Early and persistent bone marrow hematopoiesis defect in simian/human immunodeficiency virus-infected macaques despite efficient reduction of viremia by highly active antiretroviral therapy during primary infection.
The hematological abnormalities observed in human immunodeficiency virus (HIV)-infected patients appear to be mainly due to bone marrow dysfunction. A macaque models of AIDS could greatly facilitate an in vivo approach to the pathogenesis of such dysfunction. Here, we evaluated in this model the impact of infection with a pathogenic simian/human immunodeficiency virus (SHIV) on bone marrow hematopoiesis. Three groups of macaques were inoculated with 50 50% median infective doses of pathogenic SHIV 89.P, which expresses env of dual-tropic HIV type 1 (HIV-1) 89.6 primary isolate. During the primary phase of infection, animals were treated with either a placebo or highly active antiretroviral therapy (HAART) combining zidovudine, lamivudine, and indinavir, initiated 4 or 72 h postinfection (p.i.) and administered twice a day until day 28 p.i. In both placebo-treated and HAART-treated animals, bone marrow colony-forming cells (CFC) progressively decreased quite early, during the first month p.i. One year p.i., both placebo- and HAART-treated animals displayed decreases in CFC to about 56% of preinfection values. At the same time, a dramatic decrease (greater than 77%) of bone marrow CD34(+) long-term culture-initiating cells was noted in all animals were found. No statistically significant differences between placebo- and HAART-treated monkeys were found. These data argue for an early and profound alteration of myelopoiesis at the level of the most primitive CD34(+) progenitor cells during SHIV infection, independently of the level of viremia, circulating CD4(+) cell counts, or antiviral treatment.
Thiebot
H
H
CEA, Service de Neurovirologie, CRSSA, Ecole Pratique des Hautes Etudes, Institut Paris-Sud sur les Cytokines, 92 265 Fontenay aux Roses Cedex, France.
Louache
F
F
Vaslin
B
B
de Revel
T
T
Neildez
O
O
Larghero
J
J
Vainchenker
W
W
Dormont
D
D
Le Grand
R
R
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology*; D018791:CD4 Lymphocyte Count; D017931:DNA Primers; D015658:HIV Infections / Q000188:drug therapy / Q000503:physiopathology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D008252:Macaca fascicularis; D008297:Male; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D019562:Viral Load; D014766:Viremia
D017931:DNA Primers