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Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy.
N Engl J Med 1999; 340(21):1614-22NEJM

Abstract

BACKGROUND AND METHODS

Although potent antiretroviral therapy can control infection with human immunodeficiency virus type 1 (HIV-1), a long-lived reservoir of infectious virus persists in CD4+ T cells. We investigated this viral reservoir by measuring the levels of cell-associated viral DNA and messenger RNA (mRNA) that are essential for HIV-1 replication. Approximately every 6 months, we obtained samples of peripheral-blood mononuclear cells from five men with long-standing HIV-1 infection who had had undetectable levels of plasma HIV-1 RNA for 20 months or more during treatment with potent antiretroviral drugs.

RESULTS

Before treatment, plasma levels of HIV-1 RNA correlated with the levels of cell-associated unintegrated HIV-1 DNA and unspliced viral mRNA. After treatment, plasma levels of HIV-1 RNA fell by more than 2.7 log to undetectable levels. The decrease in cell-associated integrated and unintegrated HIV-1 DNA and mRNA occurred in two phases. The first phase occurred during the initial 500 days of treatment and was characterized by substantial decreases in the levels of DNA and mRNA, but not to undetectable levels. The concentrations of cell-associated unintegrated viral DNA, integrated proviral DNA, and unspliced viral mRNA decreased by 1.25 to 1.46 log. The second phase occurred during the subsequent 300 days or more of treatment and was characterized by a plateau in the levels of HIV-1 DNA and unspliced mRNA. After an initial rapid decline, the ratio of unspliced to multiply spliced viral mRNA (a measure of active viral transcription) stabilized and remained greater than zero at each measurement.

CONCLUSIONS

Despite treatment with potent antiretroviral drugs and the suppression of plasma HIV-1 RNA to undetectable levels for 20 months or more, HIV-1 transcription persists in peripheral-blood mononuclear cells. Unless the quasi-steady state levels of HIV DNA and mRNA eventually disappear with longer periods of therapy, these findings suggest that HIV-1 infection cannot be eradicated with current treatments.

Authors+Show Affiliations

Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10341273

Citation

Furtado, M R., et al. "Persistence of HIV-1 Transcription in Peripheral-blood Mononuclear Cells in Patients Receiving Potent Antiretroviral Therapy." The New England Journal of Medicine, vol. 340, no. 21, 1999, pp. 1614-22.
Furtado MR, Callaway DS, Phair JP, et al. Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med. 1999;340(21):1614-22.
Furtado, M. R., Callaway, D. S., Phair, J. P., Kunstman, K. J., Stanton, J. L., Macken, C. A., ... Wolinsky, S. M. (1999). Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. The New England Journal of Medicine, 340(21), pp. 1614-22.
Furtado MR, et al. Persistence of HIV-1 Transcription in Peripheral-blood Mononuclear Cells in Patients Receiving Potent Antiretroviral Therapy. N Engl J Med. 1999 May 27;340(21):1614-22. PubMed PMID: 10341273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. AU - Furtado,M R, AU - Callaway,D S, AU - Phair,J P, AU - Kunstman,K J, AU - Stanton,J L, AU - Macken,C A, AU - Perelson,A S, AU - Wolinsky,S M, PY - 1999/5/26/pubmed PY - 1999/5/26/medline PY - 1999/5/26/entrez SP - 1614 EP - 22 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 340 IS - 21 N2 - BACKGROUND AND METHODS: Although potent antiretroviral therapy can control infection with human immunodeficiency virus type 1 (HIV-1), a long-lived reservoir of infectious virus persists in CD4+ T cells. We investigated this viral reservoir by measuring the levels of cell-associated viral DNA and messenger RNA (mRNA) that are essential for HIV-1 replication. Approximately every 6 months, we obtained samples of peripheral-blood mononuclear cells from five men with long-standing HIV-1 infection who had had undetectable levels of plasma HIV-1 RNA for 20 months or more during treatment with potent antiretroviral drugs. RESULTS: Before treatment, plasma levels of HIV-1 RNA correlated with the levels of cell-associated unintegrated HIV-1 DNA and unspliced viral mRNA. After treatment, plasma levels of HIV-1 RNA fell by more than 2.7 log to undetectable levels. The decrease in cell-associated integrated and unintegrated HIV-1 DNA and mRNA occurred in two phases. The first phase occurred during the initial 500 days of treatment and was characterized by substantial decreases in the levels of DNA and mRNA, but not to undetectable levels. The concentrations of cell-associated unintegrated viral DNA, integrated proviral DNA, and unspliced viral mRNA decreased by 1.25 to 1.46 log. The second phase occurred during the subsequent 300 days or more of treatment and was characterized by a plateau in the levels of HIV-1 DNA and unspliced mRNA. After an initial rapid decline, the ratio of unspliced to multiply spliced viral mRNA (a measure of active viral transcription) stabilized and remained greater than zero at each measurement. CONCLUSIONS: Despite treatment with potent antiretroviral drugs and the suppression of plasma HIV-1 RNA to undetectable levels for 20 months or more, HIV-1 transcription persists in peripheral-blood mononuclear cells. Unless the quasi-steady state levels of HIV DNA and mRNA eventually disappear with longer periods of therapy, these findings suggest that HIV-1 infection cannot be eradicated with current treatments. SN - 0028-4793 UR - https://www.unboundmedicine.com/medline/citation/10341273/Persistence_of_HIV_1_transcription_in_peripheral_blood_mononuclear_cells_in_patients_receiving_potent_antiretroviral_therapy_ L2 - http://www.nejm.org/doi/full/10.1056/NEJM199905273402102?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -