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¹ Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
² Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892
³ Human Immunology Section, Vaccine Research Center, Bethesda, MD 20892
⁴ AIDS Vaccine Program, Science Applications International Corporation (SAIC) Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702
⁵ Becton Dickinson Biosciences, San Jose, CA 95131
⁶ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
⁷ Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

CORRESPONDENCE Louis J. Picker: pickerl{at}ohsu.edu

Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4⁺ CCR5⁺ effector–memory T (T_EM) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4⁺ memory T cell proliferation appears to prevent collapse of effector site CD4⁺ T_EM cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4⁺ T_EM cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4⁺ T_EM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4⁺ T_EM cells from central–memory T (T_CM) cell precursors. The instability of effector site CD4⁺ T_EM cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5^– CD4⁺ T_CM cells. These data suggest that although CD4⁺ T_EM cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4⁺ T_CM cells.

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