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Blood, 15 January 2002, Vol. 99, No. 2, pp. 590-599
IMMUNOBIOLOGY
Adoptive transfer of simian immunodeficiency virus (SIV)
naïve autologous CD4+ cells to macaques chronically
infected with SIV is sufficient to induce long-term
nonprogressor status
Francois Villinger,
Gary T. Brice,
Ann E. Mayne,
Pavel Bostik,
Kazuyasu Mori,
Carl H. June, and
Aftab A. Ansari
From the Department of Pathology and Laboratory
Medicine, Emory University School of Medicine, Atlanta, GA; the Naval
Medical Research Institute, NMRC, Silver Spring, MD; the AIDS Research
Center, Tsukuba Primate Center for Medical Sciences, National Institute
of Infectious Diseases, Tsukuba, Japan; and the Abramson Family Cancer
Research Institute, University of Pennsylvania, Philadelphia.
Adoptive transfer of autologous preinfection-collected peripheral
blood mononuclear cells (PBMCs) or activated CD4+ T cells
was performed in simian immunodeficiency virus (SIVmac239)-infected monkeys following short-term antiviral therapy with PMPA
(9-R-[2-phosphonylmethoxypropyl] adenine). Short-term chemotherapy
alone led to a transient decrease in plasma and cellular proviral DNA
loads and transient rescue of gag/pol and env cytotoxic T-lymphocyte
precursors (pCTLs). However, cessation of therapy allowed for
SIV infection to resume its clinical course. PMPA chemotherapy coupled
with infusions of either autologous pre-SIV infection-collected PBMCs
or activated CD4+ T cells led to extended control of plasma
and cellular proviral DNA loads after infusion, in spite of the fact
that the transfused cells were not primed against SIV. However,
qualitatively different antiviral defenses were induced by infusion of
unfractionated and unmanipulated PBMCs versus purified and activated
CD4+ T cells: PBMC infusions significantly favored
development of SIVenv-specific pCTLs, neutralizing antibodies, and
secretion of soluble noncytotoxic suppressor factors of SIV
replication. In contrast, activated CD4+ T cells
predominantly promoted CTL responses to SIVgag/pol and SIVenv. In
addition, infusion of influenza-primed activated CD4+ T
cells markedly enhanced influenza-specific pCTL responses, whereas
infusion of similarly influenza-primed unfractionated PBMCs enhanced
such pCTL responses only modestly, suggesting that the predominant
immune defect after SIV infection lies in the T helper cell compartment
rather than the effector cell compartment. Thus, adoptive immunotherapy
with autologous "SIV naïve" CD4+ lymphocytes
was sufficient to rescue cell-mediated immune responses and induce
long-term anti-SIV control and immune responses in the
absence of continued antiviral chemotherapy.
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