Ashley Reynolds Georgette Kanmogne Irena Kadiu and Howard E Gendelman

Significant progress has been achieved as a result of global research efforts into the pathogenesis, epidemiology, and developmental therapeutics for human immunodeficiency virus (HIV) infection and disease (Giulian et al., 1990; Genis et al., 1992; McArthur et al., 1993; Kaul et al., 2001; Sacktor et al., 2001; McArthur, 2004). Simply put, since the discovery more than 23 years ago of HIV as the virus that causes the acquired immune deficiency syndrome (AIDS) (Barre-Sinoussi et al., 1983; Gallo et al., 1983), the molecular structure, function, regulation, tropism, and methods for viral persistence have been well elucidated (Gray et al., 2005; Burton, 2006; Ribeiro et al., 2006). Perhaps most important is that potent antiret-roviral therapies (ART) and treatments for a myriad of opportunistic infections are widely available in the developed world (Egger et al., 2002; Manzardo et al., 2005; Walensky et al., 2006). A significant global political, social, and basic research effort is now emerging to make the same drug formulations available to developing countries (Mukherjee et al., 2003; Tassie et al., 2003; Chulamokha et al., 2005; Dou et al., 2006). All together, HIV is now a treatable and chronic disorder in which the immune system can be protected through ART reductions of viral load. However, complexities and toxicities of antiretroviral medicines abound. Indeed, drugs are not always effective, especially when administered over prolonged time periods and after a protracted and often complicated clinical course (Chen et al., 2002; Badley et al., 2003; Fellay et al., 2005; Green et al., 2005; Azzam et al., 2006). The emergence of viral drug resistance, consequent immune deterioration, treatment interruptions, and short- and long-term toxicities commonly make the outcome of HIV disease at best uncertain.

Of all the complications of HIV disease, the most foreboding, long-term one is the disease's effects on the nervous system. Indeed, early after the description of AIDS, neurological impairments were described and associated with advanced disease and profound immune suppression (Navia et al., 1986a, 1986b). These can often become severe with a triad of cognitive, motor, and behavioral disturbances (Wilkie et al., 2003; Griffin et al., 2004; Weed and Steward, 2005; Worlein et al., 2005). Although ART has reduced disease severity, the prevalence of disease is on the rise. Newer medicines, improved delivery platforms, and effective adjunctive therapies are needed along with better insights into the disease diagnosis, course, and progression.

This review serves to highlight both the research advances made in understanding the effects of HIV on the nervous system and what remains undone. Particular attention is given to the effects of the virus on the nervous system at the molecular and cellular levels as well as within the infected human host. A parallel focus is on prospects for increasing ART effectiveness and availability. An emerging and interesting aspect of disease pathogenesis remains in the many similarities now known between the pathogen-esis of HIV-associated cognitive impairments and that of other neurodegenerative disorders (for example, Parkinson's and Alzheimer's disease). Similarities abound at the level of glial inflammation and dysreg-ulation of innate immune responses. Whether caused by virus or misfolded and aggregated proteins, all of these processes underlie the tempo and progression of disease (Hirsch et al., 2003; Butovsky et al., 2005; Minghetti, 2005; Zhang et al., 2005; Craft et al., 2006; Ghafouri et al., 2006; Wu et al., 2006). A significant body of data has emerged in the past quarter century on how HIV affects the brain and causes progressive clinical impairment (Navia et al., 1986a, 1986b; McArthur et al., 1993; Masliah et al., 1997; Everall et al., 1999). The key to future research strategies remains in discovering ways to protect the brain, reverse the process of impairment, or attenuate it.

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