[24]PERSISTENCE OF LOW-GRADE HIV-1 REPLICATION IN RESTING MEMORY T CELLS IN PERSONS INITIATING EARLY AND AGGRESIVE ANTIRETROVIRAL THERAPY

1st International AIDS Society Conference on HIV Pathogenesis and Treatment

Buenos Aires, Argentina - July 8-11, 2001

[TITLE:] PERSISTENCE OF LOW-GRADE HIV-1 REPLICATION IN RESTING MEMORY T CELLS IN PERSONS INITIATING EARLY AND AGGRESIVE ANTIRETROVIRAL THERAPY

[AUTHOR(S):] Brodie S, Berrey M, Patterson B, Mullins J, Stevenson M, Corey L
University Of Washington, Seattle, USA

IAS Conf HIV Pathog Treat 2001 Jul 8-11;1st: Abstract No. 24

[ABSTRACT:] Background: We use well-standardized assays with single molecule sensitivity and methods for isolating extremely pure populations of activated and resting (nonactivated and nondividing) memory (CD45RO+/CD62L-) CD4+ T cells in patients undergoing combination antiretroviral therapy first administered during the acute retroviral syndrome.

Methods: We use well-standardized assays with single molecule sensitivity and methods for isolating extremely pure populations of activated and resting (nonactivated and nondividing) memory (CD45RO+/CD62L-) CD4+ T cells in patients undergoing combination antiretroviral therapy first administered during the acute retroviral syndrome.

Results: Combination antiretroviral therapy when administered during the acute retroviral syndrome rapidly lowered plasma HIV-1 RNA to levels undetectable (<50 copies/ml, weeks 9 to 15, 95% CI) and significantly reduced the number of metabolically-active CD4+ T cells expressing HIV-1 RNA ?4-fold and the mean viral copy number within these cells >2 log₁₀ (week 16, 95% CI). Still, a small population of memory CD4+ T cells (CD45RO+/CD62L-) with a quiescent phenotype (nonactivated [HLA-DR-, CD25-/38-/69-] and nonproliferating [G0]) produced viral transcripts at relatively unchanged levels during a 12 month course of therapy. These quiescent T cells also demonstrated tat fusion transcripts, 2-LTR circles, produced infectious virus, and showed time-ordered evolution of viral env sequence throughout therapy. Thus, potent antiretroviral therapy, when administered during acute infection, markedly reduced cell-associated HIV-1 gene expression, but did not fully inhibit virus replication, having its least effect on a small but remarkably uniform population of nonactivated and nondividing memory T cells.

Conclusions: The extraordinary stability of this reservoir may imply escape from immune surveillence by mechanisms other than viral mutation and gradual reseeding of the cellular pool by a very low level of ongoing viral replication. These findings have important implications for the clinical management of HIV-1-infected individuals and eradication strategies.

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