Cell Death and Differentiation (2005) 12, 878–892 & 2005 Nature Publishing Group All rights reserved 1350-9047/05 $30.00 www.nature.com/cdd Review HIV-1 infection and AIDS: consequences for the central nervous system M Kaul1, J Zheng2, S Okamoto1, HE Gendelman2 and Introduction SA Lipton*,1 Human immunodeficiency virus-1 (HIV-1) can not only 1 Center for Neuroscience and Aging Research, The Burnham Institute, 10901 destroy the immune system and lead to acquired immuno- North Torrey Pines Road, La Jolla, CA 92037, USA deficiency syndrome (AIDS), but the virus can also induce 2 Departments of Pharmacology and Pathology and Microbiology, Center for neurological disease that culminates in frank dementia. The Neurovirology and Neurodegenerative Disorders, 985880 Nebraska Medical worldwide development of HIV-related disease is alarming, Center, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA with more than 36 million existing infections, and about 20 * Corresponding author: SA Lipton, Center for Neuroscience and Aging million deaths.1 AIDS opportunistic infections may affect the Research, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, central nervous system (CNS), but HIV infection itself can also CA 92037, USA. Tel: 858 713 6261; Fax: 858 713 6262; 2 E-mail: [email protected] induce a number of neurological syndromes. Interestingly, anemia in HIV-1 infection seems to be an early predictor for a 3 Received 16.12.04; revised 14.2.05; accepted 21.2.05; published online 15.4.05 high risk of neuropsychological impairment. Neuropatholo- Edited by M Piacentini gical conditions directly triggered by HIV-1 include peripheral neuropathies, vacuolar myelopathy and a syndrome of cognitive and motor dysfunction that has been designated Abstract HIV-associated dementia (HAD).2,4–6 A mild form of HAD is 2,4,6,7 Infection with the human immunodeficiency virus-1 (HIV-1) termed minor cognitive/motor disorder (MCMD). can induce severe and debilitating neurological problems that The mechanism of HAD and MCMD remains poorly include behavioral abnormalities, motor dysfunction and understood, but the discovery in the brain of cellular binding sites for HIV-1, the chemokine receptors, and recent progress frank dementia. After infiltrating peripheral immune compe- in neural stem cell biology are providing new and hitherto tent cells, in particular macrophages, HIV-1 provokes a unexpected insights. It is widely believed that HIV entry into neuropathological response involving all cell types in the the CNS occurs via infected monocytes.8–10 Interestingly, in brain. HIV-1 also incites activation of chemokine receptors, the brain, HIV-1 productively infects only macrophages and inflammatory mediators, extracellular matrix-degrading en- microglia, but injury and apoptotic death occur in neurons.11,12 zymes and glutamate receptor-mediated excitotoxicity, all of Activation of monocytic cells (macrophages and microglia) which can trigger numerous downstream signaling pathways through infection, viral proteins or inflammatory mediators and and disrupt neuronal and glial function. This review will their subsequent release of toxins apparently lead to neuronal and astrocytic dysfunction and thus seem to drive the discuss recently uncovered pathologic neuroimmune and 4,13–15 degenerative mechanisms contributing to neuronal damage pathogenesis of HAD. However, viral proteins might induced by HIV-1 and potential approaches for development also directly contribute to neuronal injury. Some of the neurotoxic factors excessively stimulate neurons, thus lead- of future therapeutic intervention. ing to excitotoxicity with subsequent breakdown in neurons Cell Death and Differentiation (2005) 12, 878–892. of vital cellular functions in a manner shared with other doi:10.1038/sj.cdd.4401623 neurodegenerative diseases.4,15 Advances in understanding Published online 15 April 2005 the molecular mechanisms of the disease-defining events provide hope for improved therapeutic intervention.16,17 Keywords: HIV-1; NeuroAIDS; neurodegeneration; apoptosis; immune activation; macrophages/microglia; neurotoxicity; phar- macology; inflammation; central nervous system Epidemiology of HAD before and in the Era of HAART Abbreviations: HIV-1, human immunodeficiency virus-1; AIDS, acquired immunodeficiency syndrome; CNS, central nervous In the early 1990s, the prevalence of HAD was estimated to be system; CSF, cerebrospinal fluid; HAD, HIV-associated demen- as high as 20–30% of those individuals with advanced HIV À1 3 tia; MCMD, minor cognitive motor disorder; HAART, highly active disease and low CD4 cell counts (o200 ml ). The introduc- antiretroviral therapy; BBB, blood–brain barrier; SDF-1, stromal tion of highly active antiretroviral therapy (HAART) has cell-derived factor; TNF, tumor necrosis factor; TRAIL, TNF- increased the life expectancy of people infected with HIV-1 related apoptosis-inducing ligand; MCP, monocyte chemoattrac- and resulted in an at least temporary decrease in the 18–20 tant protein; MIP, macrophage inflammatory protein; RANTES, incidence of HAD to as low as 10.5%. In fact, a case regulated upon activation-normal T-cell expressed and secreted studied by our group demonstrated near-complete reversal of clinical signs and symptoms of HAD that has been sustained for more than 7 years.21 However, while improvements in HIV-1 infection and AIDS M Kaul et al 879 control of peripheral viral replication and the treatment of leukin (IL)-16, a natural ligand of CD4. Since this cytokine opportunistic infections continue to extend survival times, inhibits HIV-1 propagation, lymphocytes might contribute to HAART failed to provide complete protection from HAD or to an innate antiviral immune response in the CNS in addition to reverse the disease in most cases.22,23 This might at least in microglia.37 Cell migration also engages adhesion molecules, part be due to poor penetration into the CNS of HIV protease and increased expression of vascular cell adhesion molecule- inhibitors and several of the nucleoside analogs.24 Therefore, 1 (VCAM-1) has been implicated in mononuclear cell an early CNS infection might evolve independently over time migration into the brain during HIV and SIV infection.30,31,38 into a protected brain reservoir. In fact, distinct viral drug As an alternative to entry via infected macrophages, it has resistance patterns in the plasma and cerebrospinal fluid been suggested that the inflammatory cytokine, tumor (CSF) compartments have recently been reported.25 Conse- necrosis factor-alpha (TNF-a), promotes a paracellular route quently, as people live longer with HIV-1 and AIDS, the for HIV-1 across the BBB.39 Interestingly, alterations in the prevalence of dementia might be rising and in recent years the BBB occur even in the absence of intact virus in transgenic incidence of HAD as an AIDS-defining illness has actually mice expressing the HIV envelope protein gp120 in a form that increased.22,26,27 Furthermore, the proportion of new cases of circulates in plasma.40 This finding suggests that circulating HAD displaying a CD4 cell count greater than 200 mlÀ1 is virus or envelope proteins may provoke BBB dysfunction growing,18 and MCMD may be more prevalent than frank during the viremic phase of primary infection. On the part of dementia in the HAART era.7 However, HAD might currently the host, a vicious cycle of immune dysregulation and BBB be the most common cause of dementia worldwide among dysfunction might be required to achieve sufficient entry of people aged 40 or less, and it remains a significant infected or activated immune cells into the brain to cause independent risk factor for death due to AIDS.7 Thus, a better neuronal injury.4,41 On the side of the virus, variations of the understanding of the pathogenesis of HAD, including viral and envelope protein gp120 might also influence the timing and host factors, is needed in order to identify additional extent of events allowing viral entry into the CNS and leading therapeutic targets for the prevention and treatment of this to neuronal injury.42 neurodegenerative disease. Potential Links between Neuropathology From HIV Entry into the Brain to of HIV Infection and Pathogenesis of HAD Development of MCMD/HAD The neuropathological hallmarks of HIV infection in the brain Soon after infection in the periphery HIV penetrates into the are termed HIV encephalitis and include widespread reactive CNS where the virus primarily resides in microglia and astrocytosis, myelin pallor, microglial nodules, activated macrophages.8,9 Viral load in brain can be measured by resident microglia, multinucleated giant cells, and infiltration quantitative PCR, and the highest concentrations of virus are predominantly by monocytoid cells, including blood-derived detected in those subcortical structures most often affected in macrophages.43 Surprisingly, measures of cognitive function patients with HAD.28,29 However, infection of macrophages do not correlate well with numbers of HIV-infected cells, and microglia alone does not seem to initiate neurodegenera- multinucleated giant cells or viral antigens in CNS tissue.44,45 tion, and it has therefore been proposed that additional factors In contrast, increased numbers of microglia,44 elevated TNF-a associated with advanced HIV infection in the periphery, thus mRNA in microglia and astrocytes,46 evidence of excito- outside the CNS, provide important triggers for events leading toxins,47–49 decreased synaptic and dendritic density,45,50 and to dementia.9 An elevated number