Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.
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.
Okoye
Afam
A
Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., USA.
Meier-Schellersheim
Martin
M
Brenchley
Jason M
JM
Hagen
Shoko I
SI
Walker
Joshua M
JM
Rohankhedkar
Mukta
M
Lum
Richard
R
Edgar
John B
JB
Planer
Shannon L
SL
Legasse
Alfred
A
Sylwester
Andrew W
AW
Piatak
Michael
M
Lifson
Jeffrey D
JD
Maino
Vernon C
VC
Sodora
Donald L
DL
Douek
Daniel C
DC
Axthelm
Michael K
MK
Grossman
Zvi
Z
Picker
Louis J
LJ
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