CNS as an HIV-1 reservoir; BBB and drug delivery.

In September of last year, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored an AIDS Program Panel meeting entitled `CNS as an HIV-1 Reservoir: BBB and Drug Delivery'. The main objective of this highly focused meeting was to discuss the latest understandings of systemic drug delivery to the brain and the dif®culties which may be associated with developing optimal treatment for HIV-1-associated CNS disorders. To address this issue the participants, which consisted of clinical and basic science experts in AIDS and HIV-1/CNS infection along with vascular cell biologists, pharmacologists and brain tumor biologists, initially had a general discussion on the pathogenesis of HIV-1-induced neurological dysfunction. The participants presented their views in three sessions: NeuroAIDS, the Blood-Brain Barrier (BBB), and drug delivery to the CNS; to attempt to clarify many uncertainties pertaining to current treatment modalities for HIV-1-induced pathology in the brain. Once general concepts of the neuropathogenesis of HIV-1-induced disease were discussed, special effort was made to de®ne the areas of research which require increased attention, such as the identi®cation of ef®cient mechanisms of CNS drug delivery for the treatment of neurological dysfunction seen in AIDS patients. The current model as to how HIV-1 infection of the CNS occurs was acknowledged. According to this model, the virus may either access the CNS through traf®cking of infected leukocytes into the brain, and/or through transfer of the virus via the brain endothelium. In addition to microglia, the major viral reservoir in the CNS, restricted infection of astrocytes and brain endothelial cells was further emphasized. It was noted that HIV-1 strains present in CNS-speci®c cellular targets are genetically distinct from those in the periphery. It is the CNS variants that may develop resistance to current antiviral therapies as a result of a sub-optimal level of pharmacological agents in the brain, which in turn, may provide a reservoir of virus in the brain. Much focus was given to the signi®cance of studying chemokine receptors as attachment sites for HIV-1. It was noted that neurons contain such receptors, however since the infection of neurons by HIV-1 is still uncertain, it remains unclear as to how expression of such receptors relates to earlier reports of limited, if any, infection of neurons in the AIDS brain. On a different note, it was also suggested that chemokines and their receptors may be involved in mediating the in ̄ux of infected macrophages into the CNS. In light of the high degree of diversity in these classes of receptors, further study is required to decipher their direct and indirect roles in HIV-1-induced CNS pathology. Nevertheless, the current data suggest that viral receptors and co-receptors may serve as potential targets for the development of therapeutic strategies against HIV-1 in brain. With regard to the BBB and drug delivery, experts on cerebral vasculature commented on the complex nature of BBB integrity and the effect of HIV-1 infection on BBB permeability in infected individuals. Earlier observations have noted an enhanced permeability of the BBB in HIV-1 subjects based on the detection of increased levels of serum proteins, evidence of in ̄ammation of the brain parenchyma, and an increase in the expression of cell adhesion molecules in the brain. However, neuroimaging studies have failed to support these observations. It was, therefore, suggested that BBB permeability should be tested with compounds such as dextrancoated iron conjugates through the use of animal models in order to clarify this important issue. Several in vitro models of the BBB were presented with special emphasis on perturbation of its integrity by HIV-1. Although some appear to represent suitable in vitro models, correlation of the in vitro ®ndings is limited due to the acute nature of changes in the in vitro models as opposed to chronic changes in vitro. Another topic that attracted a great deal of attention was the delivery of therapeutic drugs across the BBB. There was a consensus among the participants that HIV-1 within the CNS may be protected from the currently used highly aggressive anti-retroviral therapy (HAART). It was emphasized that assessment of the viral load and the presence of *Correspondence: S Amini Journal of NeuroVirology (1999) 5, 113 ± 114 ã