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Previous reports from our lab had shown that sera obtained from SIV mac -infected animals neutralized SIV mac infectivity in CD4 + T cells but failed to protect monkey primary macrophages from infection with the virus. However, the antibodies could inhibit completion of the viral life cycle in the macrophages at the postentry stage(s). In this report we examined the mechanisms...
HIV-1 is dual-tropic for CD4 + T lymphocytes and macrophages, but virus production in the macrophages becomes manifest only during late-stage infection, after CD4 + T cell functions are lost, and when opportunistic pathogens begin to flourish. In this study, the SHIV/macaque model of HIV pathogenesis was used to assess the role of cytokines in regulating virus replication in the two...
Vpr is an HIV-1 auxiliary regulatory protein packaged in the virion. It has been shown to enhance the nuclear transport of the HIV-1 pre-integration complex, activate transcription of cellular and viral promoters, and arrest the cell cycle at the G2/M check-point. We previously identified a cellular protein of 180 kDa (RIP) that interacted with HIV-1 Vpr specifically. We now rename this cellular protein...
Therapeutic intervention with highly active antiretroviral therapy (HAART) can lead to the suppression of HIV viremia below the threshold of detection for several years. However, impact of HAART on reconstitution of virus-specific immune responses remains poorly understood. In this study, four macaques were infected with pathogenic SHIV KU . One week postinoculation two of the four animals...
Four rhesus macaques were sequentially immunized with live vaccines ΔvpuΔnefSHIV-4 (vaccine-I) and Δvpu SHIV PPC (vaccine-II). The vaccine viruses did not replicate productively in the peripheral blood mononuclear cells (PBMCs) of the vaccinated animals. All four animals developed binding antibodies against both the vaccine-I and -II envelope glycoproteins but neutralizing antibodies only...
SHIV KU2 replicates to high levels in inoculated macaques and reproducibly causes an acute depletion of CD4 + T cells. We evaluated the ability of treatment with the antiretroviral drug 9-R-(2-phosphonomethoxypropyl)adenine (PMPA; tenofovir), begun 7 days postinoculation, to inhibit viral replication and associated pathogenesis. Highly productive infection (plasma viral RNA > 10...
The simian human immunodeficiency virus (SHIV) macaque model of AIDS has provided a very useful system for evaluation of envelope-based candidate vaccines against HIV-1. Eight rhesus macaques were immunized with monomeric recombinant gp120 of HIV-1 LAI (rgp120) and used to evaluate whether this vaccine conferred protection against challenge with pathogenic SHIVs (SHIV KU-2 and SHIV...
HIV-1 causes cognitive and motor deficits and HIV encephalitis (HIVE) in a significant proportion of AIDS patients. Neurological impairment and HIVE are thought to result from release of cytokines and other harmful substances from infected, activated microglia. In this study, the quantitative relationship between microglial activation and neurological impairment was examined in the simian immunodeficiency...
Previously, we described the derivation of a pathogenic strain of simian–human immunodeficiency virus (SHIV KU-2 ) consisting of the tat, rev, vpu, and env genes of HIV-1 (strain HXB2) in a genetic background of SIV mac 239 that causes AIDS and productive infection of the CNS in rhesus macaques (Macca mulatta) (Raghavan et al., 1997, Brain Pathol. 7, 851–861). We report here on the...
A chimeric simian-human immunodeficiency virus (SHIV-4) containing thetat, rev, vpu,andenvgenes of HIV type 1 (HIV-1) in a genetic background of SIV mac 239 was used to develop an animal model in which a primate lentivirus expressing the HIV-1 envelope glycoprotein caused acquired immune deficiency syndrome (AIDS) in macaques. An SHIV-infected pig-tailed macaque that died from AIDS at 24 weeks...
Recently, we developed a highly pathogenic variant of simian–human immunodeficiency virus, SHIV-4 (containing thetat, rev, vpu,andenvof the HXB2 strain of HIV-1 in a genetic background of SIV mac 239), through a series of four bone marrow-bone marrow passages—first in rhesus monkeys and then in pig-tailed macaques [Joaget al. (1996) J. Virol.70, 3189–3197]. Inoculation of pig-tailed macaques...
Twenty macaques were used to evaluate the ability of nonpathogenic SIV mac or nonpathogenic chimeric SIV-HIV (SHIV) to induce protection in macaques against superinfection with a pathogenic variant of SHIV (SHIV KU-1 ) originally containing thetat, rev, vpu,andenvof HIV-1 (strain HXB2) in a genetic background of SIV mac 239. Specifically, three macaques inoculated with molecularly...
We have examined both the sequence changes in the LTR,gag, vif, vpr, vpx, tat, rev, vpu, env,andnefgenes and the cell tropism of a cell-free stock of chimeric simian–human immunodeficiency virus (SHIV) isolated from the cerebrospinal fluid of a pig-tailed macaque (PNb) that developed AIDS. This virus (SHIV KU-1 ) is highly pathogenic when inoculated into other macaques. DNA sequence analysis...
We examined plasma from macaques infected with three different phenotypes of SIV mac for their ability to neutralize the infectivity of homologous and heterologous virus in lymphocyte (CEMx174 cells or normal rhesus macaque peripheral blood lymphocytes) or normal rhesus macaque macrophage (Mφ) cultures. Similar to previous findings, we observed that some plasmas failed to neutralize or poorly...
Ovine and caprine lentiviruses are closely related genetically and antigenically although the diseases that these viruses cause in their respective host animals can vary greatly. In sheep, syndromes consist primarily of interstitial pneumonia with rare occurrences of arthritis and encephalitis, whereas in goats, the disease expresses mainly as arthritis in adult animals with rare cases of encephalitis...
Human immunodeficiency virus type 1 (HIV-1) replicates productively in vitro in CD4 + -T cells and/or macrophages. In the host, however, HIV-1 replication may be restricted by the quiescence of susceptible cells. Vpr is a 15-kDa late viral gene product, which is assembled in the virion and suspected to enhance HIV-1 replication in the infected host. We demonstrated previously that Vpr interacted...
SIVmac251 and its closely related derivatives SIVmac239 and SIVmac239/17E vary greatly in their susceptibility to neutralization with homologous and heterologous antisera. Whereas SIVmac251 induces homologous neutralizing antibodies, the antibodies induced by SIVmac239 rarely neutralize infectivity of this virus in lymphocyte cultures. In contrast, SIVmac239/17E is remarkably susceptible to neutralization...
Caprine arthritis–encephalitis virus (CAEV) is a natural lentivirus pathogen of goats. CAEV, like all members of the ovine/caprine lentivirus family, has anin vivotropism for cells of the monocyte/macrophage cell lineage and activation of viral gene expression is observed only following differentiation of monocytes to macrophages. In addition to cells of the monocyte/macrophage lineage, CAEV and the...
Antigenic variation is a characteristic feature of lentiviral infection. The SIV/macaque model of AIDS provides an ideal system in which to investigate the molecular basis of antigenic variation. The purpose of this study was to genetically map the nucleotide changes inenvthat alter the neutralization phenotype of SIV. Serum taken from an SIV mac 239-infected macaque (2D) at 30 weeks postinoculation...
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