CD34⁺ and CFU‐GM progenitors are significantly decreased in sivsmm9 infected rhesus macaques with minimal evidence of direct viral infection by polymerase chain reaction

Abstract

Hematologic abnormalities in the peripheral blood and bone marrow are associated with human immunodeficiency and simian immunodeficiency virus (HIV, SIV) infection. The reasons for these abnormalities remain unclear. Bone marrow specimens collected from uninfected animals (Group A, Controls) and from rhesus macaques experimentally infected with SIVsmm9 during the asymptomatic stage (Group B, SIV+ "well") and during the clinically ill stage (Group C, SIV+ "sick"), underwent a variety of in vitro assays of hematopoiesis. Colony forming unit-granulocyte/macrophage (CFU-GM) per plate growth was 46.7 +/- 7.7, 31.9 +/- 8.4 and 6.5 +/- 5.0 (mean +/- sd, P < .02 each mean compared to the others) in the 3 groups respectively. Burst forming unit-erythroid (BFU-E) growth was similarly decreased in bone marrow samples from the SIV+ animals. There was no change in the number of CFU-GM per plate with the removal of plastic adherent or T-cell mononuclear cell fractions. There was no increase in CFU-GM per plate growth with the addition of low dose GM-CSF (1 or 5 ng/mL) though there was a near 67% increase (48 to 80 CFU-GM per plate) with the addition of 100 ng/mL recombinant rhesus IL-3 and 100 ng/mL GM-CSF in SIV+ "sick" animals. Variation in frequency of CD34+ progenitor cells in SIV+ animals was seen, with 3.0% CD34+ cells in SIV- controls, 4.9% CD34+ cells in SIV+ "well" animals and 0.5% CD34+ progenitor cells in SIV+ "sick" monkeys (P < .01, each mean compared to the others). Finally, there was minimal evidence of SIV sequences by polymerase chain reaction in pooled cultured CFU-GM, and no evidence in flowcytometrically sorted CD34+ progenitor cells from selected animals. Thus, the SIV seropositive rhesus monkey appears to have similar hematopoietic aberrations as are found in HIV infected human subjects and may be an excellent model for studying the interaction of lentiviruses on the kinetics of blood formation.

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

“…Therefore, this virus is potentially infectious for an extended range of target cells. However, we did not detect viral DNA in highly purified CD34 ϩ bone marrow cells, which is in accordance with previously reported data for HIV-infected patients and for simian models of AIDS (17,24). Absence of infection of CD34…”

“…SIV and SHIV have biological properties similar to those of HIV, and infection of macaques with pathogenic isolates reliably induces in macaques an immunodeficiency syndrome strikingly mimicking human AIDS (33). In the same manner as in HIV-positive patients, hematological alterations are commonly found in SIV-infected macaques (16,17). We recently reported that treatment of macaques with a combination of zidovudine, lamivudine, and indinavir, initiated as early as 4 h after intravenous exposure to SHIV 89.6P and maintained for 4 weeks, failed to prevent infection but has long-lasting beneficial effects on the plasma viral load and blood CD4 ϩ cell counts (21).…”

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).…”

“…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). On the other hand, it has been suggested that primitive bone marrow progenitor cells are most likely not a major reservoir for HIVs (6,13,28).…”

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).…”