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Transient rebound of plasma HIV-1 RNA is not followed by repopulation of the lymphoid compartment with HIV-1-infected cells

Joos, Bedaa; Fischer, Mareka; Opravil, Milosa; Ott, Peterb; Weber, Rainera; Cone, Richard W.a

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aDivision of Infectious Diseases, Department of Internal Medicine and bDepartment of Otorhinolaryngology, University Hospital Zurich, Switzerland.

Sponsorship: This study was financially supported by the Swiss Federal Office of Public Health (grant nos. 3246016.95 and 3600.010.1), the Swiss HIV Cohort Study (project no. 144), Glaxo Wellcome and Abbott Laboratories.

Received: 28 September 1999; accepted: 22 December 1999.

Potent antiretroviral therapy can reduce HIV RNA in the plasma of HIV-infected patients to levels below the limit of detection of the most sensitive assays. However, recent evidence suggests that low-level viral replication may persist and thus present a barrier to the eradication of HIV (see Ref. [1] for a recent overview). Escapes from effective antiretroviral therapy present a potential threat to patients because they risk a rebound of plasma HIV RNA, which is thought to result in repopulation of the lymphoid tissue reservoir with HIV. We studied this concept by measuring viral nucleic acids in lymphoid tissue during continuously successful and intermittently successful therapy in HIV-1-infected, asymptomatic patients.

A prospective study was started to compare double therapy comprising two reverse transcriptase inhibitors with a triple therapy regimen consisting of two reverse transcriptase inhibitors and a protease inhibitor in asymptomatic, therapy-naive patients with CD4 cell counts greater than 400 cells/μl [2,3]. Because of inadequate virological response during the first months in the double treatment group, therapy was changed to a three-drug combination in some patients. Blood samples were obtained at weeks −4, 0, 2, 4, and then every 4 weeks after the start of treatment. Tonsil biopsy specimens were obtained at weeks 0, 4, 24, and 48.

For the present analysis, we stratified patients in the study who had regular tonsil biopsies to three groups using the following criteria: (i) (n = 8) immediate and sustained virus suppression defined as a decrease to less than 250 plasma RNA copies/ml after week 8 and less than 20 copies/ml after week 24; (ii) (n = 6) delayed virus suppression to less than 100 copies/ml at week 48 after an initial 1–3 log decrease and subsequent rebound to over 1000 copies/ml at weeks 12 and 24; (iii) (n = 3) virological failure with or without initial response, and plasma RNA of over 500 copies/ml at weeks 36 and 48.

All patients (four women, 13 men, average age at entry 34.5 years) had been followed for more than one year. The average CD4 cell count was 492 ± 39 cells/μl at baseline and 656 ± 71 cells/μl at week 48 (P  = 0.05).

HIV-1 DNA was determined by a modification of the previously described quantitative competitive polymerase chain reaction method [4], which was adjusted for improved sensitivity (measurement range 1–100 HIV copies per reaction, detection limit ≤ 15 HIV copies per 106 cells, coefficient of variation < 24% at 30, 10, and three copies per reaction). HIV-1 RNA was quantified using the Amplicor HIV-1 Monitor test (Roche Diagnostic Systems, Basel, Switzerland) and with an ultrasensitive modification thereof [5] [detection limits ≤ 20 copies/ml plasma, ≤ 6 and ≤ 12 copies/μg RNA for peripheral blood mononuclear cells (PBMC) and tissue specimens, respectively].

Plasma HIV-1 RNA was 39 400 ± 10 260 copies/ml before therapy and declined rapidly after 4 weeks. Patients in group 1 had average plasma virus loads below 50 copies/ml from weeks 12 to 48. Patients in group 2 had a 1.8 log (range 0.9–2.8) decrease in plasma virus by week 4, followed by a 0.8 log (range 0.2–2.1) increase to 8.4 × 103 copies/ml (range 1.1 × 103 to 2.7 × 104) by weeks 12–24. These patients were switched to more potent triple therapies, resulting in a plasma virus load of 36 copies/ml (range < 6–90) by week 48 (Fig. 1a). Sharp decreases occurred in lymphoid tissue DNA from groups 1 and 2 by week 4 (average change −72%), followed by a slow decline (half-life 38.7 weeks) or a plateau (Fig. 1b). No significant difference in HIV-1 DNA levels was found between the two groups. DNA levels in the PBMC exhibited a less pronounced initial decrease (−35%) and a similar average elimination half-life (32.1 weeks) in these 14 patients. At week 48 the HIV-1-DNA concentrations in the tissue and PBMC compartments were approximately equal. HIV-1-RNA levels in lymphoid tissue and in PBMC tended to follow the changes in the plasma virus load.

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In contrast, virological failure was observed in the three patients from group 3. Two of them had initial decreases in plasma virus by 2.0 and 3.1 log, but rebounded thereafter, reaching almost pre-treatment levels by week 48. Their HIV-1 DNA and also the cell-associated RNA had returned to pretreatment levels by week 48.

In this study, renewed, short-term low-level viral replication did not appear to increase the number of HIV-1-infected cells in the lymphoid reservoir appreciably as long as effective therapy was reinstated within approximately 12 weeks. Therapeutic failure persisting for over 24 weeks, however, eventually leading to a repopulation of the lymphoid tissue. This suggests that in patients on potent antiretroviral therapy, temporary escapes from complete virus suppression may not hamper the virological response in the lymphoid tissue.

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Acknowledgements

The authors would like to thank Huldrych Günthard for helpful cooperation and discussions, Friederike Burgener, Erika Schläpfer, Bärbel Sauer and Herbert Kuster for technical assistance and Christina Grube for clinical assistance.

Beda Joosa

Marek Fischera

Milos Opravila

Peter Ottb

Rainer Webera

Richard W. Conea

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References

1. Siliciano RF. Latency and reservoirs for HIV-1. AIDS 1999, 13 (Suppl. A) : S49–S58.

2. Bisset LR, Cone RW, Huber W. et al. Highly active antiretroviral therapy during early HIV infection reverses T-cell activation and maturation abnormalities. Swiss HIV Cohort Study. AIDS 1998, 12: 2115–2123.

3. Opravil M, Cone RW, Fischer M, et al. Effects of early antiretroviral treatment on HIV-1 RNA in blood and lymphoid tissue: a randomized trial of double versus triple therapy. J AIDS Hum Retrovirol 2000, in press.

4. Cone RW, Gowland P, Opravil M, Grob P, Ledergerber B. Levels of HIV-infected peripheral blood cells remain stable throughout the natural history of HIV-1 infection. Swiss HIV Cohort Study. AIDS 1998, 12: 2253–2260.

5. Fischer M, Huber W, Kallivroussis A. et al. Highly sensitive methods for quantitation of human immunodeficiency virus type 1 RNA from plasma, cells, and tissues. J Clin Microbiol 1999, 37: 1260–1264.

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© 2000 Lippincott Williams & Wilkins, Inc.

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