Medical records for animals used in research, teaching, and testing: public statement from the American College of Laboratory Animal Medicine.

Medical records are considered to be a key element of a program of adequate veterinary care for animals used in research, teaching, and testing. However, prior to the release of the public statement on medical records by the American College of Laboratory Animal Medicine (ACLAM), the guidance that was available on the form and content of medical records used for the research setting was not consistent and, in some cases, was considered to be too rigid. To address this concern, ACLAM convened an ad hoc Medical Records Committee and charged the Committee with the task of developing a medical record guideline that was based on both professional judgment and performance standards.

Progressive Anemia in a Pig-tail Macaque With AIDS.

The present report is a diagnostic exercise of a case of progressive anemia in a pigtail macaque with AIDS. In summary, the immune suppression of the macaque by the KUSHIV-1B virus prevented an effective immune response to simian parvovirus (SPV), resulting in persistent infection with progressive anemia. Simian parvovirus should be considered in the differential diagnosis of anemia in macaques typically used in research.

Development of virus-specific immune responses in SHIV(KU)-infected macaques treated with PMPA.

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).

Lasting effects of transient postinoculation tenofovir [9-R-(2-Phosphonomethoxypropyl)adenine] treatment on SHIV(KU2) infection of rhesus macaques.

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(6) copy eq/mL) was present and CD4 depletion had started when treatment was initiated.

Sensory evoked potentials in SIV-infected monkeys with rapidly and slowly progressing disease.

Human immunodeficiency virus (HIV-1) infects the central nervous system (CNS) early in the course of disease progression and leads to some form of neurological disease in 40-60% of cases. Both symptomatic and asymptomatic HIV-infected subjects also show abnormalities in evoked potentials. As part of an effort to further validate an animal model of the neurological disease associated with lentiviral infection, we recorded multimodal sensory evoked potentials (EPs) from nine rhesus macaques infected with passaged strains of SIVmac (R71/E17), prior to and at 1 month intervals following inoculation.

A molecular clone of simian-human immunodeficiency virus (DeltavpuSHIV(KU-1bMC33)) with a truncated, non-membrane-bound vpu results in rapid CD4(+) T cell loss and neuro-AIDS in pig-tailed macaques.

We report on the role of vpu in the pathogenesis of a molecularly cloned simian-human immunodeficiency virus (SHIV(KU-1bMC33)), in which the tat, rev, vpu, env, and nef genes derived from the uncloned SHIV(KU-1b) virus were inserted into the genetic background of parental nonpathogenic SHIV-4. A mutant was constructed (DeltavpuSHIV(KU-1bMC33)) in which 42 of 82 amino acids of Vpu were deleted. Phase partitioning studies revealed that the truncated Vpu was not an integral membrane protein, and pulse-chase culture studies revealed that cells inoculated with DeltavpuSHIV(KU-1bMC33) released viral p27 into the culture medium with slightly reduced kinetics compared with cultures inoculated with SHIV(KU-1bMC33).

Morphological correlates of neurological dysfunction in macaques infected with neurovirulent simian immunodeficiency virus.

The pattern of neurological disease caused by human immunodeficiency virus (HIV) infection of the central nervous system (CNS) was investigated using a macaque model of acquired immune defiency syndrome (AIDS). Seven of nine macaques inoculated with neurovirulent simian imunodeficiency virus (SIVmac ) developed AIDS within 3 months. Four of these had clinically obvious neurological disease and extensive conduction defects in the form of latency increases in evoked potential (EP) responses.

Motor skill impairment in SIV-infected rhesus macaques with rapidly and slowly progressing disease.

A number of studies have shown that simian immunodeficiency virus (SIV) infection in rhesus macaques parallels many aspects of HIV disease in humans. The purpose of this study was to further characterize the rhesus macaque infected with neurovirulent SIV as a model of neuroAIDS. Using a motor skill task, our objective was to detect SIV-related movement impairments in behaviorally trained macaques.

Motor evoked potentials in a rhesus macaque model of neuro-AIDS.

Previous work using bone marrow passaged SIVmac239 (simian immunodeficiency virus) has shown that macrophage tropic strains of this virus enter the rhesus macaque brain early following inoculation (Sharma et al, 1992; Desrosiers et al, 1991; Zhu et al, 1995; and Narayan et al, 1997). As part of an effort to more fully characterize the extent of neurologic impairment associated with SIV infection of the brain, we used transcranial electrical stimulation of motor cortex and the spinal cord to evoke EMG potentials in two forelimb (EDC and APB) and two hindlimb (LG and AH) muscles. The latencies, magnitudes and thresholds of motor evoked potentials (MEPs) recorded from nine monkeys infected with neurovirulent SIVmac R71/17E were compared to pre-inoculation records from the same monkeys.

Simple and choice reaction time performance in SIV-infected rhesus macaques.

It is well established that HIV infection can lead to motor/cognitive disorders in humans. A number of studies have shown that simian immunodeficiency virus (SIV) infection in rhesus macaques parallels many aspects of HIV disease in humans. The purpose of this study was to define further the SIV-infected rhesus macaque as a model of neuro-AIDS.

Characterization of a neutralization-escape variant of SHIVKU-1, a virus that causes acquired immune deficiency syndrome in pig-tailed macaques.

A chimeric simian-human immunodeficiency virus (SHIV-4) containing the tat, rev, vpu, and env genes of HIV type 1 (HIV-1) in a genetic background of SIVmac239 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 postinoculation experienced two waves of viremia: one extending from weeks 2-8 and the second extending from week 18 until death. Virus (SHIVKU-1) isolated during the first wave was neutralized by antibodies appearing at the end of the first viremic phase, but the virus (SHIVKU-1b) isolated during the second viremic phase was not neutralized by these antibodies.

Passively administered neutralizing serum that protected macaques against infection with parenterally inoculated pathogenic simian-human immunodeficiency virus failed to protect against mucosally inoculated virus.

Macaques inoculated orally, vaginally, or parenterally with SHIV(KU-1) develop severe systemic infection, acute loss of CD4+ T cells, and AIDS. We showed in a previous report that passive immunization with neutralizing serum protected macaques against infection with parenterally inoculated pathogenic SHIV given 24 hr later. In the study reported here we asked whether the identical passive immunization protocol would protect macaques against infection with pathogenic SHIV following oral inoculation of the virus.

Auditory brainstem responses in a Rhesus Macaque model of neuro-AIDS.

Nine rhesus macaques (Macaca mulatta) were inoculated with a combination of two passaged strains of SIVmac (R71 and 17E), both of which are known to be neurovirulent. Auditory brainstem responses (ABRs) were recorded at regular intervals from these animals both before and after inoculation. Increases in ABR peak and interpeak latency were observed corresponding to progression of SIV disease.

Oral immunization of macaques with attenuated vaccine virus induces protection against vaginally transmitted AIDS.

The chimeric simian-human immunodeficiency virus SHIVKU-1, bearing the envelope of human immunodeficiency virus type 1 (HIV-1), causes fulminant infection with subtotal loss of CD4(+) T cells followed by development of AIDS in intravaginally inoculated macaques and thus provides a highly relevant model of sexually transmitted disease caused by HIV-1 in human beings. Previous studies using this SHIV model had shown that the vpu and nef genes were important in pathogenesis of the infection, and so we deleted portions of these genes to create two vaccines, DeltavpuDeltanefSHIV-4 (vaccine 1) and DeltavpuSHIVPPc (vaccine 2). Six adult macaques were immunized subcutaneously with vaccine 1, and six were immunized orally with vaccine 2.

Chimeric SHIV that causes CD4+ T cell loss and AIDS in rhesus macaques.

By animal to animal passage in rhesus and pig-tailed macaques, we developed a rhesus model of HIV-1 disease in humans. Rhesus macaques infected with a cell-free stock of SHIVKU-2 developed CD4+ T cell loss, primary lentiviral encephalitis and pneumonia, and AIDS. Six of nine rhesus macaques died within eight months post-inoculation, while the remaining three are at five, five, and eight months post-inoculation, respectively.

Neutralizing antibodies administered before, but not after, virulent SHIV prevent infection in macaques.

By subcutaneous inoculation of SHIV(KU-2) in the hands of macaques, we developed a model of human immunodeficiency virus type-1 (HIV-1) occupational infection due to needle-stick injury and used the model to determine whether neutralizing serum to SHIV administered before or after virus inoculation could either prevent or abort infection, respectively. Six rhesus macaques were given 15 ml/kg pooled anti-SHIV plasma and challenged 24 hr later with approximately 300 animal infectious doses of SHIV(KU-2), subcutaneously. Three of the six macaques completely resisted infection with SHIV(KU-2).

Simian-human immunodeficiency virus (SHIV) containing the nef/long terminal repeat region of the highly virulent SIVsmmPBj14 causes PBj-like activation of cultured resting peripheral blood mononuclear cells, but the chimera showed No increase in virulence.

SIVsmmPBj14 is a highly pathogenic lentivirus which causes acute diarrhea, rash, massive lymphocyte proliferation predominantly in the gastrointestinal tract, and death within 7 to 14 days. In cell culture, the virus has mitogenic effects on resting macaque T lymphocytes. In contrast, SIVmac239 causes AIDS in rhesus macaques, generally within 2 years after inoculation.

Neuroinvasion by ovine lentivirus in infected sheep mediated by inflammatory cells associated with experimental allergic encephalomyelitis.

Maedi Visna Virus (MVV) is a prototypic lentivirus that causes infection only in cells of macrophage lineage, unlike the primate lentiviruses which infect both CD4+ T lymphocytes and macrophages. In primates, the earliest viral invasion is associated with the ability of the virus to infect and activate T cells which convey virus to the brain. Infected monocytes in blood rarely cause CNS infection in absence of activation of CD4+ T cells.

Infected macaques that controlled replication of SIVmac or nonpathogenic SHIV developed sterilizing resistance against pathogenic SHIV(KU-1).

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 the tat, rev, vpu, and env of HIV-1 (strain HXB2) in a genetic background of SIV(mac)239. Specifically, three macaques inoculated with molecularly cloned, macrophage-tropic SIV(mac)LG1 developed an early systemic infection but recovered with only traces of SIV(mac) DNA in visceral lymphoid tissues. These animals were then inoculated parenterally with pathogenic SHIV(KU-1).

Significance of macrophage tropism of SIV in the macaque model of HIV disease.

Microglia, alveolar macrophages, and Langerhans cells are representatives of cells of macrophage lineage that are susceptible to infection with HIV-1 and they play important roles in the pathogenesis of AIDS dementia, lymphoid interstitial pneumonia, and systemic viral invasion from mucosal surfaces, respectively. In contrast, elimination of CD4+ T cells with resultant development of immunosuppression and AIDS is thought to be reflective of the exclusive tropism of the virus for CD4+ T cells. Examination of these concepts in macaques infected with molecularly cloned strains of SIVmac suggested that all strains of the virus are both macrophage- and lymphocyte-tropic and that all aspects of pathogenesis including loss of CD4+ T cells are dependent on infection in both cell types.

Neuropathogenesis of chimeric simian/human immunodeficiency virus infection in pig-tailed and rhesus macaques.

We recently reported that a chimeric simian/human immunodeficiency virus (SHIVKU-1) developed in our laboratory caused progressive depletion of CD4+ T lymphocytes and AIDS within 6 months of inoculation into pig-tailed macaques (M. nemestrina). None of the pig-tailed macaques showed productive SHIV infection in the central nervous system (CNS).

Texture analysis of cerebral white matter in SIV-infected macaque monkeys.

Image texture analysis is used in a wide variety of applications in medical research. Neurovirulent simian immunodeficiency virus (SIV) infection in monkeys is considered a good model for HIV-1 infection in humans and causes neuropathological changes in white matter which can include diffuse myelin pallor, subtle white matter astrocytosis, perivascular macrophage infiltrates, and microglial nodules with multinucleated giant cells. The ability of image texture analysis to quantify these changes was evaluated.

Characterization of the pathogenic KU-SHIV model of acquired immunodeficiency syndrome in macaques.

By animal-to-animal passage in macaques we derived a pathogenic chimeric simian-human immunodeficiency virus (SHIV) that caused CD4+ T cell loss and AIDS in pigtail macaques and used it to inoculate 20 rhesus and pigtail macaques by the intravaginal and intravenous routes. On the basis of the outcome of infection and patterns of CD4+ T cell loss and viral load, disease was classified into four patterns: acute, subacute, chronic, and nonprogressive infection. During the study period, 15 of the 20 animals developed fatal disease, including AIDS, encephalitis, pneumonia, and severe anemia.

Animal model of mucosally transmitted human immunodeficiency virus type 1 disease: intravaginal and oral deposition of simian/human immunodeficiency virus in macaques results in systemic infection, elimination of CD4+ T cells, and AIDS.

Chimeric simian/human immunodeficiency virus (SHIV) consists of the env, vpu, tat, and rev genes of human immunodeficiency virus type 1 (HIV-1) on a background of simian immunodeficiency virus (SIV). We derived a SHIV that caused CD4+ cell loss and AIDS in pig-tailed macaques (S. V.

Early treatment with 9-(2-phosphonylmethoxyethyl)adenine reduces virus burdens for a prolonged period in SIV-infected rhesus macaques.

We evaluated the effects of a reverse transcriptase inhibitor, 9-(2-phosphonylmethoxyethyl)adenine (PMEA), on simian immunodeficiency virus (SIV) infection in rhesus macaques (Macaca mulatta). Four macaques were given PMEA (20 mg/kg) subcutaneously on days 1 and 2 and inoculated with virus on day 2. Drug treatment was continued for 30 consecutive days, after which the virus burdens and course of infection were monitored for a further 6 months.