scholarly journals The ITAM in Nef Influences Acute Pathogenesis of AIDS-Inducing Simian Immunodeficiency Viruses SIVsm and SIVagm without Altering Kinetics or Extent of Viremia

2002 ◽  
Vol 76 (9) ◽  
pp. 4379-4389 ◽  
Author(s):  
Houman Dehghani ◽  
Charles R. Brown ◽  
Ronald Plishka ◽  
Alicia Buckler-White ◽  
Vanessa M. Hirsch
Keyword(s):  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Clinical Symptoms ◽  
Macaca Nemestrina ◽  
Viral Reservoir ◽  
Immunodeficiency Virus ◽  
Active Viral Replication ◽  
Activation Motif

ABSTRACT The role of the immunoreceptor tyrosine-based activation motif (ITAM) that is unique to the Nef protein of the acutely pathogenic simian immunodeficiency virus SIVsmPBj was studied in the context of two AIDS-inducing simian immunodeficiency virus molecular clones. NefY+ variants of SIVagm9063-2 and SIVsmE543-3 replicated in and induced proliferation of unstimulated pig-tailed macaque PBMC. The pathogenesis of the NefY+ and NefY− clones of SIVagm9063-2, SIVsmE543-3, and PBj6.6 were evaluated by intravenous inoculation of pig-tailed macaques (Macaca nemestrina). Introduction of the ITAM did not increase plasma viral RNA levels nor alter the kinetics of viremia compared with the NefY− versions of each clone. Clinical symptoms were not observed in animals inoculated with the NefY− variants. In contrast, characteristic PBj symptoms were observed in animals inoculated with any of the three NefY+ clones. Blunting and fusion of intestinal villi and multifocal infiltration of mononuclear cells were observed in the gastrointestinal tracts of macaques inoculated with the NefY+ versions. Lesions were associated with active viral replication, as demonstrated by simian immunodeficiency virus-specific in situ hybridization. However, only the macaque inoculated with wild-type NefY+ SIVsmPBj developed fatal disease; lesions were more widespread and severe in this animal. A switch to macrophages as a viral reservoir and the presence of interleukin-6 in plasma was unique to the macaque infected with PBj6.6. Overall, these data suggest that the ITAM in SIV Nef alters the pathogenesis of simian immunodeficiency virus regardless of the viral background. The change in pathogenesis occurs without enhancement of viral replication. However, NefY+ variants of SIVagm and SIVsm did not fully recapitulate the virulence of SIVsmPBj, implicating additional viral factors in this unique virus pathogenesis.

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.

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 High Viral Load in the Cerebrospinal Fluid and Brain Correlates with Severity of Simian Immunodeficiency Virus Encephalitis

1999 ◽  
Vol 73 (12) ◽  
pp. 10480-10488 ◽  
Author(s):  
M. Christine Zink ◽  
Kalachar Suryanarayana ◽  
Joseph L. Mankowski ◽  
Anding Shen ◽  
Michael Piatak ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Viral Load ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Acute Phase ◽  
Viral Rna ◽  
Macaca Nemestrina ◽  
Immunodeficiency Virus ◽  
The Brain ◽  
Cns Lesions

ABSTRACT AIDS dementia and encephalitis are complications of AIDS occurring most frequently in patients who are immunosuppressed. The simian immunodeficiency virus (SIV) model used in this study was designed to reproducibly induce AIDS in macaques in order to examine the effects of a neurovirulent virus in this context. Pigtailed macaques (Macaca nemestrina) were coinoculated with an immunosuppressive virus (SIV/DeltaB670) and a neurovirulent molecularly cloned virus (SIV/17E-Fr), and more than 90% of the animals developed moderate to severe encephalitis within 6 months of inoculation. Viral load in plasma and cerebrospinal fluid (CSF) was examined longitudinally to onset of AIDS, and viral load was measured in brain tissue at necropsy to examine the relationship of systemic and central nervous system (CNS) viral replication to the development of encephalitis. In all animals, plasma viral load peaked at 10 to 14 days postinfection and remained high throughout infection with no correlation found between plasma viremia and SIV encephalitis. In contrast, persistent high levels of CSF viral RNA after the acute phase of infection correlated with the development of encephalitis. Although high levels of viral RNA were found in the CSF of all macaques (six of six) during the acute phase, this high level was maintained only in macaques developing SIV encephalitis (five of six). Furthermore, the level of both viral RNA and antigen in the brain correlated with the severity of the CNS lesions. The single animal in this group that did not have CNS lesions had no detectable viral RNA in any of the regions of the brain. The results substantiate the use of CSF viral load measurements in the postacute phase of SIV infection as a marker for encephalitis and CNS viral replication.

scholarly journals High Levels of Viral Replication during Primary Simian Immunodeficiency Virus SIVagm Infection Are Rapidly and Strongly Controlled in African Green Monkeys

2000 ◽  
Vol 74 (16) ◽  
pp. 7538-7547 ◽  
Author(s):  
Ousmane Madiagne Diop ◽  
Aïssatou Gueye ◽  
Marisa Dias-Tavares ◽  
Christopher Kornfeld ◽  
Abdourahmane Faye ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Chronic Phase ◽  
Peripheral Blood Mononuclear ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Green Monkeys

ABSTRACT In contrast to pathogenic human immunodeficiency virus and simian immunodeficiency virus (SIV) infections, chronic SIVagm infections in African green monkeys (AGMs) are characterized by persistently low peripheral and tissue viral loads that correlate with the lack of disease observed in these animals. We report here data on the dynamics of acute SIVagm infection in AGMs that exhibit remarkable similarities with viral replication patterns observed in peripheral blood during the first 2 weeks of pathogenic SIVmac infections. Plasma viremia was evident at day 3 postinfection (p.i.) in AGMs, and rapid viral replication led by days 7 to 10 to peak viremias characterized by high levels of antigenemia (1.2 to 5 ng of p27/ml of plasma), peripheral DNA viral load (104 to 105 DNA copies/106 peripheral blood mononuclear cells [PBMC]), and plasma RNA viral load (2 × 106 to 2 × 108 RNA copies/ml). The lymph node (LN) RNA and DNA viral load patterns were similar to those in blood, with peaks observed between day 7 and day 14. These values in LNs (ranging from 3 × 105 to 3 × 106 RNA copies/106LN cell [LNC] and 103 to 104 DNA copies/106 LNC) were at no time point higher than those observed in the blood. Both in LNs and in blood, rapid and significant decreases were observed in all infected animals after this peak of viral replication. Within 3 to 4 weeks p.i., antigenemia was no longer detectable and peripheral viral loads decreased to values similar to those characteristic of the chronic phase of infection (102to 103 DNA copies/106 PBMC and 2 × 103 to 2 × 105 RNA copies/ml of plasma). In LNs, viral loads declined to 5 × 101 to 103 DNA copies and 104 to 3 × 105 RNA copies per 106 LNC at day 28 p.i. and continued to decrease until day 84 p.i. (<10 to 3 × 104 RNA copies/106 LNC). Despite extensive viremia during primary infection, neither follicular hyperplasia nor CD8+ cell infiltration into LN germinal centers was detected. Altogether, these results indicate that the nonpathogenic outcome of SIVagm infection in its natural host is associated with a rapidly induced control of viral replication in response to SIVagm infection, rather than with a poorly replicating virus or a constitutive host genetic resistance to virus replication.

scholarly journals Role of Microglial Cells in Selective Replication of Simian Immunodeficiency Virus Genotypes in the Brain

2003 ◽  
Vol 77 (1) ◽  
pp. 208-216 ◽  
Author(s):  
Tahar Babas ◽  
Daniel Muñoz ◽  
Joseph L. Mankowski ◽  
Patrick M. Tarwater ◽  
Janice E. Clements ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Simian Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Selection Process ◽  
Macaca Nemestrina ◽  
Microglial Cells ◽  
Envelope Gene ◽  
Time Of Death ◽  
Immunodeficiency Virus ◽  
The Brain

ABSTRACT An accelerated, consistent macaque simian immunodeficiency virus (SIV) model in which over 90% of pigtailed macaques (Macaca nemestrina) coinoculated with SIV/17E-Fr and SIV/DeltaB670 developed encephalitis was used to determine whether central nervous system (CNS) lesions are associated with the replication of specific genotypes in the brain and, more specifically, in the microglia. Ten of 11 inoculated macaques had severe (n = 3), moderate (n = 5), or mild (n = 2) encephalitis at 3 months postinoculation. To compare actively replicating viral genotypes in the CNS and in microglia with those in the periphery, the V1 region of the SIV envelope gene was amplified and sequenced from RNA extracted from basal ganglia, from microglial cells isolated from the brain, and from peripheral blood mononuclear cells (PBMC) isolated from blood at the time of death. To distinguish between actively replicating with latent viral genotypes in the CNS, viral genotypes in RNA and DNA from basal ganglia were compared. Two macrophage-tropic, neurovirulent viruses, SIV/17E-Fr and SIV/DeltaB670 Cl-2, predominated in the brain RNA of macaques with encephalitis, comprising 95% of the genotypes detected. The same two viral genotypes were present at the same frequencies in microglial cell RNA, suggesting that microglia are pivotal in the selective replication of neurovirulent viruses. There was a significantly greater number of viral genotypes in DNA than there were in RNA in the brain (P = 0.004), including those of both the macrophage- and lymphocyte-tropic viral strains. Furthermore, significantly fewer viral genotypes were detected in brain RNA than in PBMC RNA at the time of death (P = 0.004) and the viral strain that predominated in the brain frequently was different from that which predominated in the PBMC of the same animal. These data suggest that many viral genotypes enter the brain, but only a limited subset of macrophage-tropic, neurovirulent viruses replicate terminally in the brains of macaques with encephalitis. They further suggest that the selection of macrophage-tropic, neurovirulent viruses occurs not at the level of the blood-brain barrier but at a stage after virus entry and that microglial cells may play an important role in that selection process.

scholarly journals Significant Depletion of CD4+T Cells Occurs in the Oral Mucosa during Simian Immunodeficiency Virus Infection with the Infected CD4+T Cell Reservoir Continuing to Persist in the Oral Mucosa during Antiretroviral Therapy

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Jeffy George ◽  
Wendeline Wagner ◽  
Mark G. Lewis ◽  
Joseph J. Mattapallil
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Simian Immunodeficiency Virus ◽  
Oral Mucosa ◽  
Mucosal Immunity ◽  
Viral Reservoir ◽  
Long Term Outcome ◽  
Immunodeficiency Virus ◽  
A Minor

Human and simian immunodeficiency virus (HIV and SIV) infections are characterized by manifestation of numerous opportunistic infections and inflammatory conditions in the oral mucosa. The loss of CD4+T cells that play a critical role in maintaining mucosal immunity likely contributes to this process. Here we show that CD4+T cells constitute a minor population of T cells in the oral mucosa and display a predominantly central memory phenotype mirroring other mucosal sites such as the rectal mucosa. Chronic SIV infection was associated with a near total depletion of CD4+T cells in the oral mucosa that appear to repopulate during antiretroviral therapy (ART). Repopulating CD4+T cells harbored a large fraction of Th17 cells suggesting that ART potentially reconstitutes oral mucosal immunity. However, a minor fraction of repopulating CD4+T cells harbored SIV DNA suggesting that the viral reservoir continues to persist in the oral mucosa during ART. Therapeutic approaches aimed at obtaining sustainable CD4+T cell repopulation in combination with strategies that can eradicate the latent viral reservoir in the oral mucosa are essential for better oral health and long-term outcome in HIV infected patients.

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.

Chronic binge alcohol and ovariectomy dysregulate omental adipose tissue metaboproteome in simian immunodeficiency virus-infected female macaques

2021 ◽  
Author(s):  
Jonquil Marie Poret ◽  
Jessie J Guidry ◽  
Liz Simon ◽  
Patricia E. Molina
Keyword(s):  
Metabolic Disease ◽  
Adipose Tissue ◽  
Simian Immunodeficiency Virus ◽  
People Living With Hiv ◽  
Infected Female ◽  
Omental Adipose Tissue ◽  
Immunodeficiency Virus ◽  
Z Scores ◽  
Functional Pathways

Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH), and the prevalence of at-risk alcohol use is higher among PLWH. Increased survival and aging of PLWH is associated with increased prevalence of metabolic comorbidities especially among menopausal women, and adipose tissue metabolic dysregulation may be a significant contributing factor. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome in a subset of simian immunodeficiency virus (SIV)-infected macaques of a longitudinal parent study. Quantitative discovery-based proteomics identified 1429 differentially expressed proteins. Ingenuity Pathway Analysis (IPA) was used to calculate z-scores, or activation predictions, for functional pathways and diseases. Results revealed protein changes associated with functional pathways centered around the "OmAT metaboproteome profile". Based on z-scores, CBA did not affect functional pathways of metabolic disease but dysregulated proteins involved in AMPK signaling and lipid metabolism. OVX-mediated proteome changes were predicted to promote pathways involved in glucose- and lipid-associated metabolic disease. Proteins involved in apoptosis, necrosis, and reactive oxygen species (ROS) pathways were also predicted to be activated by OVX, and these were predicted to be inhibited by CBA. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administration produced larger metabolic and cellular effects, which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.

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