Progressive CD4+ central-memory T cell decline results in CD4+ effector-memory insufficiency and overt disease in chronic SIV infection

doi:10.1084/jem.20070567

A correction to this article has been published: Okoye et al., J. Exp. Med. 204 (10) 2493
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doi:10.1084/jem.20070567
The Journal of Experimental Medicine, Vol. 204, No. 9, 2171-2185
The Rockefeller University Press, 0022-1007 $30.00
© Okoye et al.

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Article

Progressive CD4⁺ central–memory T cell decline results in CD4⁺ effector–memory insufficiency and overt disease in chronic SIV infection

Afam Okoye¹, Martin Meier-Schellersheim², Jason M. Brenchley³, Shoko I. Hagen¹, Joshua M. Walker¹, Mukta Rohankhedkar¹, Richard Lum¹, John B. Edgar¹, Shannon L. Planer¹, Alfred Legasse¹, Andrew W. Sylwester¹, Michael Piatak, Jr.⁴, Jeffrey D. Lifson⁴, Vernon C. Maino⁵, Donald L. Sodora⁶, Daniel C. Douek³, Michael K. Axthelm¹, Zvi Grossman²^,7, and Louis J. Picker¹

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 rhesusmacaques result in the dramatic depletion of CD4⁺ CCR5⁺ effector–memoryT (T_EM) cells from extra-lymphoid effector sites, but in mostinfections, an increased rate of CD4⁺ memory T cell proliferationappears to prevent collapse of effector site CD4⁺ T_EM cell populationsand acute-phase AIDS. Eventually, persistent SIV replicationresults in chronic-phase AIDS, but the responsible mechanismsremain controversial. Here, we demonstrate that in the chronicphase of progressive SIV infection, effector site CD4⁺ T_EM cellpopulations manifest a slow, continuous decline, and that thedegree of this depletion remains a highly significant correlateof late-onset AIDS. We further show that due to persistent immuneactivation, effector site CD4⁺ T_EM cells are predominantly short-lived,and that their homeostasis is strikingly dependent on the productionof new CD4⁺ T_EM cells from central–memory T (T_CM) cellprecursors. The instability of effector site CD4⁺ T_EM cell populationsover time was not explained by increasing destruction of thesecells, but rather was attributable to progressive reductionin their production, secondary to decreasing numbers of CCR5^–CD4⁺ T_CM cells. These data suggest that although CD4⁺ T_EM celldepletion is a proximate mechanism of immunodeficiency, thetempo of this depletion and the timing of disease onset arelargely determined by destruction, failing production, and gradualdecline of CD4⁺ T_CM cells.

Abbreviations used: ART, antiretroviral therapy; BAL, bronchoalveolarlavage; PID, postinfection day; PLN, peripheral LN; pvl, plasmaviral load; RM, rhesus macaque; SHIV, simian immunodeficiencyvirus/HIV hybrid virus; SIV, simian immunodeficiency virus;T_CM, central–memory T; T_EM, effector–memory T.

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