Cell death mechanisms in HIV-associated dementia: the involvement of syncytia

HIV-1 affects the central nervous systems in two ways: directly, producing distinct neurological disease, or indirectly, by causing immunodeficiency with increased susceptibility to opportunistic infections and neoplasms. The typical presentation of HIV-associated dementia (HAD) is characterized by cognitive, behavioural and motor dysfunction, and has been defined as a subcortical dementia.¹ Direct neurological involvement includes motor disturbances, cognitive impairments and behavioural changes in various degrees of severity.² The initial symptoms of HAD can be subtle and overlooked, or misdiagnosed as depression, and mild forms are known as HIV-1-associated minor cognitive/motor disorders (MCMD) and are characterized by impaired motor speed, working memory and attention, whereas episodic memory and visuo-constructive abilities are relatively unaffected. In the early stages of HAD, memory loss, mental slowing, reading and comprehension difficulties and apathy are frequent complaints. More advanced forms of HAD are characterized by psychomotor slowing, severe memory impairment, disturbances in complex attentional tasks and executive functioning, as well as behavioural manifestations. New onset psychiatric disorders, or a heightened sensitivity to neuroleptic agents, can also be observed. All these findings define a well-characterised syndrome observed during the historical years before the introduction of antiretrovirals. More recently, a severe form of leukoencephalopathy was also reported in HIV-1-infected individuals.³ This syndrome developed in patients failing highly active antiretroviral therapy (HAART), and the neuropathological features included widespread myelin loss, axonal injury, microgliosis, astrogliosis, and intense perivascular infiltration by monocytes/macrophages and lymphocytes.

HAD commonly occurred during the late stage of HIV-1 infection, when the CD4+ T lymphocytes were most severely depleted, and, even though it occasionally may develop before profound immunosuppression, in general, it results as rare among healthy HIV-1-infected persons. According to historical data, prevalence of HAD was only 0.4% during the asymptomatic phase of infection, but increase to 16% among patients with symptomatic HIV-1 infection. Before the advent of highly antiretroviral therapy, the cumulative risk of developing HAD was estimated to be 15–20%.⁴ The HAART introduction resulted in a marked reduction in incidence and severity of opportunistic infections and improvements in survival of patients with HIV-1 infection as well as with a decreased incidence of HIV dementia.^{5, 6}

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