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Biomedical subjects

D E Mosier

Publications and source records attributed to D E Mosier.

At least 37 records · Page 2Linked to original sources
PubMed1997

Deletion of nef slows but does not prevent CD4-positive T-cell depletion in human immunodeficiency virus type 1-infected human-PBL-SCID mice.

The pathogenicity of four human immunodeficiency virus type 1 (HIV-1) isolates with nef deleted for SCID mice repopulated with human peripheral blood leukocytes (hu-PBL-SCID mice) was studied. Deletion of nef led to a substantial reduction in CD4-positive T-cell depletion and delayed kinetics of plasma viremia in infected hu-PBL-SCID mice. Deletion of the nef gene impacts both the efficiency of primary infection and the cytopathicity of virus for infected CD4-positive T cells in this animal model of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Chemokine receptor CCR5 genotype influences the kinetics of human immunodeficiency virus type 1 infection in human PBL-SCID mice.

Individuals homozygous for a 32-bp deletion (delta 32) in the CCR5 gene encoding the coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1) are resistant to virus infection, and heterozygous individuals show some slowing of disease progression. The impact of the CCR5 genotype on HIV-1 infection was assessed in vitro and in the human PBL-SCID (hu-PBL-SCID) model. Cells and hu-PBL-SCID mice from CCR5 delta 32/delta 32 donors were resistant to infection with macrophage-tropic HIV-1 and showed slower replication of dual-tropic HIV-1. hu-PBL-SCID mice derived from CCR5 delta 32/+ heterozygotes showed delayed replication of macrophage-tropic HIV-1 despite a small and variable effect of heterozygosity on viral replication in vitro. The level of CCR5 expression appears to limit replication of macrophage-tropic and dual-tropic HIV-1 strains in vivo.

Amino Acid Sequence↗
PubMed1996

Apoptosis induced by HIV infection in H9 T cells is blocked by ICE-family protease inhibition but not by a Fas(CD95) antagonist.

Infection of human CD4-positive T lymphocytes by human immunodeficiency virus type 1 (HIV-1) is thought to lead to death of infected cells by apoptosis, although one recent report questions this conclusion. Here we demonstrate that HIV-1-induced apoptosis of the H9 human T cell line is blocked by peptide inhibitors of IL-1 beta converting enzyme (ICE)-family proteases, but not by the antagonistic M3 anti-Fas Ab. Apoptosis occurred in all phases of the cell cycle, not selectively in G2 as a consequence of vpr-mediated cell cycle arrest. We conclude that apoptosis accounts for all cell death related to HIV-1 infection of the human CD4-positive cell line H9, requires an ICE-like protease but is not Fas mediated, and occurs in all phases of the cell cycle.

Amino Acid Chloromethyl Ketones↗
PubMed1996

Modeling AIDS in a mouse.

Mice that are lacking their own lymphocytes are given a human immune system, which then is infected with HIV. Such models are proving themselves in studies of immunization techniques. They also yield insights into HIV, including its capacity for infecting particular cell types and its so-called accessory genes. The models may even help in establishing precisely how HIV kills host CD4 T cells.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Viral pathogenesis in hu-PBL-SCID mice.

The transplantation of human cells into immunodeficient mice has provided new models for human immune function, infection by pathogenic viruses that grow in lymphocytes or other hematopoietic cells, and development of hematopoietic lineages. SCID mice reconstituted with adult peripheral blood mononuclear cells (hu-PBL-SCID mice) maintain some established immune responses, but do not produce a full spectrum of primary cellular or humoral responses. Nonetheless, hu-PBL-SCID mice are a valuable tool for studying primary infection with human immunodeficiency virus (HIV) and reactivation of latent Epstein-Barr virus (EBV) infection. This review will summarize findings from such studies.

Animals↗
PubMed1996

The envelope gp120 gene of human immunodeficiency virus type 1 determines the rate of CD4-positive T-cell depletion in SCID mice engrafted with human peripheral blood leukocytes.

We have used envelope recombinant viruses generated between two molecular clones of human immunodeficiency virus type 1 (HIV-1), T-cell-tropic HIV-1SF2 and macrophage-tropic HIV-1SF162, to assess pathogenic potential in the human peripheral blood leukocyte-reconstituted severe combined immune deficiency mouse model. Recombinant HIV-1SF2 viruses expressing the envelope gp120 gene of HIV-ISF162 caused as rapid a CD4+ T-cell depletion as did HIV-1SF162. The reciprocal HIV-1SF162 recombinant virus with the HIV-1SF2 envelope caused slower CD4+ T-cell loss. Although changing the V3 loop sequence of HIV-1SF162 to that of HIV-1SF2 did not change the rate of CD4+ T-cell depletion, replacing the V3 of HIV-1SF2 with the sequence of HIV-1SF162 resulted in virus that was poorly infectious in vivo but not in vitro. These studies suggest that the envelope gene determines properties important for pathogenesis in vivo as well as for cell tropism in vitro. HIV-1 infection in vivo may have more stringent requirements for envelope conformation.

Amino Acid Sequence↗
PubMed1995

Lack of pseudotype formation between human immunodeficiency virus type 1 and Epstein-Barr virus in productively coinfected B lymphoblastoid cell lines.

Human immunodeficiency virus (HIV) can form pseudotypes with other enveloped viruses, including herpes simplex virus, when the two viruses coinfect the same cell. Pseudotypes between HIV and Epstein-Barr virus (EBV) have not been described. We observed unusually high levels of HIV-1 replication in SCID mice transplanted with human peripheral blood mononuclear cells (hu-PBL-SCID mice) when the mice developed EBV-associated human B cell lymphoproliferative disease. If this enhancement of HIV-1 replication were due to pseudotype formation rather than direct infection of B lymphoblastic cells by HIV-1, the pseudotypes could pose a novel biohazard to laboratory workers. To assess whether HIV-1 and EBV can form such pseudotypes, we established and characterized CD4-positive B lymphoblastoid cell lines (LCL) that contained cells infected with both EBV and HIV-1. A high-titered virus pool from these LCL could induce HIV infection in the Burkitt's lymphoma (BL) line BJA-B, but not in the BL line Ramos. Infection of BJA-B was blocked by neutralizing antibody to HIV gp120 but not by neutralizing anti-EBV gp350. These experiments provide no evidence for pseudotype formation, suggesting a low risk for EBV:HIV pseudotypes in natural infection of humans or in human cells transplanted to SCID mice.

Animals↗
PubMed1995

Distinct rate and patterns of human CD4+ T-cell depletion in hu-PBL-SCID mice infected with different isolates of the human immunodeficiency virus.

The most fundamental question about infection with the human immunodeficiency virus is the mechanism by which infection leads to depletion of CD4+ T lymphocytes, a critical cell type for the regulation of both cellular and humoral immunity. We have studied this issue using a unique small-animal model that is highly susceptible to infection with human immunodeficiency virus. Severe combined immune deficient mice are transplanted with human peripheral blood leukocytes to create hu-PBL-SCID mice, which maintain human T and B lymphocytes and some elements of functional immunity. The hu-PBL-SCID mice respond to human immune deficiency virus infection by the relatively rapid loss of human CD4+ T cells, while other human cells remain unaffected. In this paper, we review evidence showing that different isolates of human immunodeficiency virus-2 cause different rates of CD4+ T-cell depletion and that these rates reflect differences in local spread of infection with lymphoid organs.

Animals↗
PubMed1995

Protection against HIV-1 infection in hu-PBL-SCID mice by passive immunization with a neutralizing human monoclonal antibody against the gp120 CD4-binding site.

OBJECTIVE: Mice with severe combined immunodeficiency (SCID) transplanted with human peripheral blood lymphocytes (hu-PBL) have been shown to be useful as an animal model for HIV-1 infection. This model was used to assess the ability of a human anti-gp120 antibody to protect against HIV-1 infection. DESIGN AND METHODS: hu-PBL-SCID mice were injected with an HIV-1 broadly neutralizing human monoclonal antibody against the gp120 CD4-binding site prior to challenge with HIV-1SF2. The antibody b12, employed for these studies, was isolated from an antibody phage-display library prepared from bone-marrow of a long-term asymptomatic HIV-1-seropositive donor. Both Fab fragments and whole immunoglobulin (Ig) G1 b12 antibody were assessed for protection. RESULTS: Fab b12, tested at a dose approximately 1.9 mg/kg, was able to protect 25% of hu-PBL-SCID mice from HIV-1 infection. IgG1 b12, which displayed favorable pharmacokinetic properties, showed a dose-dependent protection that was complete with a regimen of two injections of 100 micrograms per mouse. The in vivo protective dose of antibody at the time of virus challenge was estimated to be 4.5-7 mg/kg from antibody clearance data. CONCLUSIONS: This study demonstrates for the first time that complete protection against HIV-1 infection can be achieved in the hu-PBL-SCID model by passive immunization with physiologically relevant doses of a human gp120 CD4-binding site antibody derived from natural infection.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Differential Epstein-Barr virus gene expression in B-cell subsets recovered from lymphomas in SCID mice after transplantation of human peripheral blood lymphocytes.

We have analyzed the human B-cell tumors that arise spontaneously in SCID mice who have been given transplants of peripheral blood lymphocytes from Epstein-Barr virus (EBV)-seropositive donors to determine if patterns of EBV gene expression are correlated with phenotypic changes in the tumor B cells. Tumor cells were separated into two B-cell subsets by cell sorting on the basis of differential coexpression of membrane CD23 and CD38. One subset showed intermediate levels of CD23 and CD38 expression (CD23intCD38int), while a second subset had low-level CD23 but high-level CD38 expression (CD23loCD38hi). The CD23intCD38int cells had a high proliferative index and secreted little immunoglobulin in vitro; the CD23loCD38hi cells had a low proliferative index and high-level immunoglobulin secretion. We next analyzed the sorted cells for viral transcripts associated with latency (EBNA-1, EBNA-2, and LMP-1) or lytic cycle replication (ZEBRA and gp350 envelope protein). Only latent cycle transcripts were found in CD23intCD38int cells, whereas lytic cycle transcripts and transforming virus were present in the CD23loCD38hi cells. Finally, we generated short-term cell lines from the sorted CD23intCD38int cells and transferred these cells to SCID recipients. The resulting secondary tumors were predominantly CD23loCD38hi, suggesting that the CD23intCD38int lymphoblastoid cells are precursors to the well-differentiated, plasmacytoid CD23loCD38hi cells. These observations are discussed in the context of a three-step model for EBV-associated lymphomagenesis in humans.

Animals↗
PubMed1994

Cloned human CD8+ cytotoxic T lymphocytes protect human peripheral blood leukocyte-severe combined immunodeficient mice from HIV-1 infection by an HLA-unrestricted mechanism.

The ability to infect human peripheral blood leukocyte-reconstituted severe combined immunodeficient (hu-PBL-SCID) mice with HIV has allowed evaluation of several strategies for preventing or treating infection. In one study, hu-PBL-SCID mice derived from HIV gp160-vaccinated donors were shown to resist HIV infection, and resistance correlated best with in vitro assays of cellular immunity. We have assessed directly the importance of cellular immunity to HIV in the present experiments by the adoptive transfer of HLA-A3-restricted HIV-1 Nef-specific or HLA-B14-restricted Gag-specific CD8+ CTL clones to SCID mice bearing HLA-matched or mismatched PBL grafts. Multiple inoculations of CTL before and after HIV-1 exposure protected HLA-matched hu-PBL-SCID mice from infection, but initiation of CTL therapy on the same day as HIV infection was much less effective. However, at the high numbers of CTL required for complete protection from HIV infection, many HLA-mismatched hu-PBL-SCID mice were also protected by pre-exposure CTL transfer. Transfer of CTL with a different specificity (HTLV-1 Tax) to HLA-matched hu-PBL-SCID mice also afforded partial protection. These results suggest that HLA-restricted cytotoxicity may be less important than other nonspecific effector mechanisms for the inhibition of HIV-1 infection in vivo.

Animals↗
PubMed1994

VH11 bias and normal V-D-J junctions in SCID B lymphocytes rescued by neonatal T cell transfer.

The scid mutation interferes with normal rearrangement of antigen receptor genes, leading to an absence of T and B lymphocytes in most SCID mice. However, the SCID phenotype is "leaky", with an age- and strain-dependent increase in the incidence of mice with small number of T and B cells and readily detectable serum immunoglobulin. Introduction of neonatal T cells into young SCID mice results in a 100% incidence of the leaky phenotype. We have identified the location of antibody secreting cells in T cell-induced leaky SCID mice as the spleen and peritoneal cavity, and we have sequenced 35 productively rearranged immunoglobulin genes from these sites to determine if normal V-D-J recombination was occurring. VH11 sequences with potential autoreactivity were observed frequently in both the peritoneal cavity and spleen of T cell-induced leaky SCID mice, and these sequences were indistinguishable from those recovered from peritoneal cavity B cells from normal C.B-17 mice. Non-VH11 SCID sequences showed fewer N nucleotides and slightly more P nucleotides than normal V-D-J sequences. Many SCID junctions occurred at the site of short sequence homologies. These results suggest that successful V-D-J recombination is occurring with low frequency in all SCID mice, and that neonatal T cell transfer plus autoantigen stimulation allows the long term survival of these B cells.

Animals↗
PubMed1994

Consequences of secondary or co-infections for immunity.

While remarkable progress has been made using genetically altered mice to understand the importance of different cytokines in protecting against experimental infections or co-infections, an examination of the opportunistic infections that occur during HIV infection of humans does not yet show a clear picture of cytokine imbalance. Opportunistic infections appear to result from impairments in cells mediating innate resistance, such as natural killer cells, macrophages, and neutrophils. Some of these defects may not be corrected even if CD4+ T cells were suddenly restored to normal. The lessons from immunodeficient and gene knockout mice now need to be put to the test in the clinic.

AIDS-Related Opportunistic Infections↗