Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: Current status of dopamine system vulnerability in NeuroAIDS

Abstract

There are roughly 30–40 million HIV-infected individuals in the world as of December 2007, and drug abuse directly contributes to one-third of all HIV infections in the United States. Antiretroviral therapy has increased the lifespan of HIV-seropositives, but CNS function often remains diminished, effectively decreasing quality of life. A modest proportion may develop HIV-associated dementia, the severity and progression of which is increased with drug abuse. HIV and drugs of abuse in the CNS target subcortical brain structures and DA systems in particular. This toxicity is mediated by a number of neurotoxic mechanisms, including but not limited to, aberrant immune response and oxidative stress. Therefore, novel therapeutic strategies must be developed that can address a wide variety of disparate neurotoxic mechanisms and apoptotic cascades. This paper reviews the research pertaining to the where, what, and how of HIV and cocaine/methamphetamine toxicity in the CNS. Specifically, where these toxins most affect the brain, what aspects of the virus are neurotoxic, and how these toxins mediate neurotoxicity.

Introduction

The year 2007 saw the number of people infected with human immunodeficiency virus (HIV) reach an all time high, as “the global prevalence of HIV infection is remaining at the same level, although the global number of persons living with HIV is increasing because of ongoing accumulation of new infections with longer survival times, measured over a continuously growing general population” (UNAIDS/WHO, 2007). As of December 2007, there are an estimated 30–40 million people infected with HIV worldwide, with little indication that HIV incidence rates are decreasing (UNAIDS/WHO, 2007). This figure represents roughly 1.0% of the world's adult population, but regional adult prevalence rates reach as high as 5.0% of the population, as in Sub-Saharan Africa for example (UNAIDS/WHO, 2007).

Multiple behavioral risk factors are responsible for the propagation of HIV; in the United States, injection drug use is the second most risky behavior directly associated with the transmission of HIV, even exceeding heterosexual intercourse. Through the year 2002, injection drug use directly accounted for one-third of the total number of acquired immunodeficiency syndrome (AIDS) cases in the United States (the National Institute on Drug Abuse; NIDA, 2004). HIV DNA has been positively identified on paraphernalia such as needles and syringes from drug “shooting galleries” (Shah et al., 1996). In a longitudinal study encompassing the early years (1978–1983) of the HIV/AIDS epidemic in the United States, parenteral cocaine (COC) and heroin drug users in New York City were found to be “disproportionately HIV-infected” (Novick et al., 1989). Furthermore, NIDA notes that drug abuse (injection or non-injection) can also indirectly lead to HIV transmission through interference with sound judgments in regard to sexual behavior, thereby increasing the likelihood of infection through sexual intercourse. They note that crack smokers (i.e., non-injectors) in inner-city neighborhoods are three times more likely to contract HIV than those who do not smoke crack (NIDA, 2004). Clearly, drug abuse propagates HIV infection. Moreover, drugs of abuse such as COC and methamphetamine (METH), may act in concert with HIV to wreak havoc on glial systems in the brain, ultimately leading to glial and neuronal injury and/or death. This neurotoxicity is of a magnitude which exceeds the neurotoxicity of COC, METH, or HIV alone. A wealth of scientific research has substantiated HIV- and drug-induced concerted neurotoxicity and its precursory mechanism(s) of action. Thus, the current review of the extant literature of HIV and drug abuse is timely.

The general purpose of this paper is twofold: first, to review the research pertaining to dopamine (DA) neurotoxicity of HIV, as well as theories regarding the neurotoxic mechanism(s) of action. Reviews concerning the neurotoxicity of HIV are hardly lacking (Table 1), yet the utility of this review remains undiminished for two reasons. One, the comprehensiveness of the current paper incorporates and consolidates the broad range of reviews regarding HIV neurotoxicity and neurotoxic mechanisms of action. Two, reviewing the neurotoxic effects of HIV provides a springboard for the second general purpose of the paper; to review the relatively novel area of research on the concerted/synergistic, neurotoxic effects of COC or METH abuse plus (+) HIV. Possible mechanisms for this synergistic toxicity are covered as well as novel protective factors for the brain of HIV-infected, COC or METH abusers. Table 1 is included to direct interested readers to specific reviews of topics presented throughout this article, the purpose of which is to present the literature with both breadth and depth.

This review will be organized so as to mimic the general cellular/systemic pathology of HIV in the brain and to attempt to examine the where, what, and how of HIV neurotoxicity, beginning each major section with theories and research pertaining to HIV entrance into the CNS through the blood–brain barrier (BBB). Breaching of the BBB occurs early in HIV infection (An et al., 1999, Toborek et al., 2005), and toxicity of BBB endothelial cells occurs throughout the infection in parallel with toxicity of neurons (Price et al., 2005). Therefore, theories and research pertaining to the kinetic aspects of HIV neurotoxicity, with a special emphasis placed on DA systems, will then be reviewed. This will provide an understanding of where HIV most affects the brain. HIV neurotoxicity and related mechanisms of action are mediated by a number of HIV structural and regulatory proteins. Therefore, a description of the most prominently studied HIV-proteins (Tat and gp120) and their ability to mediate cell death will be reviewed, which will highlight what aspects of HIV are detrimental to brain parenchyma. Since evidence highlights the fact that DA neurons may succumb to HIV-induced oxidative stress (Aksenov et al., 2001, Aksenov et al., 2003, Pocernich et al., 2005), a review of this mechanism of neurotoxicity will be presented following the review of HIV-proteins, giving one example as to how HIV might induce neurotoxicity. A review of the individual effects of COC and METH, as well as the concerted toxicity of HIV + COC and/or METH, and their mechanisms of action will receive individual attention and will be incorporated in the context of the topics of where, what, and how.