title: Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection.
abstract: The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n=14) or CXCR4-tropic SIVmac155T3 (n=4), 4 of the former group manifested end-stage SIV disease by 200 d after infection. In SIVmac155T3 infections, naive CD4+ T cells were dramatically depleted, but this population was spared by SIVmac239, even in rapid progressors. In contrast, all SIVmac239-infected RMs demonstrated substantial systemic depletion of CD4+ memory T cells by day 28 after infection. Surprisingly, the extent of CD4+ memory T cell depletion was not, by itself, a strong predictor of rapid progression. However, in all RMs destined for stable infection, this depletion was countered by a striking increase in production of short-lived CD4+ memory T cells, many of which rapidly migrated to tissue. In all rapid progressors (P <0.0001), production of these cells initiated but failed by day 42 of infection, and tissue delivery of new CD4+ memory T cells ceased. Thus, although profound depletion of tissue CD4+ memory T cells appeared to be a prerequisite for early pathogenesis, it was the inability to respond to this depletion with sustained production of tissue-homing CD4+ memory T cells that best distinguished rapid progressors, suggesting that mechanisms of the CD4+ memory T cell generation play a crucial role in maintaining immune homeostasis in stable SIV infection.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, West Campus, 505 NW 185th Ave., Beaverton, OR 97006, USA. pickerl@ohsu.edu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Picker
authors.forename: Shoko I
authors.initials: SI
authors.lastname: Hagen
authors.forename: Richard
authors.initials: R
authors.lastname: Lum
authors.forename: Edward F
authors.initials: EF
authors.lastname: Reed-Inderbitzin
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Daly
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Sylwester
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Walker
authors.forename: Don C
authors.initials: DC
authors.lastname: Siess
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.forename: Chenxi
authors.initials: C
authors.lastname: Wang
authors.forename: David B
authors.initials: DB
authors.lastname: Allison
authors.forename: Vernon C
authors.initials: VC
authors.lastname: Maino
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kodama
authors.forename: Michael K
authors.initials: MK
authors.lastname: Axthelm
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007156:Immunologic Memory; D008253:Macaca mulatta; D008297:Male; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000503:physiopathology*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*; D013045:Species Specificity
chemical_list: D001973:Bromodeoxyuridine