expression of a form of nef with multiple deletions may contribute to this process by increasing viral replication.

scholarly journals Expanded Tissue Targets for Foamy Virus Replication with Simian Immunodeficiency Virus-Induced Immunosuppression

2006 ◽  
Vol 80 (2) ◽  
pp. 663-670 ◽  
Author(s):  
S. M. Murray ◽  
L. J. Picker ◽  
M. K. Axthelm ◽  
M. L. Linial
Keyword(s):  
Small Intestine ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Foamy Virus ◽  
Viral Rna ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus

ABSTRACT Foamy viruses (FV) are the oldest known genus of retroviruses and have persisted in nonhuman primates for over 60 million years. FV are efficiently transmitted, leading to a lifelong nonpathogenic infection. Transmission is thought to occur through saliva, but the detailed mechanism is unknown. Interestingly, this persistent infection contrasts with the rapid cytopathicity caused by FV in vitro, suggesting a host defense against FV. To better understand the tissue specificity of FV replication and host immunologic defense against FV cytopathicity, we quantified FV in tissues of healthy rhesus macaques (RM) and those severely immunosuppressed by simian immunodeficiency virus (SIV). Contrary to earlier findings, we find that all immunocompetent animals consistently have high levels of viral RNA in oral tissues but not in other tissues examined, including the small intestine. Strikingly, abundant viral transcripts were detected in the small intestine of all of the SIV-infected RM, which has been shown to be a major site of SIV (and human immunodeficiency virus)-induced CD4+ T-cell depletion. In contrast, there was a trend to lower viral RNA levels in oropharyngeal tissues of SIV-infected animals. The expansion of FV replication to the small intestine but not to other CD4+ T-cell-depleted tissues suggests that factors other than T-cell depletion, such as dysregulation of the jejunal microenvironment after SIV infection, likely account for the expanded tissue tropism of FV replication.

scholarly journals Simian immunodeficiency virus types 1 and 2 (SIV mnd 1 and 2) have different pathogenic potentials in rhesus macaques upon experimental cross-species transmission

2009 ◽  
Vol 90 (2) ◽  
pp. 488-499 ◽  
Author(s):  
Sandrine Souquière ◽  
Richard Onanga ◽  
Maria Makuwa ◽  
Ivona Pandrea ◽  
Paul Ngari ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Virus Replication ◽  
Rhesus Macaques ◽  
Natural Infection ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Viral Loads ◽  
Cell Counts ◽  
Immunodeficiency Virus

The mandrill (Mandrillus sphinx) is naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd types 1 and 2. Both of these viruses cause long-term, non-progressive infections in their natural host despite high plasma viral loads. This study assessed the susceptibility of rhesus macaques to infection by these two types of SIVmnd and compared the virological and basic immunological characteristics of the resulting infections with those observed in natural infection in mandrills. Whilst both SIVmnd types induced similar levels of virus replication during acute infection in both mandrills and macaques, they produced a more pronounced CD4+ T-cell depletion in rhesus macaques that persisted longer during the initial stage of infection. Pro-inflammatory cytokine responses were also induced at higher levels in rhesus macaques early in the infection. During the chronic phase of infection in mandrills, which in this case was followed for up to 2 years after infection, high levels of chronic virus replication did not induce significant changes in CD4+ or CD8+ T-cell counts. In rhesus macaques, the overall chronic virus replication level was lower than in mandrills. At the end of the follow-up period, although the viral loads of SIVmnd-1 and SIVmnd-2 were relatively similar in rhesus macaques, only SIVmnd-1-infected rhesus macaques showed significant CD4+ T-cell depletion, in the context of higher levels of CD4+ and CD8+ T-cell activation, compared with SIVmnd-infected mandrills. The demonstration of the ability of both SIVmnd types to induce persistent infections in rhesus macaques calls for a careful assessment of the potential of these two viruses to emerge as new human pathogens.

Rapid mucosal CD4+ T-cell depletion and enteropathy in simian immunodeficiency virus–infected rhesus macaques

1999 ◽  
Vol 116 (5) ◽  
pp. 1115-1123 ◽  
Author(s):  
Stephan Kewenig ◽  
Thomas Schneider ◽  
Karin Hohloch ◽  
Kathrin Lampe–Dreyer ◽  
Reiner Ullrich ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Cd4 T Cell ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus

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 >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 Intestinal Intraepithelial Lymphocytes Are Primed for Gamma Interferon and MIP-1β Expression and Display Antiviral Cytotoxic Activity despite Severe CD4+ T-Cell Depletion in Primary Simian Immunodeficiency Virus Infection

1998 ◽  
Vol 72 (8) ◽  
pp. 6421-6429 ◽  
Author(s):  
Joseph J. Mattapallil ◽  
Zeljka Smit-McBride ◽  
Michael McChesney ◽  
Satya Dandekar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Intraepithelial Lymphocytes ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Ifn Γ ◽  
Ctl Activity

ABSTRACT Intraepithelial lymphocytes (IEL) are a critical effector component of the gut-associated lymphoid tissue (GALT) and play an important role in mucosal immunity as well as in the maintenance of the epithelial cell integrity and barrier function. The objective of this study was to determine whether simian immunodeficiency virus (SIV) infection of rhesus macaques would cause alterations in the immunophenotypic profiles of IEL and their mitogen-specific cytokine (gamma interferon [IFN-γ] and MIP-1β) responses (by flow cytometry) and virus-specific cytotoxic T-cell (CTL) activity (by the chromium release assay). Virally infected IEL were detected through the entire course of SIV infection by in situ hybridization. Severe depletion of CD4+ single-positive and CD4+CD8+ double-positive T cells occurred early in primary SIV infection, which was coincident with an increased prevalence of CD8+ T cells. This was in contrast to a gradual depletion of CD4+ T cells in peripheral blood. The CD8+ IEL were the primary producers of IFN-γ and MIP-1β and were found to retain their potential to produce both IFN-γ and MIP-1β through the entire course of SIV infection. SIV-specific CTL activity was detected in primary IEL at 1, 2, and 4 weeks post-SIV infection. These results demonstrated that IEL may be involved in generating antiviral immune responses early in SIV infection and in suppressing viral infection thereafter. Alterations in homeostasis in epithelia due to severe CD4+ T-cell depletion accompanied by changes in the cytokine and chemokine production by IEL may play a role in the enteropathogenesis of SIV infection.

scholarly journals Identifying the Target Cell in Primary Simian Immunodeficiency Virus (SIV) Infection: Highly Activated Memory CD4+ T Cells Are Rapidly Eliminated in Early SIV Infection In Vivo

2000 ◽  
Vol 74 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Ronald S. Veazey ◽  
Irene C. Tham ◽  
Keith G. Mansfield ◽  
MaryAnn DeMaria ◽  
Amy E. Forand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cell Depletion ◽  
Cell Type ◽  
T Cell Depletion ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT It has recently been shown that rapid and profound CD4+T-cell depletion occurs almost exclusively within the intestinal tract of simian immunodeficiency virus (SIV)-infected macaques within days of infection. Here we demonstrate (by three- and four-color flow cytometry) that this depletion is specific to a definable subset of CD4+ T cells, namely, those having both a highly and/or acutely activated (CD69+ CD38+HLA-DR+) and memory (CD45RA−Leu8−) phenotype. Moreover, we demonstrate that this subset of helper T cells is found primarily within the intestinal lamina propria. Viral tropism for this particular cell type (which has been previously suggested by various studies in vitro) could explain why profound CD4+ T-cell depletion occurs in the intestine and not in peripheral lymphoid tissues in early SIV infection. Furthermore, we demonstrate that an acute loss of this specific subset of activated memory CD4+ T cells may also be detected in peripheral blood and lymph nodes in early SIV infection. However, since this particular cell type is present in such small numbers in circulation, its loss does not significantly affect total CD4+ T cell counts. This finding suggests that SIV and, presumably, human immunodeficiency virus specifically infect, replicate in, and eliminate definable subsets of CD4+ T cells in vivo.

scholarly journals Elite Control, Gut CD4 T Cell Sparing, and Enhanced Mucosal T Cell Responses in Macaca nemestrina Infected by a Simian Immunodeficiency Virus Lacking a gp41 Trafficking Motif

2015 ◽  
Vol 89 (20) ◽  
pp. 10156-10175 ◽  
Author(s):  
Matthew W. Breed ◽  
Samra E. Elser ◽  
Workineh Torben ◽  
Andrea P. O. Jordan ◽  
Pyone P. Aye ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Immune Activation ◽  
Rhesus Macaques ◽  
Macaca Nemestrina ◽  
Viral Control ◽  
Content Type ◽  
Immunodeficiency Virus

ABSTRACTDeletion of Gly-720 and Tyr-721 from a highly conserved GYxxØ trafficking signal in the SIVmac239 envelope glycoprotein cytoplasmic domain, producing a virus termed ΔGY, leads to a striking perturbation in pathogenesis in rhesus macaques (Macaca mulatta). Infected macaques develop immune activation and progress to AIDS, but with only limited and transient infection of intestinal CD4+T cells and an absence of microbial translocation. Here we evaluated ΔGY in pig-tailed macaques (Macaca nemestrina), a species in which SIVmac239 infection typically leads to increased immune activation and more rapid progression to AIDS than in rhesus macaques. In pig-tailed macaques, ΔGY also replicated acutely to high peak plasma RNA levels identical to those for SIVmac239 and caused only transient infection of CD4+T cells in the gut lamina propria and no microbial translocation. However, in marked contrast to rhesus macaques, 19 of 21 pig-tailed macaques controlled ΔGY replication with plasma viral loads of <15 to 50 RNA copies/ml. CD4+T cells were preserved in blood and gut for up to 100 weeks with no immune activation or disease progression. Robust antiviral CD4+T cell responses were seen, particularly in the gut. Anti-CD8 antibody depletion demonstrated CD8+cellular control of viral replication. Two pig-tailed macaques progressed to disease with persisting viremia and possible compensatory mutations in the cytoplasmic tail. These studies demonstrate a marked perturbation in pathogenesis caused by ΔGY's ablation of the GYxxØ trafficking motif and reveal, paradoxically, that viral control is enhanced in a macaque species typically predisposed to more pathogenic manifestations of simian immunodeficiency virus (SIV) infection.IMPORTANCEThe pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) reflects a balance between viral replication, host innate and adaptive antiviral immune responses, and sustained immune activation that in humans and Asian macaques is associated with persistent viremia, immune escape, and AIDS. Among nonhuman primates, pig-tailed macaques following SIV infection are predisposed to more rapid disease progression than are rhesus macaques. Here, we show that disruption of a conserved tyrosine-based cellular trafficking motif in the viral transmembrane envelope glycoprotein cytoplasmic tail leads in pig-tailed macaques to a unique phenotype in which high levels of acute viral replication are followed by elite control, robust cellular responses in mucosal tissues, and no disease. Paradoxically, control of this virus in rhesus macaques is only partial, and progression to AIDS occurs. This novel model should provide a powerful tool to help identify host-specific determinants for viral control with potential relevance for vaccine development.

scholarly journals Rapid Onset of Intestinal Epithelial Barrier Dysfunction in Primary Human Immunodeficiency Virus Infection Is Driven by an Imbalance between Immune Response and Mucosal Repair and Regeneration

2007 ◽  
Vol 82 (1) ◽  
pp. 538-545 ◽  
Author(s):  
Sumathi Sankaran ◽  
Michael D. George ◽  
Elizabeth Reay ◽  
Moraima Guadalupe ◽  
Jason Flamm ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Hiv Infection ◽  
Viral Replication ◽  
Cell Depletion ◽  
Epithelial Barrier ◽  
T Cell Depletion ◽  
Primary Hiv Infection ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is a site for severe CD4+ T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4+ T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4+ T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability to control viral replication and repair and regenerate intestinal mucosal tissues.

Sign in / Sign up

Export Citation Format

Share Document