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What Can Plasma HIV Tell Us About Lymph Node HIV?
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written by Charles Boucher, M.D.
published on HIVresistanceWeb: July 24, 1998
In this study by Schapiro and colleagues of Stanford, the relationship between the development of resistance mutations and HIV RNA levels in plasma and lymph nodes was examined in patients receiving high-dose saquinavir (SQV) monotherapy. The patient population consisted of HIV-positive volunteers with CD4 counts between 200 and 500 cells/µL. Saquinavir was given in either 3600 or 7200 mg daily doses, divided over six administrations per day. Lymph node biopsies were obtained at 4-12 weeks (early) and/or weeks 24-56 (late), and sequencing of the HIV-1 protease gene was performed following PCR amplification. Changes at two positions, codons 48 and 90, were analyzed. Mutations at these positions have been reported to appear as a consequence of SQV therapy, and have been shown to confer changes in viral sensitivity to SQV.
Ten patients were included in the analysis. No changes at either codon 48 or 90 were detected in patients' plasma or lymph nodes at 4-12 weeks. Conversely, these mutations were detected in plasma HIV after 24-56 weeks of therapy in four out of five patients analyzed. In three of these four patients, identical changes were observed in lymph node samples. Lymph node virus in the fourth patient was still wild type.
Comparison of the amount of HIV RNA in both compartments showed that RNA levels were generally one thousand-fold higher (mean, 3.16 log RNA copies) in lymph nodes than in plasma. On average, approximately 10,000 and 10 million HIV RNA copies/mL were measured in plasma and lymph nodes, respectively.
This study suggests that the appearance of drug resistance mutations in plasma generally reflects the development of identical mutations in lymph nodes. These data, however, should not be interpreted to mean that in all cases analyzing the presence of mutations in plasma provides reliable information on the presence of mutations in lymph nodes. First of all, the sensitivity of the different techniques used by different laboratories to detect changes in the viral genome may differ considerably. This has been demonstrated by Schuurman and colleagues (Utrecht University, the Netherlands), who showed that even among a group of dedicated laboratories, considerable variability exists in the sensitivity of genotypic resistance testing.
Secondly, especially in patients who have been switching drugs, analysis of plasma HIV populations can be misleading. For example, in a patient whose virus develops resistance to drug A and subsequently develops resistance to drug B, the predominant viral population in his or her plasma will be the actively replicating population that is resistant to drug B. However, it is quite possible that viruses resistant to drug A are still present, as a minority population, as (latent) viruses within the lymph nodes.
Currently, it is largely unknown how long such resistant viruses can persist in cells, but we do know that it can be months and even years. In this regard, a nice follow-up to this elegant study by Schapiro et al would be to track the kinetics of HIV in the plasma and lymph nodes of patients who have been sequencing drugs. Such information could be quite useful in the clinical management of HIV infection in the future.
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