scholarly journals Human Immunodeficiency Virus Inhibits Multilineage Hematopoiesis In Vivo

1998 ◽  
Vol 72 (6) ◽  
pp. 5121-5127 ◽  
Author(s):  
Prasad S. Koka ◽  
John K. Fraser ◽  
Yvonne Bryson ◽  
Gregory C. Bristol ◽  
Grace M. Aldrovandi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Ex Vivo ◽  
Erythroid Differentiation ◽  
Inhibitory Effect ◽  
Immunodeficiency Virus ◽  
The Many ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-infected individuals often exhibit multiple hematopoietic abnormalities reaching far beyond loss of CD4+ lymphocytes. We used the SCID-hu (Thy/Liv) mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues), which provides an in vivo system whereby human pluripotent hematopoietic progenitor cells can be maintained and undergo T-lymphoid differentiation and wherein HIV-1 infection causes severe depletion of CD4-bearing human thymocytes. Herein we show that HIV-1 infection rapidly and severely decreases the ex vivo recovery of human progenitor cells capable of differentiation into both erythroid and myeloid lineages. However, the total CD34+ cell population is not depleted. Combination antiretroviral therapy administered well after loss of multilineage progenitor activity reverses this inhibitory effect, establishing a causal role of viral replication. Taken together, our results suggest that pluripotent stem cells are not killed by HIV-1; rather, a later stage important in both myeloid and erythroid differentiation is affected. In addition, a primary virus isolated from a patient exhibiting multiple hematopoietic abnormalities preferentially depleted myeloid and erythroid colony-forming activity rather than CD4-bearing thymocytes in this system. Thus, HIV-1 infection perturbs multiple hematopoietic lineages in vivo, which may explain the many hematopoietic defects found in infected patients.

Changes in human immunodeficiency virus type 1 virus load during mobilization and harvesting of hemopoietic progenitor cells

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 48-55
Author(s):  
Thomas B. Campbell ◽  
Anne Sevin ◽  
Robert W. Coombs ◽  
Gregory C. Peterson ◽  
Mary Rosandich ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Hemopoietic Stem Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Hemopoietic Progenitor ◽  
Hemopoietic Progenitor Cells ◽  
Rna Levels

Genetic modification of hemopoietic progenitor cells ex vivo, followed by the infusion of the genetically modified cells into the human immunodeficiency virus-1 (HIV-1) infected donor, has been proposed as a treatment for HIV-1 infection. The current study was undertaken to evaluate the effect of hemopoietic stem cell mobilization and harvesting on HIV-1 replication in persons with HIV-1 infection. Eighteen HIV-1–infected persons received recombinant granulocyte colony-stimulating factor (G-CSF; Filgrastim) 10 μg/kg per day, for 7 days. On days 4 and 5, peripheral blood mononuclear cells were harvested by leukapheresis. The CD4+ lymphocyte count at entry was >500/μL for 6 subjects, 200 to 500/μL for 6 subjects, and <200/μL for 6 subjects. For 9 of 18 subjects, plasma HIV-1 RNA levels increased 4- to 100-fold (>0.6 log10) above baseline between days 4 and 7 and returned to baseline by day 27. Significant increases of plasma HIV-1 RNA levels occurred in 5 subjects despite 3-drug antiretroviral therapy. Changes in CD4+ and CD34+ cells during mobilization and harvesting were similar in all subjects whether they had or did not have increased plasma HIV-1 RNA levels. Thus, mobilization and harvesting of bone marrow progenitor cells from persons infected with HIV-1 induced a transient increase in viral replication in some patients but was not associated with adverse effects. (Blood. 2000;95: 48-55)

Changes in human immunodeficiency virus type 1 virus load during mobilization and harvesting of hemopoietic progenitor cells

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 48-55 ◽  
Author(s):  
Thomas B. Campbell ◽  
Anne Sevin ◽  
Robert W. Coombs ◽  
Gregory C. Peterson ◽  
Mary Rosandich ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Hemopoietic Stem Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Hemopoietic Progenitor ◽  
Hemopoietic Progenitor Cells ◽  
Rna Levels

Abstract Genetic modification of hemopoietic progenitor cells ex vivo, followed by the infusion of the genetically modified cells into the human immunodeficiency virus-1 (HIV-1) infected donor, has been proposed as a treatment for HIV-1 infection. The current study was undertaken to evaluate the effect of hemopoietic stem cell mobilization and harvesting on HIV-1 replication in persons with HIV-1 infection. Eighteen HIV-1–infected persons received recombinant granulocyte colony-stimulating factor (G-CSF; Filgrastim) 10 μg/kg per day, for 7 days. On days 4 and 5, peripheral blood mononuclear cells were harvested by leukapheresis. The CD4+ lymphocyte count at entry was &gt;500/μL for 6 subjects, 200 to 500/μL for 6 subjects, and &lt;200/μL for 6 subjects. For 9 of 18 subjects, plasma HIV-1 RNA levels increased 4- to 100-fold (&gt;0.6 log10) above baseline between days 4 and 7 and returned to baseline by day 27. Significant increases of plasma HIV-1 RNA levels occurred in 5 subjects despite 3-drug antiretroviral therapy. Changes in CD4+ and CD34+ cells during mobilization and harvesting were similar in all subjects whether they had or did not have increased plasma HIV-1 RNA levels. Thus, mobilization and harvesting of bone marrow progenitor cells from persons infected with HIV-1 induced a transient increase in viral replication in some patients but was not associated with adverse effects. (Blood. 2000;95: 48-55)

scholarly journals Human Immunodeficiency Virus-1 Infection Interrupts Thymopoiesis and Multilineage Hematopoiesis In Vivo

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2672-2678 ◽  
Author(s):  
Morgan Jenkins ◽  
Mary Beth Hanley ◽  
Mary Beth Moreno ◽  
Eric Wieder ◽  
Joseph M. McCune
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Human Immunodeficiency Virus 1

It is still uncertain whether multilineage hematopoietic progenitor cells are affected by human immunodeficiency virus-1 (HIV-1) infection in vivo. The SCID-hu Thy/Liv model is permissive of long-term multilineage human hematopoiesis, including T lymphopoiesis. This model was used to investigate the effects of HIV-1 infection on early hematopoietic progenitor function. We found that both lineage-restricted and multilineage hematopoietic progenitors were depleted from grafts infected with either a molecular clone or a primary isolate of HIV-1. Depletion of hematopoietic progenitors (including CD34+ cells, colony-forming units in methylcellulose, and long-term culture-initiating cells) occurred several days before the onset of thymocyte depletion, indicating that the subsequent rapid decline in thymocyte numbers was due at least in part to loss of thymocyte progenitors. HIV-1 proviral genomes were not detected at high frequency in hematopoietic cells earlier than the intrathymic T-progenitor cell stage, despite the depletion of such cells in infected grafts. Proviral genomes were also not detected in colonies derived from progenitor cells from infected grafts. These data demonstrate that HIV-1 infection interrupts both lineage-restricted and multilineage hematopoiesis in vivo and suggest that depletion of early hematopoietic progenitor cells occurs in the absence of direct viral infection.

scholarly journals Use of a Combined Ex Vivo/In Vivo Population Approach for Screening of Human Genes Involved in the Human Immunodeficiency Virus Type 1 Life Cycle for Variants Influencing Disease Progression

2005 ◽  
Vol 79 (20) ◽  
pp. 12674-12680 ◽  
Author(s):  
Gabriela Bleiber ◽  
Margaret May ◽  
Raquel Martinez ◽  
Pascal Meylan ◽  
Jürg Ott ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Life Cycle ◽  
Human Immunodeficiency Virus Type ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Humans differ substantially with respect to susceptibility to human immunodeficiency virus type 1 (HIV-1). We evaluated variants of nine host genes participating in the viral life cycle for their role in modulating HIV-1 infection. Alleles were assessed ex vivo for their impact on viral replication in purified CD4 T cells from healthy blood donors (n = 128). Thereafter, candidate alleles were assessed in vivo in a cohort of HIV-1-infected individuals (n = 851) not receiving potent antiretroviral therapy. As a benchmark test, we tested 12 previously reported host genetic variants influencing HIV-1 infection as well as single nucleotide polymorphisms in the nine candidate genes. This led to the proposition of three alleles of PML, TSG101, and PPIA as potentially associated with differences in progression of HIV-1 disease. In a model considering the combined effects of new and previously reported gene variants, we estimated that their effect might be responsible for lengthening or shortening by up to 2.8 years the period from 500 CD4 T cells/μl to <200 CD4 T cells/μl.

scholarly journals Infection of human immunodeficiency virus 1 transgenic mice with Toxoplasma gondii stimulates proviral transcription in macrophages in vivo.

1996 ◽  
Vol 183 (4) ◽  
pp. 1645-1655 ◽  
Author(s):  
R T Gazzinelli ◽  
A Sher ◽  
A Cheever ◽  
S Gerstberger ◽  
M A Martin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Toxoplasma Gondii ◽  
Transgenic Mice ◽  
Transgenic Mouse ◽  
Ex Vivo ◽  
Mouse Strains ◽  
Immunodeficiency Virus ◽  
Nf Kappab ◽  
Hiv 1

Human immunodeficiency virus (HIV) 1 transgenic mice expressing low or undetectable levels of viral mRNA in lymphoid tissue were infected with the intracellular protozoan Toxoplasma gondii. Exposure to this parasite resulted in an increase in HIV-1 transcript in lymph nodes, spleens, and lungs during the acute phase of infection and in the central nervous system during the chronic stage of disease. In vivo and ex vivo experiments identified macrophages as a major source of the induced HIV-1 transcripts. In contrast, T. gondii infection failed to stimulate HIV-1 transcription in tissues of two HIV-1 transgenic mouse strains harboring a HIV-1 proviral DNA in which the nuclear factor (NF) kappa B binding motifs from the viral long terminal repeats had been replaced with a duplicated Moloney murine leukemia virus core enhancer. A role for NF-kappaB in the activation of the HIV-1 by T. gondii was also suggested by the simultaneous induction of NF-kappaB binding activity and tumor necrosis factor alpha synthesis in transgenic mouse macrophages stimulated by exposure to parasite extracts. These results demonstrate the potential of an opportunistic pathogen to induce HIV-1 transcription in vivo and suggest a mechanism for the in vivo dissemination of HIV-1 by macrophages.

scholarly journals Tissue-Resident Macrophages Are Productively Infected Ex Vivo by Primary X4 Isolates of Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 79 (8) ◽  
pp. 5220-5226 ◽  
Author(s):  
Prerana Jayakumar ◽  
Irina Berger ◽  
Frank Autschbach ◽  
Mark Weinstein ◽  
Benjamin Funke ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ex Vivo ◽  
Critical Event ◽  
Human Tonsil ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Infection of macrophages has been implicated as a critical event in the transmission and persistence of human immunodeficiency virus type 1 (HIV-1). Here, we explore whether primary X4 HIV-1 isolates can productively infect tissue macrophages that have terminally differentiated in vivo. Using immunohistochemistry, HIV-1 RNA in situ hybridization, and confocal immunofluorescence microscopy, we demonstrate that macrophages residing in human tonsil blocks can be productively infected ex vivo by primary X4 HIV-1 isolates. This challenges the model in which macrophage tropism is a key determinant of the selective transmission of R5 HIV-1 strains. Infection of tissue macrophages by X4 HIV-1 may be highly relevant in vivo and contribute to key events in HIV-1 pathogenesis.

scholarly journals Human Immunodeficiency Virus Type 1-Induced Hematopoietic Inhibition Is Independent of Productive Infection of Progenitor Cells In Vivo

1999 ◽  
Vol 73 (11) ◽  
pp. 9089-9097 ◽  
Author(s):  
Prasad S. Koka ◽  
Beth D. Jamieson ◽  
David G. Brooks ◽  
Jerome A. Zack
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Reporter Gene ◽  
Cell Function ◽  
Productive Infection ◽  
Distinct Advantage ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV)-infected individuals exhibit a variety of hematopoietic dysfunctions. The SCID-hu mouse (severe combined immunodeficient mouse transplanted with human fetal thymus and liver tissues) can be used to model the loss of human hematopoietic precursor cell function following HIV infection and has a distinct advantage in that data can be obtained in the absence of confounding factors often seen in infected humans. In this study, we establish that HIV type 1 (HIV-1) bearing a reporter gene inserted into the viralvpr gene is highly aggressive in depleting human myeloid and erythroid colony-forming precursor activity in vivo. Human CD34+ progenitor cells can be efficiently recovered from infected implants yet do not express the viral reporter gene, despite severe functional defects. Our results indicate that HIV-1 infection alone leads to hematopoietic inhibition in vivo; however, this effect is due to indirect mechanisms rather than to direct infection of CD34+ cells in vivo.

scholarly journals Targeting c-Mpl for Revival of Human Immunodeficiency Virus Type 1-Induced Hematopoietic Inhibition When CD34+ Progenitor Cells Are Re-Engrafted into a Fresh Stromal Microenvironment In Vivo

2004 ◽  
Vol 78 (20) ◽  
pp. 11385-11392 ◽  
Author(s):  
Prasad S. Koka ◽  
Christina M. R. Kitchen ◽  
Srinivasa T. Reddy
Keyword(s):  
Human Immunodeficiency Virus ◽  
Progenitor Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Severe Combined Immunodeficiency ◽  
Stromal Microenvironment ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The inhibition of multilineage hematopoiesis which occurs in the severe combined immunodeficiency mouse with transplanted human fetal thymus and liver tissues (SCID-hu Thy/Liv) due to human immunodeficiency virus type 1 (HIV-1) infection is also accompanied by a severe loss of c-Mpl expression on these progenitor cells. Inhibition of colony-forming activity (CFA) of the CD34+ progenitor cells is partially revived to about 40% of mock-infected Thy/Liv implants, following reconstitution of the CD34+ cells that were exposed to HIV-1 infection, in a new Thy/Liv stromal microenvironment of irradiated secondary SCID-hu recipients at 3 weeks post-re-engraftment. In addition, in these reconstituted animals, the proportion of c-Mpl+ CD34+ cells relative to c-Mpl− CD34+ cells increased by about 25%, to 35% of mock-infected implants, suggesting a reacquirement of c-Mpl phenotype by the c-Mpl− CD34+ cells. These results suggest a correlation between c-Mpl expression and multilineage CFA of the human CD34+ progenitor cells that have experienced the effects of HIV-1 infection. Treatment of the secondary-recipient animals with the c-Mpl ligand, thrombopoietin (Tpo), further increased c-Mpl expression and CFA of re-engrafted CD34+ cells previously exposed to virus in the primary implants to about 50 to 70% over that of those re-engrafted CD34+ cells derived from implants of untreated animals. Blocking of c-Mpl with anti-c-Mpl monoclonal antibody in vivo by injecting the SCID-hu animals resulted in the reduction or loss of CFA. Thus, inhibition, absence, or loss of c-Mpl expression as in the c-Mpl− CD34+ subset of cells is the likely cause of CFA inhibition. Further, CFA of the CD34+ cells segregates with their c-Mpl expression. Therefore, c-Mpl may play a role in hematopoietic inhibition during HIV-1 infection, and control of its expression levels may aid in hematopoietic recovery and thereby reduce the incidence of cytopenias occurring in infected individuals.

scholarly journals CD4-Immunoglobulin G2 Protects Hu-PBL-SCID Mice against Challenge by Primary Human Immunodeficiency Virus Type 1 Isolates

1998 ◽  
Vol 72 (4) ◽  
pp. 3475-3478 ◽  
Author(s):  
Marie-Claire Gauduin ◽  
Graham P. Allaway ◽  
William C. Olson ◽  
Raymond Weir ◽  
Paul J. Maddon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ex Vivo ◽  
Immunodeficiency Virus ◽  
Scid Mouse Model ◽  
Hiv 1

ABSTRACT CD4-immunoglobulin G2 (IgG2) is a fusion protein comprising human IgG2 in which the Fv portions of both heavy and light chains have been replaced by the V1 and V2 domains of human CD4. Previous studies found that CD4-IgG2 potently neutralizes a broad range of primary human immunodeficiency virus type 1 (HIV-1) isolates in vitro and ex vivo. The current report demonstrates that CD4-IgG2 protects against infection by primary isolates of HIV-1 in vivo, using the hu-PBL-SCID mouse model. Passive administration of 10 mg of CD4-IgG2 per kg of body weight protected all animals against subsequent challenge with 10 mouse infectious doses of the laboratory-adapted T-cell-tropic isolate HIV-1LAI, while 50 mg of CD4-IgG2 per kg protected four of five mice against the primary isolates HIV-1JR-CSF and HIV-1AD6. In contrast, a polyclonal HIV-1 Ig fraction exhibited partial protection against HIV-1LAI at 150 mg/kg but no significant protection against the primary HIV-1 isolates. The results demonstrate that CD4-IgG2 effectively neutralizes primary HIV-1 isolates in vivo and can prevent the initiation of infection by these viruses.

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