IntroductionHIV type 1 (HIV-1) infection typically involves a progressive loss of blood CD4 ϩ T lymphocytes, associated with functional T-cell abnormalities and immunodeficiency. There may be several reasons for the decrease in CD4 ϩ T-cell counts, including direct and indirect virus-mediated cell destruction and defective homeostasis. 1,2 The half-life of peripheral blood T cells, which is approximately 82 days in healthy individuals, is more than 50 days shorter in HIV-infected patients 3 and T-cell numbers appear to be maintained at high levels principally by an increase in the production of CD8 ϩ T cells.Different mechanisms have been proposed for explaining defective production of T lymphocytes, including deregulated thymus activity, infection, and depletion of immature thymocytes expressing CD4 and alteration of early progenitors including at the level of bone marrow (BM) CD34 ϩ precursors. To our knowledge, this last point has never been clearly addressed and was therefore the purpose of our work.Defective de novo production of T lymphocytes by the thymus may make a significant contribution to CD4 ϩ T-cell lymphopenia. In HIV infection, a low proportion of recent thymic emigrants, with episomal DNA formed by rearrangement of the T-cell receptor genes (TREC), 4 is correlated with disease progression, although the value of quantitative TREC measurement in HIV-seropositive patients remains unclear. 5,6 Highly active antiretroviral therapy (HAART) helps to increase the number of CD4 ϩ T cells in the periphery, probably due to both the expansion and redistribution of cell populations present in lymphoid tissues and the de novo generation of T lymphocytes by the thymus. 7-9 T-cell counts are restored to high levels in a biphasic manner following the initiation of HAART. There is an initial rapid increase in the numbers of CD4 ϩ and CD8 ϩ T cells of the memory phenotype (CD45RO ϩ ), and then the proportion of naive T cells (CD45RA ϩ CD62L ϩ ) increases. 7 Changes in thymus volume and an increase in TREC levels in the periphery 10 also provide evidence that successful HAART increases thymus activity. 11 However, CD4 ϩ T-cell counts remain below normal values in treated patients, suggesting that thymic production is not completely restored and is not necessarily associated with an increase in lymphocyte half-life 3 and the complete restoration of efficient antiviral immunity.Changes in thymus function in patients infected with HIV-1 result directly from degeneration of the stroma, infection of immature thymocytes, and dysregulation of thymocyte/stromal cell interactions. [12][13][14] Decreases in the pool of early progenitor stem cells, including the most primitive CD34 ϩ hematopoietic BM cells, may also limit T-cell regeneration. 15 18 and the antibiotics commonly used in patients with AIDS may all affect the production of blood cells. However, although hematopoietic cells do not seem to undergo direct infection with HIV, they may be directly damaged due to the inhibitory effect of HIV-related proteins 19 or proi...
B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...
Background: Prolonged, altered hematopoietic reconstitution is commonly observed in patients undergoing myeloablative conditioning and bone marrow and/or mobilized peripheral blood-derived stem cell transplantation. We studied the reconstitution of myeloid and lymphoid compartments after the transplantation of autologous CD34 + bone marrow cells following gamma irradiation in cynomolgus macaques.
This study was aimed at evaluating the in vitro and in vivo haematopoietic potential in macaque skeletal muscle cells. Biopsy samples showed the presence of CD34 þ (7.6%),þ , side population (SP) cells (7-10%) and a low number of CD45 þ cells. In clonogenic and long-term culture-initiating cell assays, no haematopoietic potential could be detected in either total mononuclear cells or SP cells. Regarding in vivo studies, two animals were transplanted with unfractionated fresh muscle cells after lethal irradiation. Both animals died early after transplant without any evidence of haematopoietic reconstitution. In two other monkeys, harvested muscle cells were frozen and secondarily marked using a green fluorescent protein (GFP)-lentiviral vector. After sublethal irradiation, both animals were transplanted with GFP-expressing muscle cells followed by a bone marrow rescue. Both animals had haematopoietic reconstitution at days 22 and 25, but no GFP-expressing haematopoietic cells could be detected by flow cytometry, either in the blood or in clonogenic cells from marrow aspirates. Using PCR assays, GFP þ cells were detected in a single marrow sample of one animal at 41 days after transplantation. These results strongly suggest that as opposed to murine muscle, the non-human primate skeletal muscle does not harbour cells with a straightforward haematopoietic potential.
Infection of primates by HIV-1 and SIV induces multiple hematological abnormalities of central hematopoietic origin. Although these defects greatly contribute to the pathophysiology of HIV-1 infection, the molecular basis for altered BM function remains unknown. Here we show that when cynomolgus macaques were infected with SIV, the multipotent potential of their hematopoietic progenitor cells was lost, and this correlated with down regulation of STAT5A and STAT5B expression. However, forced expression of STAT5B entirely rescued the multipotent potential of the hematopoietic progenitor cells. In addition, an accessory viral protein required for efficient SIV and HIV replication and pathogenicity, “Negative factor” (Nef), was essential for <SIV-mediated impairment of the multipotent potential of hematopoietic progenitors ex vivo and in vivo. This newly uncovered property of Nef was both conserved between HIV-1 and SIV strains and entirely dependent upon the presence of PPARγ in targeted cells. Further, PPARγ agonists mimicked Nef activity by inhibiting STAT5A and STAT5B expression and hampering the functionality of hematopoietic progenitors both ex vivo and in vivo. These findings have extended the role of Nef in the pathogenicity of HIV-1 and SIV and reveal a pivotal role for the PPARγ/STAT5 pathway in the regulation of early hematopoiesis. This study may provide a basis for investigating the potential therapeutic benefits of PPARγ antagonists in both patients with AIDS and individuals with hematopoietic disorders.
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