The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/5/1545/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 10, May 17, 1999 1545-1554

Articles

Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA

Richard D. Hockett*, J. Michael Kilby{ddagger}, Cynthia A. Derdeyn*, Michael S. Saag{ddagger}, Michael Sillers§, Kathleen Squires{ddagger}, Scott Chiz*, Martin A. Nowak, George M. Shaw{ddagger},||, and R. Pat Bucy*,{ddagger}

From the * Department of Pathology, the {ddagger} Department of Medicine, the § Department of Surgery, and the || Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, Alabama 35233-7331; and the Institute for Advanced Study, Princeton, New Jersey 08540

Quantitative analysis of the relationship between virus expression and disease outcome has been critical for understanding HIV-1 pathogenesis. Yet the amount of viral RNA contained within an HIV-expressing cell and the relationship between the number of virus-producing cells and plasma virus load has not been established or reflected in models of viral dynamics. We report here a novel strategy for the coordinated analysis of virus expression in lymph node specimens. The results obtained for patients with a broad range of plasma viral loads before and after antiretroviral therapy reveal a constant mean viral (v)RNA copy number (3.6 log10 copies) per infected cell, regardless of plasma virus load or treatment status. In addition, there was a significant but nonlinear direct correlation between the frequency of vRNA+ lymph node cells and plasma vRNA. As predicted from this relationship, residual cells expressing this same mean copy number are detectable (frequency <2/106 cells) in tissues of treated patients who have plasma vRNA levels below the current detectable threshold (<50 copies/ml). These data suggest that fully replication-active cells are responsible for sustaining viremia after initiation of potent antiretroviral therapy and that plasma virus titers correlate, albeit in a nonlinear fashion, with the number of virus-expressing cells in lymphoid tissue.

Key Words: HIV-1 infection • quantitative RT-PCR • lymph node biopsy • in situ hybridization • HIV pathogenesis

Address correspondence to R. Pat Bucy, Rm. W287 Spain-Wallace Bldg., Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233-7331. Phone: 205-934-6246; Fax: 205-975-7074; E-mail: Bucy{at}uab.edu

This work was partially supported by Chiron Corp. and the Adult AIDS Clinical Trials Group.

Abbreviations used: FDC, follicular dendritic cell; HAART, highly active antiretroviral therapy; ISH, in situ hybridization; LDA, limiting dilution analysis; QC-RT-PCR, quantitative, competitive RT-PCR; UTP, uridine 5'-triphosphate; vRNA, viral RNA.


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