Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis.
Depletion of CD8(+) lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8(+) lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8(+) lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4(+) effector memory T (T(EM)) cells and, to a lesser extent, transitional memory T (T(TrM)) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4(+)/CCR5(+) SIV "target" cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8(+) lymphocytes in SIV(-) RMs led to a sustained increase in the number of potential CD4(+) SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4(+) T(EM) cell proliferation of CD8(+) lymphocyte-depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4(+) T(EM) and T(TrM) cell proliferation, it did not recapitulate the viral dynamics of CD8(+) lymphocyte depletion. These data suggest that CD8(+) lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.
Okoye
Afam
A
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.
Park
Haesun
H
Rohankhedkar
Mukta
M
Coyne-Johnson
Lia
L
Lum
Richard
R
Walker
Joshua M
JM
Planer
Shannon L
SL
Legasse
Alfred W
AW
Sylwester
Andrew W
AW
Piatak
Michael
M
Lifson
Jeffrey D
JD
Sodora
Donald L
DL
Villinger
Francois
F
Axthelm
Michael K
MK
Schmitz
Joern E
JE
Picker
Louis J
LJ
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D049109:Cell Proliferation; D007156:Immunologic Memory / Q000276:immunology; D019409:Interleukin-15 / Q000097:blood / Q000235:genetics / Q000276:immunology; D008212:Lymphocyte Depletion; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D008297:Male; D019713:Receptors, CCR5 / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000472:pathogenicity; D015996:Survival Rate; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D014779:Virus Replication
D000914:Antibodies, Viral; D019409:Interleukin-15; D019713:Receptors, CCR5; D011994:Recombinant Proteins