: Given the success in highly active antiretroviral therapy (HAART) in reducing the morbidity and mortality from AIDS, why worry about the nervous system in HIV-1 infected individuals?

Although it is clear that HAART induces a marked reduction of virus from the blood and lymphoid organs, and likely the cerebrospinal-fluid (CSF) (1), effects on virus in the brain itself are unknown. In the central nervous system (CNS) the brain parenchyma (as well as the brain extracellular fluid) is a distinct compartment from the CSF (2). The reductions in viral load that have been reported in the CSF may not reflect effects on the virus in the brain. Most of the antiviral agents do not show significant penetration of the blood-brain barrier (BBB) (2)(3) although some may enter the CSF space (1). Furthermore, cells of the macrophage lineage are infected in the CNS (4). Such cells are relatively long-lived and can be persistently infected without cytolysis. Thus, the CNS may remain a reservoir as well as suffer continued damage over the treatment-prolonged course of infection. Encouragingly, however, the effectiveness of therapy on potential neurotoxins in patients with AIDS dementia has been reported (5).

Further complicating this issue are the observations that HAART is not effective in approximately 50% of HIV-infected individuals (6). This is especially the case in patients previously treated with prior regimens of ART and, other than in motivated individuals in industrialized nations, such treatment is not widely available worldwide. Additionally, with many individuals now being treated relatively early during the course of infection, worries about development of resistance by the virus and the chronic effect of long-term infection on the nervous system also arise. Finally, in addition to CNS pathologies, HIV also affects the peripheral nervous system, and some of the antiretroviral therapies (ARTs) may complicate this through their induction of peripheral neuropathy as a side effect (7).

Q: In the recent era of effective anti-HIV treatment, what is known about its effects on the HIV-1-cognitive/motor complex?

With advent of HAART, the incidence of HIV-1 associated dementia has declined by 43% (8). In contrast, the prevalence of HIV-1 associated dementia remains uncertain although it is conceivable that it may increase because people with AIDS are living longer. Prospective studies are now underway which will help address the question. In a recent study the ART abacavir™, administered for 12 weeks, failed to show significant improvement in cognitive function in AIDS patients with mild to severe dementia (MSK1-3)(9) compared to a placebo-treated group. This lack of effect may have been due to pre-existing drug-resistance mutations in the virus induced by long term use of ART in these patients, the lack of penetration or efficacy against CNS virus, or because the burden of neuronal injury was too large to reverse; the former point is more plausible because abacavir™ did not influence plasma viral load in treated patients. The effect of HAART on the minor cognitive and motor disorder caused by HIV infection remains uncertain as it has been less well studied than frank dementia but recent studies (10) indicate that such dysfunctions remain a problem.

Similar to what is now seen with HAART, the incidence of AIDS-related dementia declined following the introduction of monotherapy with Zidovudine™ (11)(12). In this pre-HAART era, the risk development of HIV-induced neurological disease was clearly related to systemic viral load or immune suppression (13). In those with AIDS both dementia and the minor cognitive-motor disorder were associated with higher CSF viral loads (14)(15), but the exact nature of these relationships for prognostic or pathogenic links in neuroAIDS is unclear. Still, CNS penetration by ARTs may not be as crucial as was initially thought, and the dramatic lowering of viral load with HAART has been an important milestone in research into, and clinical treatment of, neuroAIDS.

Q: What issues will receive attention in the near future?

It is likely the peripheral nervous system will receive more attention in the future because HIV-induced neuropathy is more common than dementia, occurs in children as well as adults, can be exacerbated by many ARTs and may be improved by treatment with Nerve Growth Factor (16). As new ARTs become available, emerging issues include the growing concern about drug-resistance mutations and their impact on neurological outcome, attempts to improve patient compliance with intensive treatment regimes, adjunct neuroprotective therapies such as the ongoing nimodipine (17) and memantine studies, and novel strategies for delivering drugs into the CNS. Quantification of viral load has been extended to brain tissue (18). In both human and animal models the relationship between plasma, CSF, and CNS viral load to treatment regimens and neurological disease can be better addressed. The role of the BBB in both treatment and pathogenic issues remains the subject of active studies. Although the BBB appears perturbed in chronic HIV infection (19)(20) and in related animal models, the mechanism(s) and significance of the breech of the BBB are still controversial.

References

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Memorial-Sloan Kettering Dementia Score, Value 1-3

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(14) Brew BJ, Pemberton L, Cunningham P, Law MG (1997). Levels of human immunodeficiency virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage. J Infect Dis 175(4):963-6. Medline

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(16) McArthur JC, Yiannoutsos C, et al (1998). Trial of recombinant human nerve growth factor for HIV-associated sensory neuropathy. Abstract, Neuroscience of HIV Infection, Chicago.

(17) Navia BA, Dafni U, Simpson D, Tucker T, Singer E, McArthur JC, Yiannoutsos C, Zaborski L, Lipton SA (1998). A phase I/II trial of nimodipine for HIV-related neurologic complications. Neurology 51(1): 221-8. Medline

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