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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1660-1667.
Prepublished online as a Blood First Edition Paper on May 19, 2005; DOI 10.1182/blood-2005-01-0206.
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IMMUNOBIOLOGY
Early proliferation of CCR5+ CD38+++ antigen-specific CD4+ Th1 effector cells during primary HIV-1 infection
John J. Zaunders,
Mee Ling Munier,
Daniel E. Kaufmann,
Susanna Ip,
Pat Grey,
Don Smith,
Tim Ramacciotti,
Dick Quan,
Robert Finlayson,
John Kaldor,
Eric S. Rosenberg,
Bruce D. Walker,
David A. Cooper,
Anthony D. Kelleher, on behalf of the PHAEDRA Study Team
From the Centre for Immunology, St. Vincent's Hospital, Sydney, New South Wales, Australia; Partners AIDS Research Center, Massachusetts General Hospital, Boston, MA; National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Holdsworth House General Practice, Sydney, New South Wales, Australia; and Taylor Square Private Clinic, Sydney, New South Wales, Australia.
We investigated whether HIV-1 antigen-specific CD4+ T cells expressed the viral coreceptor CCR5 during primary HIV-1 infection (PHI). In the peripheral blood of subjects with very early PHI (< 22 days after onset of symptoms), there was a 10- to 20-fold increase in the proportion of highly activated (CD38+++) and proliferating (Ki-67+) CD4+ T cells that expressed CCR5+, and were mostly T-cell intracellular antigen-1 (TIA-1)+ perforin+ granzyme B+. Inthe same patient samples, CD4+ T cells producing interferon (IFN)– in response to HIV group-specific antigen (Gag) peptides were readily detected (median, 0.58%) by intracellular cytokine assay—these cells were again predominantly CD38+++, Ki-67+, and TIA-++, as well as Bcl-2low. On average, 20% of the Gag-specific CD4+ T cells also expressed interleukin-2 (IL-2) and were CD127 (IL-7R)+. Taken together, these results suggest that Gag-specific T-helper 1 (Th1) effector cells express CCR5 during the primary response and may include precursors of long-term self-renewing memory cells. However, in PHI subjects with later presentation, antigen-specific CD4+ T cells could not be readily detected (median, 0.08%), coinciding with a 5-fold lower level of the CCR5+CD38+++ CD4+ T cells. These results suggest that the antiviral response to HIV-1 infection includes highly activated CCR5+CD4+ cytotoxic effector cells, which are susceptible to both apoptosis and cytopathic infection with HIV-1, and rapidly decline.
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