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

Abstract

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.

Early Bone Marrow Hematopoietic Defect in Simian/Human Immunodeficiency Virus C2/1-Infected Macaques and Relevance to Advance of Disease

“…Moreover, the reduction in CFU-GM resembles that of an animal model of AIDS experimentally induced by simian immunodeficiency virus (SIV) (13,30,32). While the precise mechanisms of such hematopoietic abnormalities remain unclear, several hypotheses have been proposed: (i) decreased levels of appropriate cytokines secondary to altered numbers of T-cell subsets or macrophages, which are commonly seen in HIV type 1 (HIV-1) infection (28); (ii) production of inhibitory factors (14,29); (iii) cytotoxic elimination of the precursor cells by the antibody-dependent cellmediated cytolytic mechanism (7); and (iv) infection of hematopoietic precursor cells with viruses, which leads to death of these cells or their metabolic alteration (7).…”

Kinetics of Lymphocyte Proliferation during Primary Immune Response in Macaques Infected with Pathogenic Simian Immunodeficiency Virus SIVmac251: Preliminary Report of the Effect of Early Antiviral Therapy

“…Four monkeys (group 2) received AZT (4.5 mg/kg of body weight), 3TC (2.5 mg/kg), and indinavir (20 mg/kg) twice per day by the oral route, through a nasogastric catheter, as described elsewhere (25,48). Four macaques (group 3) were given AZT (4.5 mg/kg) and 3TC (2.5 mg/kg) subcutaneously twice per day, to improve the pharmacokinetic action of these drugs (unpublished results), and a higher dose of indinavir (60 mg/kg), orally, twice per day.…”

“…Studies in macaques have confirmed that, as in humans, viral RNA levels during the first few weeks after inoculation with the virus are predictive of disease progression (27,47,59). We recently reported that a combination of zidovudine (AZT), lamivudine (3TC), and indinavir, given orally as soon as 4 h after intravenous inoculation with pathogenic SHIV89.6P and maintained for 4 weeks, did not prevent infection but significantly decreased plasma viral load and did prevent dramatic decrease of CD4 counts, even in the long term (25,48). Our results confirmed previous observations that a good clinical prognosis is correlated with low viremia or a lack of detection of virus in the peripheral blood and lymph nodes (12) after postexposure prophylaxis or early immunotherapy in infant or adult macaques (53,54).…”

Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARγ/STAT5 signaling pathway in macaques

“…SIV-infected macaques are a very good animal model to study how immunodeficiency viruses affect early hematopoiesis in vivo. SIV-infected macaques present immunodeficiency syndrome and hematological changes - including impaired clonogenic growth of CD34 + BM progenitors - that mimic those of human AIDS (21,22).…”