Dianne M. Rausch

Simian Immunodeficiency Virus Burden in Tissues and Cellular Compartments during Clinical Latency and AIDS

In the course of human immunodeficiency virus infection or of the related simian immunodeficiency virus (SIV), progression to AIDS is associated with high virus burdens in blood. How virus burden in the bloodstream is related to virus burden in tissue reservoirs was addressed in an animal model of rhesus macaques infected with SIV. In situ hybridization and quantitative image analysis were used to quantitate virus burden. Animals who developed AIDS had high levels of virus production and storage in lymphoid tissue reservoirs and evidence of productive infection of macrophages in the nervous system. With the quantitative approach described, it should be possible to design and assess the impact of treatment and shed light on the outstanding issues in pathogenesis.

Cytopathologic and Neurochemical Correlates of Progression to Motor/Cognitive Impairment in SIV-Infected Rhesus Monkeys

Neurochemical, pathologic, virologic, and histochemical correlates of simian immunodeficiency virus (SIV)- associated central nervous system (CNS) dysfunction were assessed serially or at necropsy in rhesus monkeys that exhibited motor and cognitive deficits after SIV infection. Some infected monkeys presented with signs of acquired immunodeficiency disease (AIDS) at the time of sacrifice. Seven of eight animals exhibited motor skill impairment which was associated with elevated quinolinic acid in cerebrospinal fluid (CSF). Examination of the brains revealed diffuse increases in glial fibrillary acidic protein immunoreacti vity in cerebral cortex in all animals, regardless of evidence of immunodeficiency disease. Reactive astrogliosis preceded or was coincident with the onset of neuropsychological impairments. Virus rescue from CSF of six of eight infected animals showed that one of three animals with AIDS and none of three animals without AIDS at necropsy had virus rescue-positive CSF. Multinucleated giant cells were seen in the brain of only one animal with end-stage AIDS and high systemic virus burden at death. Neither systemic nor CNS virus burden was associated with the onset of CNS dysfunction. SIV-associated motor/cognitive impairment is associated with subtle, widespread changes in CNS cytology and neurochemistry, rather than with large increases in brain virus burden or widespread virus-associated brain lesions.

THE SIV-INFECTED RHESUS MONKEY MODEL FOR HIV-ASSOCIATED DEMENTIA AND IMPLICATIONS FOR NEUROLOGICAL DISEASES

The neuropathogenesis of human immunodeficiency virus (HIV)‐associated dementia has remained elusive, despite identification of HIV as the causal agent. Although a number of contributing factors have been identified, the series of events that culminate in motor and cognitive impairments after HIV infection of the central nervous system (CNS) are still not known. Rhesus monkeys infected with simian immunodeficiency virus (SIV) manifest immunosuppression and CNS disease that is pathologically [L. R. Sharer et al. (1991) J. Med. Primatol. 20, 211–217] and behaviorally [E. A. Murray et al. (1992) Science 255, 1246–1249] similar to humans. The SIV model of HIV‐associated dementia (HAD) is widely recognized as a highly relevant model in which to investigate neuropathogenesis. With better understanding of neuropathogenesis comes the opportunity to interrupt progression and to design better treatments for HAD. This becomes increasingly important as patients live longer yet still harbor HIV‐infected cells in the CNS. The use of the SIV model has allowed the identification of neurochemical markers of neuropathogenesis important not only for HAD, but also for other inflammatory neurological diseases. J. Leukoc. Biol. 65: 466–474; 1999.

Brain virus burden and indoleamine-2,3-dioxygenase expression during lentiviral infection of rhesus monkey are concomitantly lowered by 6-chloro-2′,3′-dideoxyguanosine

Increased kynurenine pathway metabolism has been implicated in the aetiology of lentiviral encephalopathy. Indoleamine‐2,3‐dioxygenase (IDO) initiates the increased production of kynurenine pathway metabolites like quinolinic acid (QUIN). QUIN itself is elevated in AIDS‐diseased monkey and human brain parenchyma and cerebrospinal fluid at levels excitotoxic for neurons in vitro. This study investigates the cellular origin of IDO biosynthesis in the brain of rhesus monkeys infected with simian immunodeficiency virus (SIV) and explores the effects of CNS‐permeant antiretroviral treatment. IDO transcript and protein were absent from the brain of non‐infected and SIV‐infected asymptomatic monkeys. IDO biosynthesis was induced in the brain of monkeys exhibiting AIDS. Nodule and multinucleated giant cell‐forming macrophages were the main sources of IDO synthesis. Treatment with the lipophilic 6‐chloro‐2′,3′‐dideoxyguanosine suppressed IDO expression in the brain of AIDS‐diseased monkeys. The effectiveness of this treatment was confirmed by the reduction of virus burden and SIV‐induced perivascular infiltrates, mononuclear nodules and multinucleated giant cells. Our data demonstrate that brain IDO biosynthesis is induced in a subset of monocyte‐derived cells, depends on viral burden and is susceptible to antiretroviral treatment. Thus, IDO induction is associated with reversible overt inflammatory events localized to areas of active viral replication in the SIV‐infected brain.

Functional expression of dihydropyridine-insensitive calcium channels during PC12 cell differentiation by nerve growth factor (NGF), oncogenic ras, or src tyrosine kinase

Summary1.Recombinant retroviruses were used to introduce a temperature-sensitive v-src gene and oncogenic c-Ha-ras into PC12 cells, and stable cell lines expressing these genes were established.2.As previously reported, expression of v-src (Alemaet al., 1985) or c-Ha-ras (Nodaet al., 1985) in PC12 cells results in neurite outgrowth resembling that induced by NGF. We report here that v-src but not oncogenic c-Ha-ras induces a stable morphologic neuronal differentiation similar to treatment with NGF. Oncogenic c-Ha-ras-induced neurite outgrowth is not stable with long-term culture, rather the cells revert to an undifferentiated morphology with altered cell cycle kinetics.3.The stable neuronal phenotype induced by v-src and NGF is characterized by the functional expression of dihydropyridine-insensitive calcium currents.

Towards Multidisciplinary HIV-Cure Research: Integrating Social Science with Biomedical Research.

The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multidisciplinary approach, critical social, behavioral, ethical, and economic issues permeating the HIV-cure research agenda. As part of a search for an HIV cure, both the perspective of patients/participants and clinical researchers should be taken into account. In addition, continued efforts should be made to involve and educate the broader community.

Towards a More Coordinated Federal Response to Improving HIV Prevention and Sexual Health among Men Who Have Sex with Men

Nearly 30 years into the HIV/AIDS pandemic, the disease continues to exact a heavy toll in the United States. More than 1.1 million people are currently living with HIV in the US, and each year more than 56,000 new HIV infections occur, with nearly 18,000 people with AIDS dying annually [1]. Men who have sex with men (MSM) continue to be the group most severely impacted by HIV/AIDS, a disparity that has remained unchanged since the beginning of the epidemic, although the demographic characteristics of MSM who are impacted by HIV has changed dramatically [2]. Today, HIV affects MSM of all racial and ethnic backgrounds, with a particularly devastating impact on black and Hispanic/Latino MSM [3], and especially young MSM within these groups [4]. In this paper, we review current strategic efforts being considered or implemented by three United States government agencies (the Centers for Disease Control and Prevention, the National Institutes of Health, and the Health Resources and Services Administration) to accelerate reductions in HIV and improve sexual health among MSM. We also discuss the need for improved collaboration among federal agencies in order to achieve these goals.

Integrating behavioral and biomedical research in HIV interventions: Challenges and opportunities.

Abstract:Recent clinical trials have demonstrated overwhelming success of biomedical tools to prevent the spread of HIV infection. However, the complex and somewhat disparate results of some of these trials have highlighted the need for effective integration of biomedical and behavioral sciences in the design and implementation of any future intervention trial. Integrating behavioral and biomedical sciences will require appropriate behavioral theories that can be used in the context of biomedical clinical trials and multidisciplinary teams working together from the earliest stages of trial design through to completion. It is also clear that integration of behavioral science will be necessary to implement prevention at the population level and reverse the HIV epidemic.

CD4(81–92)-based peptide derivatives: Structural requirements for blockade of HIV infection, blockade of HIV-induced syncytium formation, and virostatic activity in vitro

CD4(81-92) peptide block human immunodeficiency virus (HIV) infection, virus-induced cell fusion, and antigen production by HIV-1-infected cells when derivatized on specific amino acid residues. An extensive series of structural variants of 1,4,5-tribenzyl-10-acetyl-CD4(81-92) were tested as anti-viral agents in an attempt to define the sequence and derivatization requirements for antiviral activity, and to maximize potency and stability for use as potential therapeutic agents. Alteration of the primary amino acid sequence of the stem compound 1,4,5-tribenzyl-CD4(81-92) diminished or abolished in parallel all three indices of anti-viral activity in a series of altered sequence compounds. Replacement of d- for l-amino acid residues at positions 1, 2, 3, 4, 5, or 6 but not position 10 decreased anti-viral potency, again with parallel effects on infection, synctium formation, and virostatic activity. Omission of the glutamine residue at position 9 did not affect anti-viral potency, while removal of the glutamic acids at position 11 and 12 resulted in virtually complete loss of biological activity. Changes in the derivatization pattern of the CD4(81-92) peptide backbone also affected anti-viral potency and efficacy. Optimal activity was obtained with benzyl residues at positions 1, 4, and 5, whereas the 1,4,7-tribenzyl-CD4(81-92) compound was without activity in all assays tested. Replacement of one of the benzyl groups with an acetamidomethyl moiety resulted in complete loss of biological activity. The previously reported (Nara et al., Proc Natl Acad Sci USA 86: 7139-7143, 1989) virostatic activity of 1,4,5-tribenzyl-10-acetyl-CD4(81-92) (peptide #18) is apparently due to acetylation, since the desacetyl stem compound shows much less virostatic activity while still possessing full anti-infective and anti-syncytial activity, and acetylation of the N-terminus rather than the lysine of 1,4,5-tribenzyl-CD4(81-92) yields a virostatic compound equipotent to peptide #18. Cyclization of the tribenzyl peptide to further conformationally restrict the molecule resulted in a compound with anti-infection, anti-syncytial, and virostatic activity at submicromolar concentrations.

Neuronal substrates for SIV encephalopathy

Prior to the onset of immunodeficiency disease, neurochemical and neuropathological events associated with motor and/or cognitive impairment can be identified in rhesus monkeys infected with simian immunodeficiency virus (SIV). These are astrocytosis, up-regulation of mRNA encoding the neuropeptide somatostatin (SRIF) and an increased expression of MHC Class II antigen. End-stage immunodeficiency disease has been associated with robust viral expression in the CNS frequently observed as multinucleated giant cell formation. SIV encephalitis has not been observed in animals whose only clinical signs of SIV disease were motor and/or cognitive impairment. These data suggest that neuronal dysfunction discernable as altered neuropeptide expression in cortical neurons precedes frank structural damage to the CNS in SIV encephalopathy. This model is consistent with the mechanism of neuropathogenesis in human HIV encephalopathy that can be partially inferred from neurochemical and neuropathological examination of autopsy material in HIV disease.