Measuring the “viral load” in cerebrospinal fluid in human immunodeficiency virus infection: Window into brain infection?

The past two years have witnessed important progress in both the conceptualization and the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This progress has been facilitated by two technological advances working in tandem, (1) the introduction of potent antiretroviral drugs and drug combinations, and (2) development of sensitive, quantitative assays of HIV-1 RNA concentrations in blood. Two articles in this issue of Annals describe extension of the latter quantitative assays to cerebrospinal fluid (CSF) [ 1, 21. Before commenting on these useful and complimentary contributions, it is worthwhile to consider some of the context and background related to systemic HIV-1 infection that led up to them. By using the new drugs, particularly the class of viral protease inhibitors, as experimental “probes” to rapidly interrupt the production of new viral particles and the new assays to accurately measure the resultant decrement in plasma virus, it has been possible to construct models and derive half-life estimates of the rapid turnover of virus and virus-infected T lymphocytes (approximately 6 hours and 1.5 days, respectively) [3, 41. These observations, in concert with studies combining use of the polymerase chain reaction (PCR) nucleic acid amplification and in situ hybridization to sensitively detect viral nucleic acid in lymphoid tissue sections [5, 61, have provided a quantitative view of the extraordinary dynamism of HIV-1 infection, not only during its late, acquired immunodeficiency syndrome (AIDS), phase but also earlier when HIV-1 infection is clinically silent and had formerly been considered to be virologically “latent. ” More practically, these developments have also provided benefit to infected patients. Each of three major classes of antiretroviral drugs are now represented by two or more Food and Drug Administration (FDA)licensed drugs, with still more in the developmental pipeline [7]. These include the nucleosides that inhibit the viral reverse transcriptase (RT) enzyme that catalyzes the essential step of converting viral RNA to a DNA template, the nonnucleoside RT inhibitors that inhibit the same enzyme at different sites, and the aforementioned protease inhibitors that interfere with the processing of viral peptides and production of new infectious particles. Although HIV-1 with its high mutation rate can develop resistance to all of these drugs, their use in combination can powerfully reduce the level of HIV-1 replication and also prevent or delay this resistance [8]. The extent of this reduction is such that investigators are now contemplating the future prospect of very long-term suppression and even eradication of the AIDS virus [9]. Although certainly not successful in all patients, these drugs can partially restore CD4+ cell counts, reduce the incidence of opportunistic complications, and prolong life [ 101. Measurement of the HIV-1 RNA concentration in plasma, commonly called the “viral load,” is now firmly entrenched in the vocabulary of those infected and an accepted tool in their management. Before this technology became available, progression of HIV1 infection was monitored chiefly by the blood CD4+ Tlymphocyte count, which was used to categorize the risk of major opportunistic infections and to formally define AIDS [ 1 11. Measurement of the viral load has been found to serve as an independent and, indeed, even more powerful prognostic indicator [12]. To emphasize the complementary utility of these two markers, Coffin [ 131 has offered the analogy of HIV-1 infection as a train traveling toward its destination (severe immunodeficiency and death) in which the viral load serves as a measure of velocity (how fast the patient is progressing toward the terminus) and the CD4+ count as the distance traveled in that direction (how close to death). AIDS clinicians now “treat” the viral load, initiating and changing combination therapies in efforts to reduce the concentration of viral RNA in plasma to below the level of detection, to minimize the rate of disease progression and perhaps even to partially reverse its course [ 141. The use of the viral load as a surrogate end point in clinical trials has also accelerated the testing and licensure of new antiretroviral drugs. It is in the context of this exploitation of plasma viral load measurement to both address fundamental research questions and manage therapy of systemic infection that the two articles in this issue can be seen as extending this same technology to central nervous system (CNS) HIV-1 infection and resultant disease. There are two compelling reasons for heightened interest in CNS HIV-1 infection. First, with the prospect of long-term suppression or eradication of HIV-1, new attention is being directed to “sequestered compart-