Immune and hematopoietic parameters in HIV-1-infected chimpanzees during clinical progression toward AIDS.
Until recently, chimpanzees were considered susceptible to human immunodeficiency virus type 1 (HIV-1) infection, but refractory to disease induction based on the asymptomatic status of all experimentally infected chimpanzees after over 10 years postinfection (PI). However, a decline in peripheral CD4+ T cells was noted in one chimpanzee (C499) of the Yerkes cohort of HIV-1 infected apes, after 11 years PI concurrent with increasing plasma viral load. These clinical signs were followed by the occurrence of opportunistic infections, thrombocytopenia, and progressive anemia leading to euthanasia. A second chimpanzee (C455) was transfused with blood from C499 collected during the symptomatic stage. Shortly thereafter, this second animal showed a rapid decline in peripheral CD4+ T-cell levels and sustained high viral load. Hematological analyses showed a 50% decrease in CFU-GM for both apes during the symptomatic phase and a reduction of 40% and 73% of the total CFU despite normal levels of CD34+ cells in the bone marrow. Cryopreserved sequential PBMC samples from these two chimpanzees were analyzed for constitutive and PHA-P induced levels of cytokines and chemokines. Data show that whereas there were no detectable constitutive levels of mRNA coding for IL-2, 4, and 10, there appears to be a transient increase in IFN-gamma message level coincident with increased viremia and this IFN-gamma synthesis decreased with disease progression. PHA-induced cytokine mRNA analysis showed low or undetectable levels of IL-4 and IL-10 mRNA in all samples and a marked decrease in the levels of IL-2 shortly after HIV infection. In addition, there was also a gradual decrease in IFN-gamma mRNA with progression of disease. Of interest were the findings of high to normal levels of PHA-induced synthesis of the chemokines MIP-1alpha, MIP-1beta, and RANTES in samples during the asymptomatic and early symptomatic period, which also dramatically decreased at late stages of the disease. These data suggest important roles for IL-2, IFN-gamma, and the chemokines in the regulation of immune responses in HIV-1-infected chimpanzees.
Villinger
F
F
Emory Univeristy Department of Pathology, School of Medicine, Atlanta, Georgia 30322, USA.
Brar
S S
SS
Brice
G T
GT
Chikkala
N F
NF
Novembre
F J
FJ
Mayne
A E
AE
Bucur
S
S
Hillyer
C D
CD
Ansari
A A
AA
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000503:physiopathology / Q000662:veterinary; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D018420:Ape Diseases / Q000276:immunology / Q000821:virology*; D018791:CD4 Lymphocyte Count; D018450:Disease Progression; D015497:HIV-1 / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D002679:Pan troglodytes / Q000276:immunology / Q000821:virology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics*
D018952:Antigens, CD34; D007376:Interleukin-2; D012333:RNA, Messenger; D012367:RNA, Viral; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma