NEUROLOGICAL DYSFUNCTION ASSOCIATED WITH HIV-1 INFECTION
Infection by the lentivirus human immunodeficiency virus type 1 (HIV-1) results in a variety of syndromes involving both the central and the peripheral nervous systems. Although HIV-1 enters the central nervous system (CNS) early in the course of infection, the chief burden of neurological illness occurs in the later stages of systemic disease concurrent with the development of immun- odeficiency.1 The neuropathological hallmark of HIV-1 infection of the brain is HIV-encephalitis (HIVE), characterized by astrogliosis, microglial nodules, macrophage infiltration, multinucleated giant cells, white matter pallor, reduced synaptic density, and neuronal loss in the cortex and basal ganglia.2-10 These neuropathological features are associated with a subcortical clinical disorder termed HIV-associated dementia (HAD), which is defined by cognitive, behavioral, and motor dysfunction.
Although HAD increasingly develops before profound immunosuppression, it is generally a neurological syndrome associated with advanced stages of HIV-1 infection. Before the introduction of highly active antiretroviral therapy (HAART), the prevalence of HAD in the asymptomatic phase of HIV-1 infection was estimated to be only 0.4%,11 compared with 16% observed in patients who displayed symptomatic infection.12 Among children with HIV-1 infection, delays in neurological development occur, although frank encephalopathy may be evident only during advanced infection.13 In addition to HAD, a less severe form of cognitive impairment termed “minor cognitive/motor disorder” (MCMD) exists in at least 30% of symptomatic HIV-1-infected individuals.14,15 Manifestations of MCMD seems to indicate a worse prognosis for acquired immunodeficiency syndrome (AIDS)16 and a high predictive value for the subsequent detection of HIVE at autopsy.17 The introduction of HAART regimens in the mid-1990s led to a dramatic decline in381 the death rate due to AIDS, decreased rates of maternal-to-infant transmission, and reductions in the rates of opportunistic infections.
In addition, introduction of HAART almost halved the incidence rates of HAD to that now of approximately 10%,18,19 although the prevalence of HAD is on the rise.20 In addition, improvements in neurocognitive performance were observed in patients after 6 months of HAART therapy.21,22 However, HAART does not provide complete protection from or complete reversal of HAD.23,24 The incidence of HAD as an AIDS-defining illness has actually increased in recent years,23 and the prevalence of HAD in patients with higher CD4 T cell counts (greater than 200 cellsZμl) is also on the rise.19 Moreover, HAART has had little effect on the prevalence of MCMD, with current rates maintained at approximately 37%,15 and the frequency of HIVE detected in postmortem tissue has remained constant.25 These findings support the hypothesis that HAART does not provide complete protection from developing HAD, possibly as a result of the poor penetration of these drugs into the CNS.26 Although HAART has impacted on the incidence of HAD, it still remains a serious concern during AIDS. This is highlighted in a recent report, in which more than 90% of HIV-1 infected patients who died between 1996 and 2001 were newly diagnosed with HAD within 12 months of death.27 It has been suggested that HAD is now the most common form of dementia worldwide in people aged 40 years or younger and is a significant independent risk factor for death due to AIDS.28In addition to CNS disorders, HIV-1 infection gives rise to a variety of disorders of the peripheral nervous system (PNS). In fact, peripheral neuropathy has become the chief neurological complication observed among persons infected with HIV-1 in the developed world.29 Of these peripheral neuropathies, HIV-associated sensory neuropathy (HIV-SN) is the most common form recognized among patients with HIV-1 infection, affecting approximately 30% of both adults and children with AIDS.30-32 HIV-SN includes neuropathy directly related to HIV disease per se (e.g., distal symmetrical polyneuropathy [DSP]) and neuropathy associated with the use of the nucleoside analogue reverse transcriptase inhibitors (NRTIs) including zalcitabine (ddC), stavudine (d4T), and didanosine (ddI) (e.g., antiretroviral toxic neuropathy [ATN]).
In both cases, HIV-SN is predominantly defined by pain; patients exhibit hyperalgesia (lowered pain threshold) and allodynia (pain induced by otherwise nonnoxious stimuli), although, in addition, patients may suffer from paresthesia, gait instability, and autonomic dysfunction.33 The neuropathology of HIV-SN is characterized by the distal degeneration of long axons after a “dying back pattern.”33 Prominent loss of the small, unmyelinated nociceptive sensory neurons of the dorsal root ganglia (DRG) occurs together with inflammation within the nerve, although reduced density of small and large myelinated fibers has also been observed.30,34 In addition, reduced density of DRG neurons35 and degeneration of the centrally directed extensions of sensory neurons in gracile tracts of the cervical and upper thoracic spinal cord36 have been demonstrated in HIV-SN patients. Very recent studies from our group indicate that cats infected with the lentivirus feline immunodeficiency virus (FIV) develop a distal sensory neuropathy that is also defined by axonal injury and inflammation.37A burgeoning field of interest is the interaction between intravenous drug abuse, HIV-1 infection, and neurological impairment. Abuse of opiate drugs, such as heroin and morphine, not only promote HIV-1 infection and the progression to AIDS38-40 but also seem to increase the frequency and severity of HIVE.41 In addition, morphine potentiates the toxic effects of HIV-derived proteins.42,43 In a recent study, morphine enhanced the HIV-1 Tat-induced cell death of both glial precursor cells and type I astrocytes via a μ-opioid receptor-mediated mechanism involving caspase-3 activation.44 In addition to the opiates, one of the most common drugs of abuse in HIV-1 infected individuals is methamphetamine (a drug chemically similar to the CNS stimulant amphetamine), and abuse of either drug was associated with neurological impairment.45,46 In a recent study, Rippeth et al. demonstrated that although HIV-1 infection and methamphetamine dependence were both individually associated with neuropsychological defects, the additive deleterious effects of the two were greater than either risk factor alone.47 Given that intravenous drug abuse remains a driving force behind the HIV-1 epidemic in certain regions (e.g., Eastern Europe and Central Asia), its potential role in the neurological dysfunction observed in HAD requires further attention.