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Received 23 August 2010; accepted 23 August 2010; electronically published 4 November 2010. Potential conflicts of interest: none reported. Reprints or correspondence: Dr David B Clifford, Depts of Neurology and Medicine, Washington University in St. Louis, Saint Louis, Missouri, 660 South Euclid Ave, Saint Louis, Missouri, 63110 (cliffordd@wustl.edu). The Journal of Infectious Diseases 2010;202(12):1768– 1769 2010 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2010/20212-0002$15.00 DOI: 10.1086/657343 One of the ongoing challenges for human immunodeficiency virus (HIV) therapeutics is achieving optimal treatment for the infected brain. Structural and physiologic isolation of the brain, based on bloodbrain and blood–cerebrospinal fluid (CSF) barriers, typically makes the treatment of infection of the brain challenging. Because HIV is present in this compartment throughout the course of infection, successful control of viral replication in the brain is essential to effective therapy, particularly therapy aimed at eradication of HIV, an increasingly discussed research goal. Edén and colleagues in this issue of the Journal [1] have made important observations from a series of patients with stable successful control of HIV in the plasma, documenting a surprisingly high proportion (10%) of patients with still detectable virus in the CSF. Although the virus infection did not appear symptomatic in these patients, extrapolation from past experience with HIV-associated cognitive impairment [2], and recent reports of reversible symptomatic viral escape due to discordant virus [3], it is concerning that this ongoing viral presence represents a serious threat to the brain over the many years that these patients are expected to live. Additionally, it draws attention to the magnitude of the challenge that the brain is likely to represent for any eradication strategy. Understanding the biology of this persistent viral population in the CSF will be important. The authors consider the possibility that the drugs effectively controlling virus in the plasma might be less effective in reaching the CNS and CSF compartments. CNS penetration effectiveness (CPE) scoring of HIV regimens has been proposed as a useful tool for researchers and clinicians to compare different drug regimens. Letendre and colleagues [4] created this tool, which continues to evolve with emerging new data and drugs, integrating observations that reflect viral and cognitive impact of therapies, as well as theoretical aspects of drug properties, to categorize the available antiretroviral drugs for their likely contribution to viral control within the central compartments. Although the tool is the best available means of analyzing such data, it requires additional validation and likely is limited by the dearth of data regarding the effectiveness and potential toxicity of HIV drugs in the brain. Differences in the CPE ranking of treatments failed to provide an explanation for the escape of virus seen in this series, underscoring the fact that it does not provide a satisfactory understanding of this problem. Although it is critical to continue to prospectively evaluate the impact of CPE, it is clear that it is premature to make its application routine for selection of therapeutic regimens. A second and related biologic theme links immune activation in the CSF with cognitive dysfunction. Before the highly active antiretroviral therapy (HAART) era, it appeared that cognitive status was linked with the degree of immune activation in the CNS [5–7]. One of the most attractive hypotheses for understanding the high frequency of neurocognitive dysfunction, routinely seen to be 150% of treated subjects in the current era [8], links ongoing low level viral replication in the central nervous system with a smoldering and detrimental inflammatory response. Observations in the Edén et al [1] report are consistent with association of ongoing viral presence in CSF with enhanced neuroinflammation, reflected by significantly higher neopterin levels in the CSF of subjects with viral escape in this compartment. This observation reinforces the potential importance of even low viral loads on the nervous system. Perhaps the most challenging aspect of the current observations comes in the notable association of longer treatment or

Viral Escape in Cerebrospinal Fluid—An Achilles Heel of HIV Therapy?