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.

Longitudinal analysis of CD8(+) T-cell phenotype and IL-7, IL-15 and IL-16 mRNA expression in different tissues during primary simian immunodeficiency virus infection.

Infection of macaques with pathogenic isolates of simian immunodeficiency virus (SIV) represents a useful model of HIV infection that offers the unique opportunity to investigate the very early modifications that affect CD8(+) T-lymphocyte subsets and related cytokines during lentiviral infection. Herein, three cynomolgus macaques were inoculated intravenously with a pathogenic isolate of SIVmac 251. In fresh isolated mononuclear cells from blood, lymph node and bronchoalveolar lavage, we analyzed changes in the phenotype of CD8(+) T cells and we used reverse transcription-PCR to monitor the expression of IL-7, IL-15 and IL-16 mRNA. We demonstrated that an expansion of CD8(+)CD28(-) T cells occurs from the third week of infection on in the peripheral blood and in the lung, whereas CD8(+)CD28(+) T cells expand in the lymph nodes. Concomitantly, we evidenced mRNA modulations in IL-16, IL-15 and IL-7 expression in the three compartments studied. The containment of systemic viral replication was associated with an overexpression of IL-16 mRNA in the lung and in the peripheral blood. Given the immunomodulatory properties of IL-15 and IL-7 and the potential antiviral ability of IL-16, these perturbations could have important implications in early viral dissemination and HIV immunopathogenesis.

[Evaluation of the effect of early and massive tritherapy on the expression of cellular factors potentially implicated in antiretroviral therapy resistance]. / Evaluation de l'effet d'une trithérapie précoce et massive sur l'expression des facteurs cellulaires potentiellement impliqués dans l'échappement à la thérapeutique antirétrovirale.

Treatment of the human immunodeficiency virus (HIV) is restricted by therapeutic escape. The biological mechanisms of this chemoresistance rely notably on the modulation of cell kinase and P-glycoprotein (P-gp) expression. In this study, we investigated, in cynomolgus macaques, the roles of SHIV89.6P infection and of HAART in the mRNA expression of these cell factors. SHIV infection, or associated pathophysiological disorders, increase both thymidine kinase and thymidylate kinase mRNA expression and decrease those of P-gp. On the other hand, the expression of other cell kinases is not modulated. In parallel, HAART accentuates the decrease of P-gp expression and attenuates the increase of kinase expression. On the whole, such metabolic disorders, evidenced herein an animal model of HIV infection, could be involved in HIV-infected patients.

[Regulation of muscarinic potassium channels]. / Régulation des canaux potassiques muscariniques.

Inwardly rectifying muscarinic potassium channels are directly activated by M2 muscarinic receptors in heart via a Pertussis toxin-sensitive G-protein. An intracellular second messenger is not involved in their activation. These channels undergo rapid (in about 30 seconds) and short-term desensitization. This desensitization is reversible in about 5 minutes. The molecular events underlying muscarinic potassium channels desensitization are still under study and apparently involve a phosphorylation/dephosphorylation process of one the proteins, i.e. the receptor, the G-protein or the channel itself.