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 Host factors determine differential disease progression after infection with nef-deleted simian immunodeficiency virus

2014 ◽  
Vol 95 (10) ◽  
pp. 2273-2284 ◽  
Author(s):  
Sieghart Sopper ◽  
Kerstin Mätz-Rensing ◽  
Thorsten Mühl ◽  
Jonathan Heeney ◽  
Christiane Stahl-Hennig ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Replication ◽  
Disease Progression ◽  
Simian Immunodeficiency Virus ◽  
Mhc Class Ii ◽  
Cell Activation ◽  
Host Factors ◽  
Immunological Parameters ◽  
Set Point ◽  
Immunodeficiency Virus

Infection of macaques with live attenuated simian immunodeficiency virus (SIV) usually results in long-lasting efficient protection against infection with pathogenic immunodeficiency viruses. However, attenuation by deletion of regulatory genes such as nef is not complete, leading to a high viral load and fatal disease in some animals. To characterize immunological parameters and polymorphic host factors, we studied 17 rhesus macaques infected with attenuated SIVmac239ΔNU. Eight animals were able to control viral replication, whereas the remaining animals (non-controllers) displayed variable set-point viral loads. Peak viral load at 2 weeks post-infection (p.i.) correlated significantly with set-point viral load (P<0.0001). CD4+ T-cell frequencies differed significantly soon after infection between controllers and non-controllers. Abnormal B-cell activation previously ascribed to Nef function could already be observed in non-controllers 8 weeks after infection despite the absence of Nef. Two non-controllers developed an AIDS-like disease within 102 weeks p.i. Virus from these animals transmitted to naïve animals replicated at low levels and the recipients did not develop immunodeficiency. This suggested that host factors determined differential viral load and subsequent disease course. Known Mhc class I alleles associated with disease progression in SIV WT infection only marginally influenced the viral load in Δnef-infected animals. Protection from SIVmac251 was associated with homozygosity for MHC class II in conjunction with a TLR7 polymorphism and showed a trend with initial viral replication. We speculated that host factors whose effects were usually masked by Nef were responsible for the different disease courses in individual animals upon infection with nef-deleted viruses.

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 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 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 Viral Escape from Dominant Simian Immunodeficiency Virus Epitope-Specific Cytotoxic T Lymphocytes in DNA-Vaccinated Rhesus Monkeys

2003 ◽  
Vol 77 (13) ◽  
pp. 7367-7375 ◽  
Author(s):  
Dan H. Barouch ◽  
Jennifer Kunstman ◽  
Jennifer Glowczwskie ◽  
Kevin J. Kunstman ◽  
Michael A. Egan ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Cytotoxic T Lymphocytes ◽  
Rhesus Monkeys ◽  
Viral Rna ◽  
Viral Escape ◽  
Effective Control ◽  
Immunodeficiency Virus ◽  
Dominant Epitope

ABSTRACT Virus-specific cytotoxic T lymphocytes (CTL) are critical for control of human immunodeficiency virus type 1 replication. However, viral escape from CTL recognition can undermine this immune control. Here we demonstrate the high frequency and pattern of viral escape from dominant epitope-specific CTL in SIV gag DNA-vaccinated rhesus monkeys following a heterologous simian immunodeficiency virus (SIV) challenge. DNA-vaccinated monkeys exhibited initial effective control of the SIV challenge, but this early control was lost by serial breakthroughs of viral replication over a 3-year follow-up period. Increases in plasma viral RNA correlated temporally with declines of dominant SIV epitope-specific CD8+ T-lymphocyte responses and the emergence of viral mutations that escaped recognition by dominant epitope-specific CTL. Viral escape from CTL occurred in a total of seven of nine vaccinated and control monkeys, including three animals that initially controlled viral replication to undetectable levels of plasma viral RNA. These data suggest that CTL exert selective pressure on viral replication and that viral escape from CTL may be a limitation of CTL-based AIDS vaccine strategies.

scholarly journals Variability of Viral Load in Plasma of Rhesus Monkeys Inoculated with Simian Immunodeficiency Virus or Simian-Human Immunodeficiency Virus: Implications for Using Nonhuman Primate AIDS Models To Test Vaccines and Therapeutics

2001 ◽  
Vol 75 (22) ◽  
pp. 11234-11238 ◽  
Author(s):  
Robert A. Parker ◽  
Meredith M. Regan ◽  
Keith A. Reimann
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Simian Immunodeficiency Virus ◽  
Nonhuman Primate ◽  
Rhesus Monkeys ◽  
Nonhuman Primates ◽  
Viral Rna ◽  
Set Point ◽  
Immunodeficiency Virus ◽  
Aids Vaccines

ABSTRACT Viral RNA level in plasma is a sensitive experimental endpoint for evaluating the efficacy of AIDS vaccines or therapies in nonhuman primates. By quantifying viral RNA in the plasma of 77 rhesus monkeys for 10 weeks after inoculation with simian-human immunodeficiency virus 89.6P (SHIV-89.6P) or simian immunodeficiency virus mac 251 (SIVmac 251), we estimated variability in three viral load (VL) measures: peak VL, the postacute set point VL, and VL decline from peak. Such estimates of biological variability are essential for determining the number of animals needed per group and may be helpful for selecting the most appropriate measure to use as the experimental endpoint. Peak VL was positively correlated with set point VL for both viruses. Variability (standard deviation) was substantially higher in monkeys infected with SIVmac 251 than in those infected with SHIV-89.6P for set point VL and VL decline. The variability of peak VL was less than one-half that of set point VL variability and only about two-thirds of that of VL decline, implying that the same treatment-related difference in peak VL could be detected with fewer animals than set point VL or VL decline. Thus, differences in VL variability over the course of infection and between viruses need to be considered when designing studies using the nonhuman primate AIDS models.

scholarly journals Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Dima A. Hammoud ◽  
Sanhita Sinharay ◽  
Swati Shah ◽  
William Schreiber-Stainthorp ◽  
Dragan Maric ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Cerebrospinal Fluid ◽  
Viral Load ◽  
Simian Immunodeficiency Virus ◽  
Microglial Activation ◽  
Emission Tomography ◽  
Viral Loads ◽  
Positron Emission ◽  
Immunodeficiency Virus ◽  
Very High

ABSTRACTThe exact cause of neurocognitive dysfunction in HIV-positive patients despite successful control of the infection in the periphery is not completely understood. One suggested mechanism is a vicious cycle of microglial activation and release of proinflammatory chemokines/cytokines that eventually leads to neuronal loss and dysfunction. However, the exact role of microglial activation in the earliest stages of the infection with high cerebrospinal fluid (CSF) viral loads (VL) is unclear. In this study, we imaged the translocator protein (TSPO), a mitochondrial membrane receptor known to be upregulated in activated microglia and macrophages, in rhesus macaques before and multiple times after inoculation with a neurotropic simian immunodeficiency virus (SIV) strain (SIVsm804E), using 18F-DPA714 positron emission tomography (PET). The whole-brain standardized uptake values of TSPO at equilibrium reflecting total binding (SUVT) and binding potentials (BPND) were calculated and correlated with CSF and serum markers of disease, and a corresponding postmortem immunostaining analysis was also performed. SUVTwas found to be inversely correlated with both CSF VL and monocyte chemoattractant protein 1 (MCP-1) levels. In SIV-infected macaques with very high CSF VL at necropsy (>106copies/ml), we found decreased TSPO binding by PET, and this was supported by immunostaining which showed glial and neuronal apoptosis rather than microglial activation. On the other hand, with only moderately elevated CSF VL (∼104copies/ml), we found increased TSPO binding as well as focal and diffuse microglial activation on immunostaining. Our results in the SIV-infected macaque model provide insights into the relationship between HIV neuropathology and CSF VL at various stages of the disease.IMPORTANCENeurological and cognitive problems are a common complication of HIV infection and are prevalent even in treated individuals. Although the molecular processes underlying brain involvement with HIV are not completely understood, inflammation is suspected to play a significant role. Our work presents anin vivoassessment of neuroinflammation in an animal model of HIV, the simian immunodeficiency virus (SIV)-infected rhesus macaque. Using positron emission tomography (PET) imaging, we identified changes in brain inflammation after inoculation with SIV over time. Interestingly, we found decreased binding of the PET ligand in the presence of very high cerebrospinal fluid (CSF) viral loads. These findings were supported by immunostaining which showed marked glial loss instead of inflammation. This study provides insight into glial and neuronal changes associated with very high CSF viral load and could reflect similar changes occurring in HIV-infected patients.

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