title: Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.
abstract: 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.
authors.affiliation: Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., USA.
authors.forename: Afam
authors.initials: A
authors.lastname: Okoye
authors.forename: Martin
authors.initials: M
authors.lastname: Meier-Schellersheim
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Shoko I
authors.initials: SI
authors.lastname: Hagen
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Walker
authors.forename: Mukta
authors.initials: M
authors.lastname: Rohankhedkar
authors.forename: Richard
authors.initials: R
authors.lastname: Lum
authors.forename: John B
authors.initials: JB
authors.lastname: Edgar
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Planer
authors.forename: Alfred
authors.initials: A
authors.lastname: Legasse
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Sylwester
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Vernon C
authors.initials: VC
authors.lastname: Maino
authors.forename: Donald L
authors.initials: DL
authors.lastname: Sodora
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Michael K
authors.initials: MK
authors.lastname: Axthelm
authors.forename: Zvi
authors.initials: Z
authors.lastname: Grossman
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Picker
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002908:Chronic Disease; D003602:Cytotoxicity, Immunologic; D006706:Homeostasis; D007111:Immunity, Cellular; D007156:Immunologic Memory / Q000276:immunology*; D007700:Kinetics; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D008221:Lymphoid Tissue / Q000473:pathology / Q000821:virology; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D008297:Male; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013997:Time Factors; D019562:Viral Load