Murine retroviral spongiform polioencephalopathy.
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Animals↗
Biomedical subjects
C A Wiley
Publications and source records attributed to C A Wiley.
The relationship of quantitative brain magnetic resonance imaging measures to neuropathologic indexes of human immunodeficiency virus infection.
OBJECTIVE: To directly examine the relationship between magnetic resonance imaging (MRI) abnormalities and neuropathologic changes in the brains of patients with the acquired immunodeficiency syndrome. DESIGN: A total of 17 brains from patients with acquired immunodeficiency syndrome for which postmortem MRI scans were available were used in this study. Volumes of cortical gray matter, deep gray matter, and abnormal white matter were estimated from the MRIs of the left hemispheres of the formalin-fixed brains from patients with acquired immunodeficiency syndrome using quantitative morphometric techniques. Quantitative estimates of human immunodeficiency virus, gliosis, and neocortical synaptic and dendritic density were obtained from the corresponding right hemispheres. Quantification of human immunodeficiency virus and gliosis was performed on all 17 specimens, while quantification of synaptic and dendritic density was performed on 10 of the 17 specimens. SETTING: All specimens were obtained from patients with the acquired immunodeficiency syndrome who underwent autopsy between 1990 and 1992 at the University of California-San Diego Medical Center and the San Diego (Calif) Department of Veterans Affairs Hospital. RESULTS: No association was found between MRI volumes and gliosis, a nonspecific marker of central nervous system damage. Significant and regionally specific relationships were obtained, however, between the severity of central nervous system human immunodeficiency virus infection and the MRI volume estimates of gray matter and abnormal white matter. In addition, a significant association was observed between cortical gray matter volumes and cortical synaptic density. CONCLUSION: These findings indicate that the quantitative morphometric analysis of MRIs in patients may provide sensitive in vivo markers of neuropathologic changes associated with human immunodeficiency virus infection of the brain.
Brain Diseases↗
Human immunodeficiency virus encephalitis is the pathological correlate of dementia in acquired immunodeficiency syndrome.
While dementia has been observed in approximately one-fourth of terminally ill patients with acquired immunodeficiency syndrome, it has been difficult to attribute this clinical disorder to a single neuropathological substrate. We used a simple and readily reproducible scale for estimating the burden of human immunodeficiency virus (HIV) in the central nervous system (i.e., severity of HIV encephalitis) and compared this to autopsy neurological summaries of dementia. Like others, we found that multinucleated giant cells were present in only half of the dementia patients. However, all of the dementia patients had severe HIV encephalitis as assessed by measurements of intra-central nervous system viral burden. Additional patients had severe HIV encephalitis without clinical histories of dementia. We interpret these latter findings as evidence that HIV encephalitis exists for a period of time before the clinical symptomatology develops. Comparison of presence or absence of concurrent cytomegalovirus encephalitis showed no association with dementia.
AIDS Dementia Complex↗
Skeletal muscle involvement in tropical spastic paraparesis/HTLV-1-associated myelopathy.
The frequency of muscle involvement in TSP/HAM is not known, nor is the precise role that HTLV-1 and the diverse cytokines play in the genesis of HTLV-1-associated diseases. In order to better define the frequency and characteristics of the skeletal muscle involvement in TSP/HAM, we studied 11 affected patients. EMG was performed in 9 patients and muscle biopsy was performed in all 11. Muscle tissue was analyzed using: reverse transcriptase PCR for interleukin-1 in 8; PCR for HTLV-1 proviral DNA in 5; and electron microscopy for viral particles in 3. We found pathologic alterations in all 11 patients. Four patients (36%) had a neurogenic process, while a primary muscle involvement was observed in the rest (64%). Four patients (36%) had polymyositis, and 3 (27%) had a noninflammatory myopathy. Muscle weakness in the upper limbs was significantly associated with inflammation in the muscle biopsy. EMG was abnormal in only 2 of 9 patients. Reverse transcriptase PCR did not demonstrate message for interleukin-1 in any sample examined. PCR did identify HTLV-1 proviral DNA in the muscle of 3 patients. Retroviral-like particles were found, by EM, in only one biopsy. HTLV-1 may play an important role in the pathogenesis of the frequent myopathies associated with HAM/TSP.
Adult↗
Viral load and its relationship to quinolinic acid, TNF alpha, and IL-6 levels in the CNS of retroviral infected mice.
Mouse models of infection of the central nervous system (CNS) have been used to study retroviral-induced neurologic disease. Ecotropic-neurotropic murine leukemia virus (MuLV) infection of susceptible neonatal mice causes a neurologic disease characterized by progressive hindlimb paralysis. The lesions consist of chronic noninflammatory spongiform change predominantly involving brainstem and spinal cord. Two molecularly cloned strains of MuLV, ts-1, a temperature-sensitive mutant of Moloney MuLV, and pNE-8, derived from a feral mouse isolate Cas-Br-E, were used in this study. Infected mice were sacrificed at regular intervals postinoculation throughout the time-course of disease. The neuropathology was evaluated using standard histological and immunohistopathological techniques. Tissue concentrations of viral proteins and potentially cytotoxic factors were compared with the histopathology in select regions of the CNS. Areas of extensive vacuolation with neuronal and oligodendroglial infection were observed in spinal cord, brainstem, and cerebellum. High titers of infectious virus were observed within CNS lesions, whereas low titers were observed in morphologically uninvolved areas. Western blot analysis revealed abundant production of viral envelope proteins, which correlated well with infectious virus titers. Serum quinolinic acid (QUIN) concentrations in both groups of noninfected and infected mice were similar. However, CNS tissue concentrations of QUIN, TNF alpha, and IL-6 in ts-1 infected mice were significantly higher than in pNE-8 infected or noninfected mice. The difference in concentration of these factors may be the result of greater activation of macrophages/microglia in ts-1 infected mice. During murine retroviral encephalitis, CNS damage may be mediated by direct infection of CNS cells and may be enhanced by indirect effects of neurotoxic factors possibly secreted by infected/activated macrophages.
Animals↗
HIV-1 infection despite immediate combination antiviral therapy after infusion of contaminated white cells.
We present a sixth human case in which primary human immunodeficiency virus (HIV-1) infection occurred, despite antiretroviral prophylaxis, after accidental inoculation of infected blood. In the prior five instances, variables such as large virus dose, late administration of antivirals, viral resistance to zidovudine, and pre-existent immunosuppression, may have played a role in the treatment failure. In this case, high-dosage oral zidovudine was given within minutes of the accident and replaced 2 1/2 days later with interferon alpha and dideoxyinosine (ddl). Despite aggressive treatment, HIV-1 infection was demonstrated in blood, spleen, and brain tissue at autopsy 16 days later. Of the tissues studied, detection of HIV-1 was most prominent in the spleen. Double-label immunocytochemistry confirmed the morphologic impression that while some of the infected spleen cells were CD3-positive T cells, the majority were macrophages. Thus, current single or dual (zidovudine, ddl-interferon) therapies for accidental HIV-1 inoculation may not be effective in preventing early infection. Further trials in animals appear warranted to evaluate protection by other strategies, such as passive immunity or combinations of agents that penetrate the brain and attack HIV-1 viral replication at differing sites.
Aged↗
An alternative method for obtaining high-viability cell suspensions from neonatal mouse brain.
Cultured brain cells have contributed greatly to our understanding of a variety of neurobiological processes. The ability to culture brain tissue is important for studying cellular processes underlying unique neural properties. Traditional culturing techniques commonly involve triturating tissue through glass Pastuer pipets, which are inappropriate for use with potentially biohazardous materials. We therefore developed an alternative method for dissociating brain tissue. The protocol combines enzymatic digestion and mechanical dissociation with additives to the dissection medium that protect the cells against other sources of injury, including glutamate neurotoxicity, oxidative damage, and excessively alkaline pH. We find this method works well with post-natal mouse brain, consistently giving cell viabilities in the range of 92-99% and an average yield of 3.1 x 10(6) cells per mouse.
Animals↗
In vivo model of HIV infection of the human brain.
Approximately one quarter of AIDS patients develop neurologic symptoms attributable to HIV infection within the brain. Previous studies suggest that HIV associated neurologic damage may be mediated by immune factors secreted by activated/infected CNS macrophages. We developed an in vivo system in which human embryonic brain tissue can be infected with HIV and the associated pathology monitored. In this model, dissociated human brain tissue is grown in vitro as single cell suspension in serum free medium. Fetal neural cells aggregate and form "brain microspheres" that are then transplanted into SCID mice. Pilot studies suggest that brain microspheres injected in the fat pad of SCID mice differentiate and survive for several months in vivo. Study of these grafts shows presence of functional neural cells and vascular organization suggesting a blood-brain barrier. When brain microspheres are co-cultured in vitro with HIV-infected human macrophages, virus is detected inside the human neural tissue grafts in SCID mice and measurements of viral and immune factors can be performed. To promote physiologic neuronal differentiation within the human grafts, implantation in the brain of SCID mice is being tested at the present time.
AIDS Dementia Complex↗
Measurement of CNS HIV burden and its association with neurologic damage.
AIDS dementia complex affects between 20 and 30% of terminally ill AIDS patients. The histopathologic substrate of this clinical syndrome is chronic HIV infection of the nervous system termed HIV encephalitis. We hypothesize that the abundance and length of time that HIV is present in the CNS determines the severity of neurologic damage. We compared three different methods of assessing HIV burden in the CNS. While the assays vary in sensitivity, each provides a quantitative estimate of viral burden that can be compared between laboratories. Assays of provirus were readily divided into two groups, while protein assays showed a wider range. HIV-mediated neurotoxicity might be expected to more closely depend upon productive infection.
AIDS Dementia Complex↗
CMV-specific immune responses and HLA phenotypes of AIDS patients who develop CMV retinitis. HNRC Group. HIV Neurobehavioral Research Center.
HLA phenotype and immune responses to CMV were studied to determine whether the subset of AIDS patients who developed CMV retinitis were immunogenetically or immunologically predisposed. CMV retinitis develops in approximately 28-35% of AIDS patients and CMV encephalitis develops in 40% of those with retinitis, often leading to death. T-cell proliferation responses to CMV and HIV were assayed prospectively in individuals enrolled in a longitudinal study at the HIV Neurobehavioral Research Center (HNRC) in San Diego. Seventy-three participants, at various stages of disease, have been HLA typed and followed, clinically and immunologically, for up to 5 years. Six HIV infected individuals who eventually developed CMV retinitis, and were assayed prospectively, had a history of low T-cell proliferation to CMV antigens before they were profoundly immunosuppressed. All 10 individuals with CMV retinitis had at least one of three HLA alleles (or combinations): A2B44 (p = 0.02), B51(p = 0.02), or DR7 (p = 0.01) (collective p value = 0.007). Three of the 10 had two or more of these alleles. Of AIDS patients with CD4 counts below 100 and actively at risk for retinitis, 7/15 with A2B44,51, or DR7 have developed retinitis compared to 0/13 without these HLA alleles (relative risk = 23.8). All 4 patients with these alleles who have died, had retinitis. These results suggest that HIV infected individuals with HLA phenotypes A2B44, B51, and DR7 have low T-cell immune responses to CMV and are predisposed to CMV retinitis and encephalitis as immunodeficiency progresses.
AIDS-Related Opportunistic Infections↗
Detection of cytomegalovirus in cerebrospinal fluid autopsy specimens from AIDS patients.
Cytomegalovirus (CMV) is a common opportunistic pathogen infecting AIDS patients. Polymerase chain reaction (PCR) and antigen capture ELISA were used to detect CMV in 40 cerebrospinal fluid autopsy specimens from patients with AIDS. CMV DNA was detected by PCR in 70% of samples. Of the 21 samples from patients with systemic CMV infection, 57% had CMV encephalitis, while 81% had virus in cerebrospinal fluid detectable by PCR. Of the 24 samples from patients with no histologic evidence of CMV encephalitis, 58% had CMV DNA in cerebrospinal fluid detected by PCR. These results suggest that PCR of cerebrospinal fluid sensitively detects systemic CMV infection but is not specific for brain infection in autopsy specimens of AIDS patients.
AIDS-Related Opportunistic Infections↗
Long-acting therapy of viral retinitis with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine.
(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), a high-potency antiherpes and anticytomegalovirus (CMV) drug was evaluated in the treatment of experimental retinitis caused by preretinal herpes simplex virus (HSV-1) injection in rabbits. HPMPC (100 micrograms/0.1 mL) was intravitreally injected 10, 15, 21, 30, or 46 days before, concurrently, or 3, 5, or 7 days after viral inoculation. Ganciclovir (200 micrograms/0.1 mL) was intravitreally injected 3, 7, or 10 days before HSV-1 inoculation, concurrent with viral inoculation, or 3, 5, or 7 days after viral inoculation. Eyes pretreated with HPMPC were protected from retinitis for 15-21 days. Ganciclovir did not protect completely even if administered 3 days before inoculation. Early treatment of established retinitis with HPMPC markedly delayed the progression of the infection. However, with ganciclovir there was delayed progression only in rabbits treated 3 days after viral inoculation. HPMPC had a remarkably potent and prolonged (< or = 1 month) antiviral effect in this retinitis model and may prove more useful than ganciclovir in local treatment of CMV retinitis.
Animals↗
Brain viral burden in HIV infection.
We quantitated the brain viral burden in autopsy material from AIDS patients with and without HIV encephalitis. Central nervous system (CNS) samples from 45 AIDS autopsies with less than 48 hours postmortem autolysis and without significant non-viral opportunistic infections were analyzed using immunocytochemistry (ICC), antigen capture assay (ACA) and polymerase chain reaction (PCR). Approximately three-quarters of the cases contained HIV DNA by PCR. The majority of these had abundant gp41 detected by ICC, but approximately one-third had no HIV p24 detected by ACA. With all assays, HIV proteins and DNA were most abundant in deep gray matter. Approximately one-quarter of the cases contained HIV p24 by ACA in both CNS tissue and cerebrospinal fluid. In more than half of the cases cytomegalovirus was detectable in the brain by PCR, however, only in the basal ganglia of one case was human herpes virus-6 detectable by PCR. In conclusion, HIV infection of the CNS was observed in the majority of AIDS autopsies, however, the quantity of virus was variable between cases and within different neuroanatomical regions. Differences between the quantitation methods could be either technical or biological, however, any of them could be used to compare assessment of HIV burden by different laboratories.
Base Sequence↗
Neocortical pathology in chronic murine retroviral encephalitis.
Retroviral infection of the central nervous system (CNS) causes chronic functional and morphological damage in a wide variety of mammals. Neuropathological studies have focused on subcortical pathology, however, the neocortex is also affected. Because studies of human CNS pathology have been limited to the use of material from terminal stages of disease, we used two neuropathogenic murine leukemia virus (MuLV) models to study the development of neocortical damage. MuLV infection caused spongiform change in the spinal cord, brainstem and cerebellum but not in the cerebrum. However, over the course of disease, we observed a reduction of neocortical thickness, accompanied by diminished neuronal and dendritic spine density. Electron microscopic studies showed minimal to no ultrastructural alterations of dendritic spines. Since there was no evidence of extensive direct viral infection of the neocortical neurons or glia at the ultrastructural level, we hypothesize that neocortical damage may be an indirect effect of subcortical retroviral infection.
Animals↗
Retinal toxicity of the antimetabolite 5-fluorouridine 5'-monophosphate administered intravitreally using multivesicular liposomes.
BACKGROUND: Liposome-encapsulated 5-fluorouridine-5'-monophosphate (FUMP) has been shown to inhibit proliferative vitreoretinopathy in a rabbit model. Liposome encapsulation extends the intravitreal half-life of this antiproliferative drug by a factor of 28 times. METHODS: The current study investigated the retinal toxicity of intravitreal injections of 10, 50, and 100 micrograms FUMP as free drug or within liposomes in rabbits. Evaluation included ophthalmoscopic examination, electroretinography, and histologic analysis by light and electron microscopy. RESULTS: No electroretinographic evidence for toxicity of FUMP was found. Light and electron microscopy showed only mild transient vacuolization in the outer segment layer, without inflammation. Empty liposomes incurred no toxic effects on the retina. CONCLUSIONS: Our results suggest that liposome-encapsulated FUMP may be non-toxic to the retina at doses that inhibit proliferative retinopathy.
Animals↗
Cellular neuropathology in HIV encephalitis.
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AIDS Dementia Complex↗
Pathology of neurologic disease in AIDS.
The brain is a frequent target of damage in AIDS. In addition to abundant opportunistic infections, HIV itself can cause CNS destruction. Numerous important clinical questions await a basic understanding of the pathogenesis of HIV-associated nervous system destruction. Why does HIV, like many other retroviruses, attack the CNS? How does it get into the CNS, and once it is there, what controls viral replication? What is the mechanism(s) by which HIV mediates CNS damage, and how soon after infection is this process initiated? In the next few years, there will be a rapid convergence of multiple approaches to understanding the pathogenesis of HIV damage in the brain. What clinicians learn will not only aid those patients afflicted with AIDS, but very likely will provide insights into numerous other mysterious and potentially retrovirus-mediated brain diseases.
AIDS-Related Opportunistic Infections↗
Miliary toxoplasmic retinitis in acquired immunodeficiency syndrome.
A unique pattern of bilateral miliary retinitis due to ocular toxoplasmosis developed in a patient in the late stages of acquired immunodeficiency syndrome. Results of serologic tests for toxoplasmosis remained negative throughout the clinical course of his ocular disease. The retinitis was unresponsive to a brief course of anti-toxoplasmosis therapy. At autopsy, the histopathologic material was consistent with toxoplasmic retinitis and the DNA polymerase chain reaction was positive for toxoplasmosis. Recognition of this pattern of retinitis is important in the appropriate treatment of immunosuppressed patients with retinitis.
AIDS-Related Opportunistic Infections↗