Editorial [ NeuroAIDS: A Neuroscience Problem with Global Impact ]

Early in the HIV/AIDS epidemic, it was recognized that there were many syndrome-defining illnesses involving the nervous system, including peripheral neuropathies and dementia, opportunistic infections of the central nervous system (CNS) such as cryptococcal and tubercular meningitis, and progressive multifocal leukencephalopathy (PML). Fast on the heels of the discovery of HIV-1 as the causative agent for AIDS, several studies pointed to the viral envelope glycoprotein gp120 as a principal suspect for neuropathology [1,7]. The neurotoxic potential of other viral proteins has also been demonstrated, most notably Tat, however the mechanisms for delivery of these viral proteins into the central nervous system remain unclear [10]. The obvious vehicle for virus delivery to the brain would be an HIV infected T-cell, the predominant source for HIV in the periphery, yet it has been difficult to demonstrate the presence of these cells in CNS tissue. Instead, infected perivascular macrophages and microglia are often found in brain tissue from patients with viral encephalitis or HIV-associated dementia (HAD) [15,17]. Although there is clearly neuronal loss in HAD, neurons and oligodendrocytes are not infected directly by HIV. Astrocytes can be infected but without the production of virus. This profile of cellular tropism in CNS infection is consistent with several other animal lentiviruses that infect monocytic cells exclusively over T-cells [2]. The background outlined above will be discussed in much more detail in the articles to follow. While macrophages/monocytes and activated glial cells have recently taken center stage in the study of the neuropathogenesis of HIV, several key questions in HIV neurovirology remain. First, what is the mechanism by which HIV causes neuronal cell death? It remains unclear whether HAD is the product of a chronic neuroinflammatory environment set up in the course of HIV infection, or is due instead to the direct toxicity of viral gene products. Both mechanisms may ultimately be important. It is possible that traffic of HIV-infected monocytes into the CNS early in the course of the disease establishes a chronic inflammatory environment and activation of the innate immune system. This inflammation would lead to the eventual recruitment of other components of the cellular immune response to the brain, including T-cells and the potent neurotoxic viral strains that infect them. Breakdown of the neuroprotective blood-brain barrier some time in the course of disease may also be important for neuropathogenesis. Studies of animal models for neuroAIDS such as SIV infection in the macaque [3,18] or a recently developed HIV/MLV chimera which can infect the CNS of mice [11] will surely provide important answers toward understanding the mechanisms of HIV neuropathogenesis. A second question, the focus of significant efforts in neuroAIDS, is whether the CNS can serve as an immunologically and therapeutically privileged reservoir for harboring HIV. Many current anti-retroviral drugs may have limited diffusion or transport across the blood-brain barrier into the CNS [9]. Do drug-resistant viruses develop in this environment, and if so, can HIV from the CNS affect the course of patient treatment and outcomes? A recent study from Hawaii has demonstrated that patients with HAD receiving highly active antiretroviral therapy (HAART) had significantly higher levels integrated HIV provirus in peripheral blood mononuclear cells when compared to matched HAD-negative controls [14]. This finding suggests the possibility that the CNS could serve as a source of HIV-infected monocytes when there is active replication of HIV in the brain. If the CNS is a reservoir for active viral replication it is hoped that this virus can be eliminated through the development of improved HAART components with better CNS penetration or other therapeutic strategies eliminating HIV-infected cells. It is also unclear whether there is latent, non-replicating virus within the CNS. The non-productive infection of astrocytes or perhaps brain progenitor cell populations might provide such a host for latent HIV [6]. Will HAART therapy will eventually eliminate the neurological complications of AIDS? With the advent of protease inhibitors and combination therapy for HIV the landscape of HIV/AIDS neurological disorders has certainly changed. In the developed world, where HAART therapy is widely available, the incidence of opportunistic infections in the CNS of AIDS patients has declined with the rebound of their immune function. Over the past decade the incidence of HAD has also decreased. Despite these successes, some studies suggest the overall prevalence of HAD may be increasing as patients survive longer living with HIV/AIDS [4]. Peripheral neuropathies also remain a problem for patients [5]........