The latest issue of the Journal of Experimental Medicine includes a new paper from Afam Okoye and colleagues addressing the impact of SIV infection on T cell populations in macaques. TAG covered this work in detail when it was presented (by senior author Louis Picker) at the NIAID Immune Activation Workshop last year, and a webcast of a similar presentation at CROI can be viewed online (it is the second presentation on the Monday webcast). In sum, Okoye's work suggests that SIV (and, by extension, HIV) leads to a gradual attrition of functional "central memory" CD4 T cells. These central memory CD4 T cells normally circulate through the lymphatic system and are able to generate short-lived "effector memory" CD4 T cells which traffic to body tissues and mediate immune surveillance against potentially harmful pathogens. The gradual compromise of the central memory CD4 T cell population in SIV eventually staunches the supply of effector memory CD4 T cells to tissues and - as Picker's research group has shown in previously published work - this correlates with the development of opportunistic diseases (simian AIDS).
Hema Bashyam also writes a short commentary about the study, Precursor Loss Triggers AIDS, which is free to access.
Published online 27 August 2007
doi:10.1084/jem.20070567
The Journal of Experimental Medicine, Vol. 204, No. 9, 2171-2185
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
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4+ CCR5+ effector–memory T (TEM) 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+ TEM 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+ TEM 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+ TEM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4+ TEM cells from central–memory T (TCM) cell precursors. The instability of effector site CD4+ TEM 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+ TCM cells. These data suggest that although CD4+ TEM 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+ TCM cells.
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