Lentivirus-induced Pulmonary Lesions in Rhesus Monkeys (<i>Macaca mulatta</i>) Infected with Simian Immunodeficiency Virus

Gb, Baskin; Murphey‐Corb, Michael; Ln, Martin; Kf, Soike; Fs, Hu; Kuebler, Dot

doi:10.1177/030098589102800607

Cited by 38 publications

(35 citation statements)

References 27 publications

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“…The SIV/DeltaB670 stock consists of at least 22 different genotypes characterized by nucleotide sequencing of the hypervariable region V1 of the envelope gene (2) and includes both the macrophage-and lymphocyte-tropic strains (6,7,50). SIV/DeltaB670 induces the full range of SIV-associated disease, including immunosuppression, encephalitis (37,65), and pneumonia (8,36).…”

Section: Methodsmentioning

confidence: 99%

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

Babas

Muñoz

Mankowski

et al. 2003

J Virol

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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.

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Section: Methodsmentioning

confidence: 99%

“…These strains cause immunosuppression, leading to AIDS and opportunistic infections. In contrast, macrophage-tropic strains replicate in macrophages and primary lymphocytes and cause organ-specific disease syndromes, including encephalitis (17,37,65) and pneumonia (8,16,36), and can also lead to immunosuppression and AIDS.…”

mentioning

confidence: 99%

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

Babas

Muñoz

Mankowski

et al. 2003

J Virol

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“…Infection of rhesus macaques with pathogenic strains of simian immunodeficiency virus (SIV) serves as an excellent model system for HIV-1 replication and disease induction, including increased susceptibility to pulmonary infections and pathology [2,5]. The mechanisms leading to increased pulmonary complications, though, are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Increased expression of interferon-inducible genes in macaque lung tissues during simian immunodeficiency virus infection

Schaefer

Fuller

Basu

et al. 2006

Microbes and Infection

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Pulmonary infections and dysfunction are frequent outcomes during the development of immunodeficiency associated with human immunodeficiency virus type 1 (HIV-1) infection, and obtaining a better understanding of the immunologic changes that occur in lungs following HIV-1 infection will provide a foundation for the development of further intervention strategies. We sought here to identify changes in the pulmonary immune environment that arise during simian immunodeficiency virus (SIV) infection of rhesus macaques, which serves as an excellent model system for HIV-1 infection and disease. To examine the gene expression profiles of macaque lung tissues following infection with the pathogenic SIV/DeltaB670 isolate, we performed cDNA microarray hybridizations with lung total RNAs using two commercially available cDNA arrays and a custom-fabricated, immunologically focused macaque cDNA microarray. In situ hybridization and real-time RT-PCR were performed to provide additional analyses of gene expression. Among the genes exhibiting the highest level of induction in lung tissues were the IFN-gamma-inducible chemokines, CXCL10/IP-10 and CXCL9/Mig. In situ hybridization and real-time RT-PCR strongly supported these findings. Correlation analyses revealed that the levels of expression of IFN-gamma, CXCL9/Mig, and CXCL10/IP-10 mRNAs were all strongly positively correlated, and that CXCL10/IP-10 mRNA and Pneumocystis carinii rRNA were positively correlated. Taken together, these findings demonstrate that inflammatory chemokines are among the most differentially expressed mRNAs in macaque lung tissues during systemic SIV infection of rhesus macaques, and provide insight into the complicated events occurring in the lung tissues during HIV-1 infection in humans.

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“…The pathogenicity of this SIV isolate is similar to HIV. 7 The progression of SIV disease was monitored through clinical and biochemical parameters, and viral load in plasma and cerebrospinal fluid (CSF).…”

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confidence: 99%

Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus

Molina

Winsauer

Zhang

et al. 2011

AIDS Research and Human Retroviruses

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D9 -Tetrahydrocannabinol (D 9 -THC), the primary psychoactive component in marijuana, is FDA approved to ameliorate AIDS-associated wasting. Because cannabinoid receptors are expressed on cells of the immune system, chronic D 9 -THC use may impact HIV disease progression. We examined the impact of chronic D 9-THC administration (0.32 mg/kg im, 2Âdaily), starting 28 days prior to inoculation with simian immunodeficiency virus (SIV mac251 ; 100 TCID 50 /ml, iv), on immune and metabolic indicators of disease during the initial 6 month asymptomatic phase of infection in rhesus macaques. SIV mac251 inoculation resulted in measurable viral load, decreased lymphocyte CD4 þ /CD8 þ ratio, and increased CD8 þ proliferation. D 9 -THC treatment of SIV-infected animals produced minor to no effects in these parameters. However, chronic D 9 -THC administration decreased early mortality from SIV infection ( p ¼ 0.039), and this was associated with attenuation of plasma and CSF viral load and retention of body mass ( p ¼ NS). In vitro, D 9 -THC (10 mm) decreased SIV (10 TCID 50 ) viral replication in MT4-R5 cells. These results indicate that chronic D 9 -THC does not increase viral load or aggravate morbidity and may actually ameliorate SIV disease progression. We speculate that reduced levels of SIV, retention of body mass, and attenuation of inflammation are likely mechanisms for D 9 -THC-mediated modulation of disease progression that warrant further study.T he cannabinoids including cannabidiol, cannabinol, and D 9 -tetrahydrocannabinol (D 9 -THC) exert their effects by binding to two major subtypes of cannabinoid receptor, CB1 and CB2.1 The CB1 receptor is preferentially expressed in the brain where it mediates neurobehavioral effects. The CB2 receptor is expressed primarily in peripheral tissues, particularly in immune cells where they have been shown to affect cytokine production, lymphocyte phenotype, function and survival, cell-mediated immunity, and balance of Th1/ Th2 cells.2 With the advent of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection has become a chronic disease frequently coexisting with chronic use of drugs of abuse, including marijuana. Using a well-established nonhuman primate model of HIV disease, we examined the impact of chronic intramuscular D 9 -THC (provided by the National Institute on Drug Abuse, Research Technical Branch, Rockville, MD) administration on the early phase of simian immunodeficiency virus (SIV) infection in age-matched (4-6 years old) and body weight-matched healthy male Indian-derived rhesus macaques. Chronic administration of D 9 -THC [or 0.05 ml/kg vehicle (VEH)] was initiated prior to SIV with 0.18 mg/kg, a dose that eliminated responding in a complex operant behavioral task in almost all of the subjects. The dose was subsequently increased for each subject to 0.32 mg/kg, over

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Lentivirus-induced Pulmonary Lesions in Rhesus Monkeys (Macaca mulatta) Infected with Simian Immunodeficiency Virus

Cited by 38 publications

References 27 publications

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

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

Increased expression of interferon-inducible genes in macaque lung tissues during simian immunodeficiency virus infection

Cannabinoid Administration Attenuates the Progression of Simian Immunodeficiency Virus

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