scholarly journals Rev-Independent Simian Immunodeficiency Virus Strains Are Nonpathogenic in Neonatal Macaques

2002 ◽  
Vol 76 (1) ◽  
pp. 96-104 ◽  
Author(s):  
Agneta S. von Gegerfelt ◽  
Vladimir Liska ◽  
Pei-Lin Li ◽  
Harold M. McClure ◽  
Kyoji Horie ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rna Binding ◽  
Virus Propagation ◽  
Reading Frame ◽  
Type D ◽  
Novel Approach ◽  
Immunodeficiency Virus ◽  
Type D Retroviruses ◽  
Virus Strains

ABSTRACT The viral protein Rev is essential for the export of the subset of unspliced and partially spliced lentiviral mRNAs and the production of structural proteins. Rev and its RNA binding site RRE can be replaced in both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) by the constitutive RNA transport element CTE of the simian type D retroviruses. We used neonatal macaques as a sensitive animal model to evaluate the pathogenicity of a pair of SIV mutant strains generated from Rev-independent molecular clones of SIVmac239 which differ only in the presence of the nef open reading frame. After high primary viremia, all animals remained persistently infected at levels below the threshold of detection. All macaques infected as neonates developed normally, and none showed any signs of immune dysfunction or disease during follow-up ranging from 2.3 to 4 years. Therefore, the Rev-RRE regulatory mechanism plays a key role in the maintenance of high levels of virus propagation, which is independent of the presence of nef. These data demonstrate that Rev regulation plays an important role in the pathogenicity of SIV. Replacement of Rev-RRE by the CTE provides a novel approach to dramatically lower the virulence of a pathogenic lentivirus. These data further suggest that antiretroviral strategies leading to even a partial block of Rev function may modulate disease progression in HIV-infected individuals.

scholarly journals TRIM5α Resistance Escape Mutations in the Capsid Are Transferable between Simian Immunodeficiency Virus Strains

2016 ◽  
Vol 90 (24) ◽  
pp. 11087-11095 ◽  
Author(s):  
Fan Wu ◽  
Andrea Kirmaier ◽  
Ellen White ◽  
Ilnour Ourmanov ◽  
Sonya Whitted ◽  
...  
Keyword(s):  
Amino Acid ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Hiv Vaccine ◽  
Sooty Mangabey ◽  
Virus Acquisition ◽  
Vaccine Trials ◽  
Immunodeficiency Virus ◽  
Distinct Strain ◽  
Virus Strains

ABSTRACT TRIM5α polymorphism limits and complicates the use of simian immunodeficiency virus (SIV) for evaluation of human immunodeficiency virus (HIV) vaccine strategies in rhesus macaques. We previously reported that the TRIM5α-sensitive SIV from sooty mangabeys (SIVsm) clone SIVsmE543-3 acquired amino acid substitutions in the capsid that overcame TRIM5α restriction when it was passaged in rhesus macaques expressing restrictive TRIM5α alleles. Here we generated TRIM5α-resistant clones of the related SIVsmE660 strain without animal passage by introducing the same amino acid capsid substitutions. We evaluated one of the variants in rhesus macaques expressing permissive and restrictive TRIM5α alleles. The SIVsmE660 variant infected and replicated in macaques with restrictive TRIM5α genotypes as efficiently as in macaques with permissive TRIM5α genotypes. These results demonstrated that mutations in the SIV capsid can confer SIV resistance to TRIM5α restriction without animal passage, suggesting an applicable method to generate more diverse SIV strains for HIV vaccine studies. IMPORTANCE Many strains of SIV from sooty mangabey monkeys are susceptible to resistance by common rhesus macaque TRIM5α alleles and result in reduced virus acquisition and replication in macaques that express these restrictive alleles. We previously observed that spontaneous variations in the capsid gene were associated with improved replication in macaques, and the introduction of two amino acid changes in the capsid transfers this improved replication to the parent clone. In the present study, we introduced these mutations into a related but distinct strain of SIV that is commonly used for challenge studies for vaccine trials. These mutations also improved the replication of this strain in macaques with the restrictive TRIM5α genotype and thus will eliminate the confounding effects of TRIM5α in vaccine studies.

scholarly journals Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains

1997 ◽  
Vol 94 (8) ◽  
pp. 4005-4010 ◽  
Author(s):  
A. L. Edinger ◽  
A. Amedee ◽  
K. Miller ◽  
B. J. Doranz ◽  
M. Endres ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Immunodeficiency Virus ◽  
Virus Strains

scholarly journals Characterization of a Novel vpu-Harboring Simian Immunodeficiency Virus from a Dent's Mona Monkey (Cercopithecus mona denti)

2005 ◽  
Vol 79 (13) ◽  
pp. 8560-8571 ◽  
Author(s):  
Marie-Christine Dazza ◽  
Michel Ekwalanga ◽  
Monique Nende ◽  
Karhemere Bin Shamamba ◽  
Pitchou Bitshi ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Genomic Sequence ◽  
Democratic Republic Of Congo ◽  
Coding Region ◽  
Reading Frame ◽  
Immunodeficiency Virus ◽  
Primate Lentiviruses ◽  
Infected Cells ◽  
Mona Monkey ◽  
Hiv 1

ABSTRACT We report the identification of a new simian immunodeficiency virus (SIV), designated SIVden, in a naturally infected Dent's Mona monkey (Cercopithecus mona denti), which was kept as pet in Kinshasa, capital of the Democratic Republic of Congo. SIVden is genetically distinct from the previously characterized primate lentiviruses. Analysis of the full-length genomic sequence revealed the presence of a vpu open reading frame. This gene is also found in the virus lineage of human immunodeficiency virus type 1 (HIV-1) and chimpanzee immunodeficiency virus (SIVcpz) and was recently described in viruses isolated from Cercopithecus nictitans, Cercopithecus mona, and Cercopithecus cephus. The SIVden vpu coding region is shorter than the HIV-1/SIVcpz and the SIVgsn, SIVmon, and SIVmus counterparts. Unlike Pan troglodytes schweinfurthii viruses (SIVcpzPts) and Cercopithecus monkey viruses (SIVgsn, SIVmon, and SIVmus), the SIVden Vpu contains the characteristic DSGXES motif which was shown to be involved in Vpu-mediated CD4 and IκBα proteolysis in HIV-1 infected cells. Although it harbors a vpu gene, SIVden is phylogenetically closer to SIVdeb isolated from De Brazza's monkeys (Cercopithecus neglectus), which lacks a vpu gene, than to Cercopithecus monkey viruses, which harbor a vpu sequence.

scholarly journals CD4 Independence of Simian Immunodeficiency Virus Envs Is Associated with Macrophage Tropism, Neutralization Sensitivity, and Attenuated Pathogenicity

2002 ◽  
Vol 76 (6) ◽  
pp. 2595-2605 ◽  
Author(s):  
Bridget A. Puffer ◽  
Stefan Pöhlmann ◽  
Aimee L. Edinger ◽  
Dan Carlin ◽  
Melissa D. Sanchez ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Neutralization Sensitivity ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Macrophage Tropism ◽  
Glycosylation Sites ◽  
Immunodeficiency Virus ◽  
Virus Strains ◽  
Soluble Cd4

ABSTRACT To investigate the basis for envelope (Env) determinants influencing simian immunodeficiency virus (SIV) tropism, we studied a number of Envs that are closely related to that of SIVmac239, a pathogenic, T-tropic virus that is neutralization resistant. The Envs from macrophage-tropic (M-tropic) virus strains SIVmac316, 1A11, 17E-Fr, and 1100 facilitated infection of CCR5-positive, CD4-negative cells. In contrast, the SIVmac239 Env was strictly dependent upon the presence of CD4 for membrane fusion. We also found that the Envs from M-tropic virus strains, which are less pathogenic in vivo, were very sensitive to antibody-mediated neutralization. Antibodies to the V3-loop, as well as antibodies that block SIV gp120 binding to CCR5, efficiently neutralized CD4-independent, M-tropic Envs but not the 239 Env. However, triggering the 239 Env with soluble CD4, presumably resulting in exposure of the CCR5 binding site, made it as neutralization sensitive as the M-tropic Envs. In addition, mutations of N-linked glycosylation sites in the V1/V2 region, previously shown to enhance antigenicity and immunogenicity, made the 239 Env partially CD4 independent. These findings indicate that Env-based determinants of M tropism of these strains are generally associated with decreased dependence on CD4 for entry into cells. Furthermore, CD4 independence and M tropism are also associated with neutralization sensitivity and reduced pathogenicity, suggesting that the humoral immune response may exert strong selective pressure against CD4-independent M-tropic SIVmac strains. Finally, genetic modification of viral Envs to enhance CD4 independence may also result in improved humoral immune responses.

The Simian Immunodeficiency Virus Envelope Open Reading Frame Located After the Termination Codon Is Expressed In Vivo in Infected Animals

1988 ◽  
Vol 4 (4) ◽  
pp. 251-258 ◽  
Author(s):  
GENOVEFFA FRANCHINI ◽  
PHYLLIS J. KANKI ◽  
MARNIX L. BOSCH ◽  
KATHLEEN FARGNOLI ◽  
FLOSSIE WONG-STAAL
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Open Reading Frame ◽  
Termination Codon ◽  
Virus Envelope ◽  
Reading Frame ◽  
Immunodeficiency Virus

scholarly journals Derivation and Characterization of Pathogenic Transmitted/Founder Molecular Clones from Simian Immunodeficiency Virus SIVsmE660 and SIVmac251 following Mucosal Infection

2016 ◽  
Vol 90 (19) ◽  
pp. 8435-8453 ◽  
Author(s):  
Michael J. Lopker ◽  
Gregory Q. Del Prete ◽  
Jacob D. Estes ◽  
Hui Li ◽  
Carolyn Reid ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Nonhuman Primate ◽  
Tissue Damage ◽  
Lymphoid Tissue ◽  
Chronic Infection ◽  
Rhesus Macaques ◽  
Clinical Endpoints ◽  
Immunodeficiency Virus ◽  
Infectious Molecular Clones ◽  
Virus Strains

ABSTRACTCurrently available simian immunodeficiency virus (SIV) infectious molecular clones (IMCs) and isolates used in nonhuman primate (NHP) models of AIDS were originally derived from infected macaques during chronic infection or end stage disease and may not authentically recapitulate features of transmitted/founder (T/F) genomes that are of particular interest in transmission, pathogenesis, prevention, and treatment studies. We therefore generated and characterized T/F IMCs from genetically and biologically heterogeneous challenge stocks of SIVmac251 and SIVsmE660. Single-genome amplification (SGA) was used to identify full-length T/F genomes present in plasma during acute infection resulting from atraumatic rectal inoculation of Indian rhesus macaques with low doses of SIVmac251 or SIVsmE660. All 8 T/F clones yielded viruses that were infectious and replication competentin vitro, with replication kinetics similar to those of the widely used chronic-infection-derived IMCs SIVmac239 and SIVsmE543. Phenotypically, the new T/F virus strains exhibited a range of neutralization sensitivity profiles. Four T/F virus strains were inoculated into rhesus macaques, and each exhibited typical SIV replication kinetics. The SIVsm T/F viruses were sensitive to TRIM5α restriction. All T/F viruses were pathogenic in rhesus macaques, resulting in progressive CD4+T cell loss in gastrointestinal tissues, peripheral blood, and lymphatic tissues. The animals developed pathological immune activation; lymphoid tissue damage, including fibrosis; and clinically significant immunodeficiency leading to AIDS-defining clinical endpoints. These T/F clones represent a new molecular platform for the analysis of virus transmission and immunopathogenesis and for the generation of novel “bar-coded” challenge viruses and next-generation simian-human immunodeficiency viruses that may advance the HIV/AIDS vaccine agenda.IMPORTANCENonhuman primate research has relied on only a few infectious molecular clones for a myriad of diverse research projects, including pathogenesis, preclinical vaccine evaluations, transmission, and host-versus-pathogen interactions. With new data suggesting a selected phenotype of the virus that causes infection (i.e., the transmitted/founder virus), we sought to generate and characterize infectious molecular clones from two widely used simian immunodeficiency virus lineages (SIVmac251 and SIVsmE660). Although the exact requirements necessary to be a T/F virus are not yet fully understood, we generated cloned viruses with all the necessary characteristic of a successful T/F virus. The cloned viruses revealed typical acute and set point viral-load dynamics with pathological immune activation, lymphoid tissue damage progressing to significant immunodeficiency, and AIDS-defining clinical endpoints in some animals. These T/F clones represent a new molecular platform for studies requiring authentic T/F viruses.

scholarly journals Kinetic Rates of Antibody Binding Correlate with Neutralization Sensitivity of Variant Simian Immunodeficiency Virus Strains

2005 ◽  
Vol 79 (19) ◽  
pp. 12311-12320 ◽  
Author(s):  
Jonathan D. Steckbeck ◽  
Irina Orlov ◽  
Andrew Chow ◽  
Heather Grieser ◽  
Kenneth Miller ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Simian Immunodeficiency Virus ◽  
Neutralizing Antibody ◽  
Envelope Proteins ◽  
Antibody Binding ◽  
Immunodeficiency Virus ◽  
Kinetic Rates ◽  
Aids Vaccines ◽  
Virus Strains

ABSTRACT Increasing evidence suggests that an effective AIDS vaccine will need to elicit both broadly reactive humoral and cellular immune responses. Potent and cross-reactive neutralization of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) by polyclonal and monoclonal antibodies is well documented. However, the mechanisms of antibody-mediated neutralization have not been defined. The current study was designed to determine whether the specificity and quantitative properties of antibody binding to SIV envelope proteins correlate with neutralization. Using a panel of rhesus monoclonal antibodies previously characterized for their ability to bind and neutralize variant SIVs, we compared the kinetic rates and affinity of antibody binding to soluble envelope trimers by using surface plasmon resonance. We identified significant differences in the kinetic rates but not the affinity of monoclonal antibody binding to the neutralization-sensitive SIV/17E-CL and neutralization-resistant SIVmac239 envelope proteins that correlated with the neutralization sensitivities of the corresponding virus strains. These results suggest for the first time that neutralization resistance may be related to quantitative differences in the rates but not the affinity of the antibody-envelope interaction and may provide one mechanism for the inherent resistance of SIVmac239 to neutralization in vitro. Further, we provide evidence that factors in addition to antibody binding, such as epitope specificity, contribute to the mechanisms of neutralization of SIV/17E-CL in vitro. This study will impact the method by which HIV/SIV vaccines are evaluated and will influence the design of candidate AIDS vaccines capable of eliciting effective neutralizing antibody responses.

scholarly journals Improved Mg2+-Based Reverse Transcriptase Assay for Detection of Primate Retroviruses

1999 ◽  
Vol 37 (6) ◽  
pp. 1704-1708 ◽  
Author(s):  
Johnna F. Sears ◽  
Roy Repaske ◽  
Arifa S. Khan
Keyword(s):  
Reverse Transcriptase ◽  
Virus Detection ◽  
Distinct Type ◽  
Detection Sensitivity ◽  
Clinical Samples ◽  
Potential Health ◽  
Type D ◽  
Immunodeficiency Virus ◽  
Type D Retroviruses ◽  
Hiv 1

The reverse transcriptase (RT) assay is a simple, relatively inexpensive, widely used assay that can detect all retroviruses (known and novel retroviruses as well as infectious and defective retroviruses) on the basis of the divalent cation requirement of their RT enzyme, i.e., Mg2+ or Mn2+. Descriptions of various RT assays have been published; however, they cannot be directly applied to the analysis of biological products or clinical samples without further standardization to determine the lower limit of virus detection (sensitivity), assay variability (reproducibility), or ability to detect different retroviruses (specificity). We describe the detection of type E and type D primate retroviruses, which may be pathogenic for humans, by a new 32P-based, Mg2+-containing RT assay. The results show that the sensitivity of detection is <3.2 50% tissue culture infective doses (TCID50s) for human immunodeficiency virus type 1 (HIV-1) and <1 TCID50 for simian immunodeficiency virus isolated from a rhesus macaque (SIVmac). Analysis of recombinant HIV-1 RT enzyme indicated that 10−5 U, which is equivalent to 4.25 × 104 virions, could be detected. Additionally, genetically distinct type D retroviruses such as simian AIDS retrovirus and squirrel monkey retrovirus were also detected in the assay with similar sensitivities. Thus, the improved RT assay can be used to detect genetically divergent Mg2+-dependent retroviruses of human and simian origin that can infect human cells and that therefore pose a potential health risk to humans.

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