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HIV-I-associated central nervous system dysfunction
Book chapter   Peer reviewed

HIV-I-associated central nervous system dysfunction

Fred C. Krebs, Heather Ross, John McAllister and Brian Wigdahl
Advances in Pharmacology, v 49, pp 315-385
2000
DOI: https://doi.org/10.1016/S1054-3589(00)49031-9

Abstract

Despite more than 15 years of extensive investigative efforts, a complete understanding of the neurological consequences of HIV-1 CNS infection remains elusive. Although the resources of numerous investigators have been focused on studies of HIV-1-associated CNS disease, the complex nature of the disease processes that underlie the clinical, pathological, and cellular manifestations of HIV-1 CNS infection have required a larger volume of studies than was initially envisioned. Several major areas remain as the focus of current research efforts. One of the more pressing issues facing researchers and clinicians alike is the search for correlates to the development of HIV-1-associated CNS neuropathology and the onset of HIVD. Although numerous parameters have been studied, none have been shown to be absolute predictors or markers of HIV-1-related CNS dysfunction. The identification of solid correlates of HIVD is an important goal that would permit clinical identification of individuals at risk for developing potentially crippling, life-threatening CNS abnormalities and would facilitate early treatment of nascent neurological problems. A more complete comprehension of the cellular foundations of CNS dysfunction and HIVD is also a fundamental part of strategies designed to treat or prevent HIV-1-associated CNS disease. Future investigations will strive to expand the body of knowledge concerning the complex interactions between infected and uninfected neuroglial cells and the roles of numerous cytokines, chemokines, and other soluble agents that are deregulated during HIV-1 CNS infection. In particular, a thorough understanding of the mechanisms of neurotoxicity may facilitate the development of new therapies that alleviate or eliminate the clinical consequences of CNS infection. Finally, investigators will continue to study HIVD within the context of single and combination drug therapies used in the treatment of HIV-1 infection and AIDS. As newer and more effective systemic treatments for HIV-1 infection and AIDS are introduced, the effects of these treatments on the onset, incidence, and severity of HIVD will also require intensive study. The impact of drug therapies on the ability of the CNS to act as an HIV-1 reservoir will also need to be addressed. Introduction of each new drug or drug combination will necessitate studies of drug penetration into the CNS and efficacy against the development of CNS abnormalities. Furthermore, as more effective treatments prolong the lifespan of individuals infected with HIV-1, the impact of extended survival on the occurrence and severity of HIVD will also require further investigations. The quest for answers to these and other questions will be complicated by the diversity of experimental systems used to study different aspects of HIV-1 CNS infection and HIVD. Each system has its own unique strengths and weaknesses. Clinical observations provide a continuous spectrum of symptomatic findings but reveal little about the underlying mechanisms of disease. In vivo imaging techniques, such as CT and MRI, also provide a continuum of observations, but the images are limited in their resolution. Neuropathological examinations of postmortem HIV-1-infected brains offer gross, cellular, and molecular views (including phenotypic and genotypic analyses of CNS viral isolates) of the diseased brain, but only provide a snapshot of the end-stage neurologic dysfunction. Studies that rely on animal surrogates for HIV-1, including SIV, simian-HIV (SHIV), feline immunodeficiency virus (FIV ), visna virus, and HIV-1 SCID-hu models, permit experimental protocols that cannot be carried out in humans, but are limited by the fidelity with which each virus and animal model emulates the conditions and events observed in the human host. Finally, in vitro techniques, which include the use of primary cells and cell lines, adult or fetal human cell cultures, and BBB barrier model systems, are also convenient means by which aspects of HIVD can be studied. However, experiments conducted using primary cell populations can be affected by donor variability and cellular changes that arise during in vitro growth of primary cells. The multitude of investigational approaches also poses the problem of integration. Each new finding must be compared to results obtained using other systems and evaluated for its relevance to in vivo conditions. For example, numerous in vitro studies using animal cell cultures and whole-animal models have shown that gp120 can act as a potent neurotoxin. However, these results must be integrated with observations obtained using human in vitro systems and assessed within the context of neuropathogenesis associated with HIV-1 CNS infection in vivo. Clearly, a complete understanding of the molecular mechanisms of HIV-1 CNS infection and HIVD will require melding numerous observations made using a variety of experimental systems. HIV-1-associated CNS disease and HIV-1 dementia are complex disease states whose clinical and pathological hallmarks have their basis in events that take place at the cellular and molecular levels during HIV-1 replication within the CNS. Continued study of these events will certainly help further our understanding of the consequences of HIV-1 infection of the CNS and advance the search for effective treatments of HIVD.

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