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 MHC Class I Alleles Influence Set-Point Viral Load and Survival Time in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

2002 ◽  
Vol 169 (6) ◽  
pp. 3438-3446 ◽  
Author(s):  
Thorsten Mühl ◽  
Michael Krawczak ◽  
Peter ten Haaft ◽  
Gerhard Hunsmann ◽  
Ulrike Sauermann
Keyword(s):  
Viral Load ◽  
Survival Time ◽  
Simian Immunodeficiency Virus ◽  
Mhc Class I ◽  
Rhesus Monkeys ◽  
Class I ◽  
Set Point ◽  
Immunodeficiency Virus

scholarly journals Cholesterol Depletion of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus with β-Cyclodextrin Inactivates and Permeabilizes the Virions: Evidence for Virion-Associated Lipid Rafts

2003 ◽  
Vol 77 (15) ◽  
pp. 8237-8248 ◽  
Author(s):  
David R. M. Graham ◽  
Elena Chertova ◽  
Joanne M. Hilburn ◽  
Larry O. Arthur ◽  
James E. K. Hildreth
Keyword(s):  
Human Immunodeficiency Virus ◽  
Lipid Rafts ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Viral Rna ◽  
Host Proteins ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Recent evidence suggests that human immunodeficiency virus type 1 (HIV-1) particles assemble and bud selectively through areas in the plasma membrane of cells that are highly enriched with glycosylphosphatidylinositol-anchored proteins and cholesterol, called lipid rafts. Since cholesterol is required to maintain lipid raft structure and function, we proposed that virion-associated cholesterol removal with the compound 2-hydroxy-propyl-β-cyclodextrin (β-CD) might be disruptive to HIV-1 and simian immunodeficiency virus (SIV). We examined the effect of β-CD on the structure and infectivity of cell-free virions. We found that β-CD inactivated HIV-1 and SIV in a dose-dependent manner and permeabilized the viral membranes, resulting in the loss of mature Gag proteins (capsid, matrix, nucleocapsid, p1, and p6) without loss of the envelope glycoproteins. SIV also lost reverse transcriptase (RT), integrase (IN), and viral RNA. IN appeared to be only slightly diminished in HIV-1, and viral RNA, RT, matrix, and nucleocapsid proteins were retained in HIV-1 but to a much lesser degree. Host proteins located internally in the virus (actin, moesin, and ezrin) and membrane-associated host proteins (major histocompatibility complex classes I and II) remained associated with the treated virions. Electron microscopy revealed that under conditions that permeabilized the viruses, holes were present in the viral membranes and the viral core structure was perturbed. These data provide evidence that an intact viral membrane is required to maintain mature virion core integrity. Since the viruses were not fixed before β-CD treatment and intact virion particles were recovered, the data suggest that virions may possess a protein scaffold that can maintain overall structure despite disruptions in membrane integrity.

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 Importance of B-Cell Responses for Immunological Control of Variant Strains of Simian Immunodeficiency Virus

2003 ◽  
Vol 77 (1) ◽  
pp. 375-381 ◽  
Author(s):  
Welkin E. Johnson ◽  
Jeffrey D. Lifson ◽  
Sabine M. Lang ◽  
R. Paul Johnson ◽  
Ronald C. Desrosiers
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Monkeys ◽  
Peak Height ◽  
Replicative Capacity ◽  
Variable Regions ◽  
Set Point ◽  
Viral Loads ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Time Of Infection

ABSTRACT The properties of three variants of cloned simian immunodeficiency virus strain 239 (SIV239) were compared. One strain (M5) lacked five sites for N-linked carbohydrate attachment in variable regions 1 and 2 (V1 and V2) of the gp120 envelope protein, one strain (ΔV1-V2) completely lacked V1 and V2 sequences, and another (316) had nine mutations in the envelope that impart high replicative capacity for tissue macrophages. All three strains were capable of significant levels of fusion independent of CD4, and all three were considerably more sensitive to antibody-mediated neutralization than the parent strain from which they were derived. Upon experimental infection of rhesus monkeys, these three variant strains replicated to viral loads at peak height around day 14 that were indistinguishable from or only slightly less than those observed in monkeys infected with the parental SIV239 strain. Viral loads at the set point 20 to 50 weeks after infection, however, were more than 400- to 10,000-fold lower with the variant strains. Depletion of B cells around the time of infection with M5 resulted in less effective immunological control and much higher viral loads at the set point in two of three monkeys. The differences between SIV239 infection, where there is not effective immunological control, and SIVM5 infection, where there is effective immunological control, cannot be easily explained by differences in the inherent replicative capacity of the viruses; rather, they are more readily explained by differences in the effectiveness of the antibody response. These results suggest that resistance of SIV239 to antibody-mediated neutralization is very important for evading effective immunological control, for allowing continuous viral replication, for maintenance of moderate-to-high viral loads at set point, and for disease progression.

scholarly journals Structured Treatment Interruptions with Tenofovir Monotherapy for Simian Immunodeficiency Virus-Infected Newborn Macaques

2006 ◽  
Vol 80 (13) ◽  
pp. 6399-6410 ◽  
Author(s):  
Koen K. A. Van Rompay ◽  
Raman P. Singh ◽  
Walid Heneine ◽  
Jeffrey A. Johnson ◽  
David C. Montefiori ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Drug Withdrawal ◽  
Viral Rna ◽  
Resistance Mutations ◽  
In Vitro Susceptibility ◽  
Set Point ◽  
K65r Mutation ◽  
Treatment Interruptions ◽  
Viral Virulence ◽  
Immunodeficiency Virus

ABSTRACT We demonstrated previously that prolonged tenofovir treatment of infant macaques, starting early during infection with virulent simian immunodeficiency virus (SIVmac251), can lead to persistently low or undetectable viremia even after the emergence of mutants with reduced in vitro susceptibility to tenofovir as a result of a K65R mutation in reverse transcriptase; this control of viremia was demonstrated to be mediated by the generation of effective antiviral immune responses. To determine whether structured treatment interruptions (STI) can induce similar immunologic control of viremia, eight newborn macaques were infected with highly virulent SIVmac251 and started on a tenofovir STI regimen 5 days later. Treatment was withdrawn permanently at 33 weeks of age. All animals receiving STI fared much better than 22 untreated SIVmac251-infected infant macaques. However, there was a high variability among animals in the viral RNA set point after complete drug withdrawal, and none of the animals was able to achieve long-term immunologic suppression of viremia to persistently low levels. Early immunologic and viral markers in blood (including the detection of the K65R mutation) were not predictive of the viral RNA set point after drug withdrawal. These results, which reflect the complex interactions between drug resistance mutations, viral virulence, and drug- and immune-mediated inhibition of virus replication, highlight the difficulties associated with trying to develop STI regimens with predictable efficacy for clinical practice.

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.

Detection of Viral RNA in CD4-CD8-and CD4-CD8+Lymphocytesin Vivoin Rhesus Monkeys Infected with Simian Immunodeficiency Virus of Macaques

2001 ◽  
Vol 17 (4) ◽  
pp. 349-360 ◽  
Author(s):  
José M. Benito Huete ◽  
Pamela A. Chatis ◽  
Jörn E. Schmitz ◽  
Marcelo J. Kuroda ◽  
Norman L. Letvin ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Monkeys ◽  
Viral Rna ◽  
Immunodeficiency Virus

scholarly journals Increased APOBEC3G and APOBEC3F expression is associated with low viral load and prolonged survival in simian immunodeficiency virus infected rhesus monkeys

Retrovirology ◽  
2011 ◽  
Vol 8 (1) ◽  
pp. 77 ◽  
Author(s):  
Bianka Mußil ◽  
Ulrike Sauermann ◽  
Dirk Motzkus ◽  
Christiane Stahl-Hennig ◽  
Sieghart Sopper
Keyword(s):  
Viral Load ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Monkeys ◽  
Prolonged Survival ◽  
Immunodeficiency Virus

scholarly journals Molecularly Tagged Simian Immunodeficiency Virus SIVmac239 Synthetic Swarm for Tracking Independent Infection Events

2014 ◽  
Vol 88 (14) ◽  
pp. 8077-8090 ◽  
Author(s):  
Gregory Q. Del Prete ◽  
Haesun Park ◽  
Christine M. Fennessey ◽  
Carolyn Reid ◽  
Leslie Lipkey ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Sequence Analysis ◽  
Simian Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nonhuman Primates ◽  
Virus Isolate ◽  
Functional Differences ◽  
Immunodeficiency Virus

ABSTRACTFollowing mucosal human immunodeficiency virus type 1 transmission, systemic infection is established by one or only a few viral variants. Modeling single-variant, mucosal transmission in nonhuman primates using limiting-dose inoculations with a diverse simian immunodeficiency virus isolate stock may increase variability between animals since individual variants within the stock may have substantial functional differences. To decrease variability between animals while retaining the ability to enumerate transmitted/founder variants by sequence analysis, we modified the SIVmac239 clone to generate 10 unique clones that differ by two or three synonymous mutations (molecular tags). Transfection- and infection-derived virus stocks containing all 10 variants showed limited phenotypic differences in 9 of the 10 clones. Twenty-nine rhesus macaques were challenged intrarectally or intravenously with either a single dose or repeated, limiting doses of either stock. The proportion of each variant within each inoculum and in plasma from infected animals was determined by using a novel real-time single-genome amplification assay. Each animal was infected with one to five variants, the number correlating with the dose. Longitudinal sequence analysis revealed that the molecular tags are highly stable with no reversion to the parental sequence detected in >2 years of follow-up. Overall, the viral stocks are functional and mucosally transmissible and the number of variants is conveniently discernible by sequence analysis of a small amplicon. This approach should be useful for tracking individual infection events in preclinical vaccine evaluations, long-term viral reservoir establishment/clearance research, and transmission/early-event studies.IMPORTANCEHuman immunodeficiency virus type 1 transmission is established by one or only a few viral variants. Modeling of limited variant transmission in nonhuman primates with a diverse simian immunodeficiency virus isolate stock may increase the variability between animals because of functional differences in the individual variants within the stock. To decrease such variability while retaining the ability to distinguish and enumerate transmitted/founder variants by sequence analysis, we generated a viral stock with 10 sequence-identifiable but otherwise genetically identical variants. This virus was characterizedin vitroandin vivoand shown to allow discrimination of distinct transmission events. This approach provides a novel nonhuman primate challenge system for the study of viral transmission, evaluation of vaccines and other prevention approaches, and characterization of viral reservoirs and strategies to target them.

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