The Cellular Basis of Central Nervous System HIV-1 Infection and the AIDS Dementia Complex

Richard W Price, John J Sidtis

• Editorial: Routledge
• Año: 2014
• ISBN:
  9781135907976
• Edición: 1
• Categoría: Medicine
• Categoría: Diseases & Allergies

In this exciting symposium, the editor brings to print important new information on AIDS and how HIV affects the brain. Each chapter focuses on one or more of the cell types that reside in or traffic through the central nervous system (CNS). Each of these cells is important to considerations of the pathogenesis of the CNS. Neurologists, AIDS physicians, and other professionals caring for AIDS patients will find that this "cell-based" view provides a unique perspective and that it will guide and stimulate future investigation of this clinically important and pathogenetically intriguing disorder. The editor also introduces some general considerations for therapeutic intervention of AIDS dementia complex (ADC).The contributors to The Cellular Basis of Central Nervous System HIV-1 Infection and the AIDS Dementia Complex deal with the cells and mechanisms involved in HIV-1 brain infection and the resultant ADC. Each author was asked to review the involvement of their assigned cells in CNS HIV-1 infection and how these cells might be involved in the pathology and process of brain injury associated with ADC. Readers will be enlightened on the functional roles of various cells and how these cells and mechanisms might fit into the broader picture of ADC pathogenesis.

The Cellular Basis of Central Nervous System HIV-1 Infection and the AIDS Dementia Complex: Introduction

Richard W. Price

KEYWORDS. AIDS, AIDS, dementia complex, brain, HIV, pathogenesis, dementia, neurodegeneration

This volume is devoted to a symposium on “The Cellular Basis of Central Nervous System HIV-1 Infection and the AIDS Dementia Complex.” Seven invited papers follow this introduction, each focussing on one or more of the cell types that either are resident in or traffic through the central nervous system (CNS). Each of these cells is important to considerations of the pathogenesis of CNS HIV-1 infection and its major clinical manifestation, the AIDS dementia complex (ADC). It is hoped that this ‘cell-based’ view will provide a unique perspective and that it will guide and stimulate future investigation of this clinically important and pathogenet- ically intriguing disorder.

ADC (Navia, Jordan, and Price 1986), now also referred to as HIV-1-associated cognitive!motor complex and in its more severe form involving cognitive impairment as HIV-1-associated dementia (Working Group of the American Academy of Neurology AIDS Task Force 1991; World Health Organization 1990), was identified early in the AIDS epidemic, albeit using a variety of other terms (Britton and Miller 1984; Gopinathan et al. 1983; Snider et al. 1983). Its clinical character has subsequently been more clearly defined as a subcortical dementia affecting the ‘domains’ of cognition, motor function and behavior (Benson 1987; Navia, Jordan, and Price 1986; Sidtis 1994). While there remains some controversy regarding both its nomenclature and formal diagnosis (Price 1995), ADC is nonetheless acknowledged to be both a common and clinically important complication of late HIV-1 infection. While certain aspects of its epidemiology and natural history remain incompletely characterized, more rigorous longitudinal studies have begun to define these more clearly (Bacellar et al. 1994; McArthur et al 1993; Neaton et al. 1994).

While it was initially speculated that ADC is caused by cytomegalovirus or another opportunistic infection (Snider et al. 1983), not long after the discovery of the retroviral etiology of AIDS, high copy numbers of HIV-1 proviral DNA were detected in brains of patients with ADC and its pediatric equivalent (Shaw et al. 1985). This observation, which was subsequently amplified by immuno- histochemical and in situ hybridization studies demonstrating infection of brain cells (Budka et al. 1991; Koenig et al. 1986; Kure et al. 1990a; Michaels, Price, and Rosenblum 1988; Pumarole-Sune et al. 1987; Stoler et al. 1986; Vazeux et al. 1987; Wiley et al. 1986), along with the concomitant recognition that HIV-1 should be classified among the lentiviruses that cause brain infection and neurological disease in animals (Gonda et al. 1985), appeared to solve the problem of ADC pathogenesis, at least at first blush. It could be viewed simply as a new type of ‘slow’ virus encephalitis. However, as is so often the case, with deeper inquiry and the accumulation of additional information, the pathogenesis no longer appears so simple. Particularly troublesome are the mechanisms linking the etiological virus with neurological dysfunction and a seemingly heterogeneous neuropathology (Price et al. 1988). Concepts of pathogenesis now focus on a more complex web of virus-cell and cell-cell interactions rather than a simple effect of the virus on infected brain target cells (Epstein and Gendelman 1993; Price 1994).

While HIV-1, itself, rather than another opportunistic pathogen, remains the favored etiologic agent causing ADC, a number of observations underlie the concept that brain injury is not caused simply by the direct effects of viral gene expression on infected neurons from within, as occurs, for example, in poliomyelitis or rabies, but rather involves indirect pathways of brain injury initiated by infection of non-neuronal cells and leading to subsequent pathogenic cell-cell interactions. Table 1 summarizes some of the observations that support the HIV-1 etiology of ADC along with others that argue in favor of these indirect mechanisms. These issues have been reviewed in more detail elsewhere (Price 1994; Price 1995; Price in press).

The contributions to this symposium deal with the cells and mechanisms involved in HIV-1 brain infection and resultant ADC. The point of departure and theme of each review relates to a cell type or, in the case of the choroid plexus, an organelle within the CNS. Each of the authors was asked to review the involvement of their assigned cells in CNS HIV-1 infection and how these cells might be involved in the pathology and process of brain injury associated with ADC. In this introduction I will outline a general model of HIV-1 infection and ADC that identifies ‘functional roles’ for different cells and in this context consider how the various cells covered in the contributing reviews might ‘fit’ into a broader picture of ADC pathogenesis. I will also extend this model to introduce some general considerations of therapeutic intervention.

A GENERAL CELL MODEL OF HIV-1 PATHOGENESIS

To deal with the concept of indirect pathogenesis involving multiple steps and more than one cell, investigators have proposed a number of models, usually embodied in diagrams that connect participating cells by arrows depicting mediators of various cell-celL interactions. While differing in detail and their emphasis on one or another cell type or mediator (usually depending upon the particular investigator’s studies or interests), in fact, these models are often very similar and attest to a growing convergence of theories of ADC pathogenesis. Like these other investigators, my colleagues and I have also proposed multi-cell models of ADC neuropathogenesis (Price 1994; Price, Brew, and Rosenblum 1990; Spencer and Price 1992). In a ‘generic’ model we have emphasized ‘functional roles’ for certain cells, rather than specifying either individual cell types or specific biochemical mediators, hoping that this approach would be useful in segregating individual pathogenetic components both descriptively and for subsequent analysis. I will present a variation of this model here and use it to introduce the invited contributions and place them into a more unified context.

TABLE 1. Some observations bearing on the causative role and pathogenetic mechanisms relating HIV-1 brain infection to ADC

Supporting the Etiological Role of CNS HIV-1 Infection in ADC

ADC is unique to HIV-1 infection and not reported in other states of immunosuppression.

Animal lentiviruses related to HIV-1, including visna and simian immunodeficiency virus, infect the CNS and cause neurological dysfunction.

HIV-1 infects the brain, at times intensely, and some studies suggest a correlation between the CNS Virus load’ and neuronal changes, particularly in severe cases.

Severe brain infection involves strains of the virus that share macrophage-tropism and perhaps other genetic and phenotypic features.

No alternative pathogen has been consistently correlated with ADC.

Neurotoxicity has been observed both in vitro and in vivo (including in a transgenic mouse model) related to HIV-1 gene products, most notably gp 120.

Treatment with the antiretroviral nucleoside, zidovudine, can ameliorate and probably prevent ADC.

Observations Suggesting that CNS HIV-1 Infection Causes ADC by ‘Indirect’ Mechanisms

Productive HIV-1 infection of the brain is confined (principally or exclusively) to cells of bone marrow origin, including monocyte-macrophages and microglia, rather than involving the ‘functional’ brain cells of neuroectodermal lineage, i.e., neurons, oligodendrocytes and astrocytes.

Neither multinucleated-cell encephalitis nor immunocytochemical evidence of infection is invariably present in ADC patients, particularly in milder cases, and even when present brain infection may seem ‘less intense’ than the extent of histopathology or clinical dysfunction.

Immune activation, as revealed in CSF and brain, may correlate better with the ADC severity than does the CNS virus load.

Before describing the model, it is useful to first consider some of the major aspects of pathogenesis with which it must deal. ADC can be considered to result from the interaction of three major ‘systems’ of genes or gene expression: (1) the invading retrovirus that serves as the primary agonist, driving the toxic reactions by continued replication and expression of its genome as it persists in the host; (2) the immune system that acts not only both as the target of infection and the host’s principal means of defense (with the balance of these two roles evolving over the course of infection and systemic disease) but also as an important source of neurotoxicity; and (3) the target organ, the brain (Price 1994). The virus and the immune system interact both outside and within the brain. Their interaction outside of the CNS determines the course of systemic disease and the development of its late phase, AIDS. ADC can be considered an epiphenomenon of this interaction. It is neither essential to the course of systemic infection and disease nor a uniform development that affects all of those who are infected, despite the fact that the HIV-1 likely reaches the CNS of all. ADC is nonetheless common and for afflicted patients, it can be a principal and even fatal burden. Theories of ADC pathogenesis must deal with: (1) the role of the viral genome and its products both outside and within the CNS, (2) the multifaceted role of the immune system also both outside and within the brain, and (3) the subsequent injury and functional perturbation of the brain.

In the effort to simplify, the model to be described below largely neglects the details of systemic infection. This requires some explanation and qualification. Systemic HIV-1 infection provides the foundation for the development and evolution of ADC in several ways. It is, of course, the source of the virus that seeds the brain. The cells that defend against the virus within the brain are similarly derived from the systemic circulation. Thus, both virus and immune cells ‘migrate’ into the brain. In this sense brain infection is a metastatic process with differences between systemic and brain infections determined by restrictions on cell traffic into the brain and perhaps the effects of its local milieu. Moreover, the stage of systemic disease and consequent immunosuppression critically determines the rate of HIV-1 replication in the brain, since defenses in the brain are derived from those of the systemic circulation and therefore share in their ineffectiveness in the late stage of disease. Finally, systemic infection is subject to mutation and selection, generating variants of the infecting HIV-1 quasispecies that can both escape immune surveillance and replicate within the brain (Hahn et al. 1986; Li et al. 1992). Thus, events depicted in the model are an outcome and extension of systemic virus-immune interactions. Additionally, just as these systemic interactions are extensions of systemic infection, some of the additional neuro- pathogenic processes encompassed by the model and depicted as occurring within the brain likely also take place outside of the brain. These may likewise release signals and toxins into the bloodstream which may have important effects on the brain vasculature and perhaps brain cells themselves. In this way, the primary events depicted and discussed in the context of the model to be presented can be considered to also apply to infection outside the brain to some extent.

However, to circumscribe the model in the context of this symposium, attention here is directed on those aspects of HIV-1 infection that are peculiar to CNS infection and on the effects of such infection on the brain. The details of systemic infection and aspects that CNS infection therefore share with systemic infection are largely omitted from consideration. This includes consideration of the complex process of viral replication, as well as the details of host defense mechanisms that control HIV-1 replication.

The Figure depicts an extension of our previously described multi- cell model of HIV-1 neuropathogenesis and divides the participating cells into two general ‘compartments’: the primary compartment involves the processes related to infection and host defenses (and thus represents the processes that were discussed earlier as metastatic to brain) and the secondary compartment includes the processes involved in brain injury and therefore the aspects of pathogenesis that are unique to the brain. This division is useful in separating the more general aspects of viral pathogenesis which involve the same issues as systemic infection, on the one hand, from neuropathological mechanisms and their relation to the processes operating in other neurodegener...