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Journal of Virology, October 2002, p. 10099-10108, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10099-10108.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Quantitation of Human Immunodeficiency Virus Type 1 DNA Forms with the Second Template Switch in Peripheral Blood Cells Predicts Disease Progression Independently of Plasma RNA Load

Leondios G. Kostrikis,1* Giota Touloumi,1 Rose Karanicolas,2 Nikos Pantazis,1 Cleo Anastassopoulou,1 Anastasia Karafoulidou,3 James J. Goedert,4 Angelos Hatzakis,1 and for the Multicenter Hemophilia Cohort Study Group{dagger}

Department of Hygiene and Epidemiology, Athens University Medical School,1 Hemophilia Center, Laikon Hospital, Athens, Greece,3 College of Physicians and Surgeons, Columbia University, New York, New York,2 Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland4

Received 8 March 2002/ Accepted 1 July 2002

There are several forms of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 732] copies per 106 PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4+ T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval {CI}, 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 106 PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virological response to combination antiretroviral therapy.

* Corresponding author. Mailing address: Athens University Medical School, Department of Hygiene and Epidemiology, 75 Mikras Asias, 11527 Athens, Greece. Phone: 30-1-748-6382. Fax: 30-1-748-6382. E-mail: lkostrik{at}med.uoa.gr.

{dagger} Collaborating investigators in the Multicenter Hemophilia Cohort Study Group were: J. J. Goedert, T. R. O'Brien, P. S. Rosenberg, C. S. Rabkin, E. A. Engels, M. H. Gail, S. J. O'Brien, M. Dean, M. Carrington, M. Smith, and C. Winkler (National Cancer Institute, Rockville and Frederick, Md.); B. Konkle (Cardeza Foundation Hemophilia Center, Philadelphia, Pa.); M. Manco-Johnson (Mountain States Regional Hemophilia and Thrombosis Program, University of Colorado, Aurora, Colo.); D. DiMichele and M. W. Hilgartner (Hemophilia Treatment Center, New York Presbyterian Hospital, New York, N.Y.); Philip Blatt (Christiana Hospital, Newark, Del.); L. M. Aledort and S. Seremetes (Hemophilia Center, Mount Sinai Medical Center, New York, N.Y.); K. Hoots (Gulf States Hemophilia Center, University of Texas at Houston, Houston, Tex.); A. L. Angiolillo and N. L. C. Luban (Hemophilia Center, Children's Hospital National Medical Center, Washington, D.C.); A. Cohen and C. S. Manno (Hemophilia Center, Children's Hospital of Philadelphia, Philadelphia, Pa.); C. Leissinger (Tulane University Medical School, New Orleans, La.); G. C. White II (Comprehensive Hemophilia Center, University of North Carolina, Chapel Hill, N.C.); M. M. Lederman, S. Purvis, and J. Salkowitz (Case Western Reserve University School of Medicine, Cleveland, Ohio); C. M. Kessler (Georgetown Univeristy Medical Center, Washington, D.C.); A. Karafoulidou and T. Mandalaki (Hemophilia Center, Second Regional Blood Transfusion Center, Laikon General Hospital, Athens, Greece); A. Hatzakis and G. Touloumi (National Retrovirus Reference Center, Athens University Medical School, Athens, Greece); W. Schramm and F. Rommel (Medizinische Klinik Innerstadt der Maximilian, Universitaet Muenchen, Munich, Germany); P. de Moerloose (Haemostasis Unit, Hôpital Cantonal Universitaire, Geneva, Switzerland); S. Eichinger (University of Vienna Medical School, Vienna, Austria); K. E. Sherman (University of Cincinnati Medical Center, Cincinnati, Ohio); D. Waters (Scientific Applications International Corporation, Frederick, Md.); and V. Lamprecht and B. L. Kroner (Research Triangle Institute, Rockville, Md.).

Journal of Virology, October 2002, p. 10099-10108, Vol. 76, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.20.10099-10108.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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