Biomedical subjects

B D Jamieson

Publications and source records attributed to B D Jamieson.

32 records · Page 2Linked to original sources

PubMed1995

In vivo pathogenic properties of two clonal human immunodeficiency virus type 1 isolates.

We have investigated the in vivo pathogenic properties of two molecularly cloned strains of human immunodeficiency virus type 1 (HIV-1), HIV-1NL4-3 and HIV-1JR-CSF, in human fetal thymus/liver implants in severe combined immunodeficient mice. Studies comparing their in vivo replication kinetics and abilities to induce CD4+ thymocyte depletion were performed. HIV-1NL4-3 replicated in vivo with faster kinetics and induced greater levels of CD4+ thymocyte depletion than did HIV-1JR-CSF. These results demonstrate that different viral isolates have different pathogenic properties in this system. In the SCID-hu model, this pathogenesis most likely occurs in the absence of an immune response. Therefore, we investigated whether the absence of immune selection resulted in extensive genetic variation and the generation of viral quasispecies. To this end, DNA corresponding to the fourth variable domain region of the viral envelope gp120 protein recovered from biopsy samples at 6 weeks postinfection was sequenced. Little genetic variation was noted in either HIV-1JR-CSF- or HIV-1NL4-3-infected implants. The mutation levels demonstrated in both viral strains were more reflective of the acute rather than the chronic phase of HIV-1 infection in humans. These results suggest that the SCID-hu mouse model can be used to study the in vivo pathogenicity of different HIV-1 isolates in the absence of host immune selective pressures.

Acquired Immunodeficiency Syndrome↗

PubMed1994

Cytotoxic T-cell memory without antigen.

Memory is a hallmark of the immune system and ever since its recognition there has been considerable interest in understanding how immunity is maintained. The current model is that long-term memory is dependent on persistent antigenic stimulation. We report here results that challenge this view and provide evidence that antigen is not essential for the maintenance of CD8+ T-cell memory. We show that memory CD8+ cytotoxic T lymphocytes persist indefinitely in the absence of priming antigen, retain the memory phenotype (CD44hi), and provide protection against virus challenge. These findings suggest a re-evaluation of our current thinking on mechanisms involved in maintaining immunity and have implications towards designing effective vaccination strategies.

Animals↗

PubMed1994

Requirement of human immunodeficiency virus type 1 nef for in vivo replication and pathogenicity.

The role of human immunodeficiency virus type 1 (HIV-1) accessory genes in pathogenesis has remained unclear because of the lack of a suitable in vivo model. The most controversial of these genes is nef. We investigated the requirement for Nef for in vivo replication and pathogenicity of two isolates of HIV-1 (HIV-1JR-CSF and HIV-1NL4-3) in human fetal thymus and liver implants in severe combined immunodeficient mice. HIV-1JR-CSF and HIV-1NL4-3 differ in their in vitro phenotypes in that HIV-1JR-CSF does not induce syncytia and is relatively noncytopathic, while HIV-1NL4-3 is highly cytopathic and readily induces syncytia. The nef mutants of both isolates grew with kinetics similar to those of parental virus strains in stimulated peripheral blood lymphocytes but demonstrated attenuated growth properties in vivo. HIV-1NL4-3 induced severe depletion of human thymocytes within 6 weeks of infection, whereas its nef mutant did not. Thus, HIV-1 Nef is required for efficient in vivo viral replication and pathogenicity.

Animals↗

PubMed1992

Viral infection of the thymus.

We have examined infection of the thymus during congenitally acquired chronic lymphocytic choriomeningitis virus (LCMV) infection of mice, a classic model of antigen-specific T-cell tolerance. Our results show that (i) infection starts at the fetal stage and is maintained throughout adulthood, and (ii) this chronic infection of the thymus can be eliminated by transfer of virus-specific cytotoxic T lymphocytes (CTL) that infiltrate the thymus and clear all viral products from both medullary and cortical regions. Elimination of virus from the thymus results in abrogation of tolerance. During the fetal stage, the predominant cell type infected is the earliest precursor of T cells with a surface phenotype of Thy1+ CD4- CD8- J11d+. In the adult thymus, infection is confined primarily to the cortisone-resistant thymocytes present in the medullary region. The infected cells are CD4+ and J11d+. The presence of J11d, a marker usually associated with immature thymocytes, on infected single positive CD4+ "mature" thymocytes is intriguing and suggests that infection by this noncytolytic virus may affect development of T cells. There is minimal infection of the CD8+ medullary thymocytes or of the double positive (CD4+ CD8+) cells present in the cortex. Infection within the cortex is confined to the stromal cells. Interestingly, there is infection of the double negative (CD4- CD8-) thymocytes in the adult thymus, showing that even during adulthood the newly developing T cells are susceptible to infection by LCMV. Virus can be eliminated from the thymuses of these carrier mice by adoptive transfer of medullary region first and then from the thymic cortex. This result clearly shows the need to reevaluate the widely held notion that mature T cells are unable to reenter the thymus. In fact, in our experiments the donor T cells made up to 20 to 30% of the total cells in the thymus at 5 to 7 days after the transfer. The number of donor T cells declined as virus was eliminated from the thymus, and at 1 month posttransfer, the donor T cells were hardly detectable. The results of this study examining the dynamics of viral infection and clearance from the thymus, the primary site of T-cell development, have implications for understanding tolerance induction in chronic viral infections.

Aging↗

PubMed1991

Abrogation of tolerance to a chronic viral infection.

This study documents failure of peripheral tolerance mechanisms in a chronic viral infection and shows that T cell tolerance to a viral Ag seen as self from fetal life can be broken despite the presence of this Ag in extrathymic tissues. Congenital infection of mice with lymphocytic choriomeningitis virus (LCMV) results in T cell tolerance to the virus. Such mice become carriers for life harboring virus in many tissues including the thymus and exhibit no LCMV-specific CTL responses. Our previous studies have documented the curing of this congenitally acquired chronic infection after adoptive transfer of CD8+ T cells from LCMV-immune mice and the presence of host-derived, LCMV-specific CTL in these "cured" carriers. In this study we have examined the mechanism by which these carriers acquired T cell competence and show that these CTL differentiated from the bone marrow after elimination of viral Ag from the thymus. These results demonstrate that even when a chronic infection has been established in utero, the adult thymus retains the ability to restore immunocompetence to the host and to provide protection against reinfection. Surprisingly, these LCMV specific CTL were acquired at a time when infectious virus and intracellular viral Ag, although cleared from the thymus, were readily detectable in organs such as the kidney, testes, and brain. In fact, active viral replication in peripheral tissues was ongoing when these mice acquired new virus-specific T cells. These results show that clearance of virus form the thymus was sufficient to abrogate tolerance to a congenitally acquired chronic infection and that Ag in peripheral tissues did not tolerize newly developing T cells. These findings suggest that mechanisms that operate on immature cells within the thymus to silence self-reactive T cells are effective in induction of tolerance to viruses, but mechanisms of tolerizing mature T cells are likely to breakdown. This has implications for virus-induced autoimmunity and for treatment of chronic infections.

Animals↗

PubMed1989

T cell memory. Long-term persistence of virus-specific cytotoxic T cells.

This study documents that virus-specific CTL can persist indefinitely in vivo. This was accomplished by transferring Thy-1.1 T cells into Thy-1.2 recipient mice to specifically identify the donor T cell population and to characterize its antigenic specificity and function by using a virus-specific CTL assay. Thy-1.1+ T cells from mice previously immunized with lymphocytic choriomeningitis virus (LCMV) were transferred into Thy-1.2 mice persistently infected with LCMV. The transferred LCMV-specific CTL (Thy-1.1+ CD8+) eliminate virus from the chronically infected carriers and persist in the recipient mice in small numbers, comprising only a minor fraction of the total T cells. Upon re-exposure to virus, these long-lived "resting" CD8+ T cells proliferate in vivo to become the predominant cell population. These donor CD8+ T cells can be recovered up to a year post-transfer and still retain antigenic specificity and biological function. They kill LCMV infected H-2-matched cells in vitro and can eliminate virus upon transfer into a second infected host. In addition, these long-lived CD8+ T cells appear not to be dependent on help from CD4+ T cells, since depletion of CD4+ T cells has minimal or no effect on their biological properties (proliferation, CTL response, viral clearance). These donor CTL also exhibit an immunodominance over the host-derived LCMV-specific CTL response. When both host and donor T cells are present, the donor CTL response is dominant over the potential CTL response of the cured carrier host. Taken together, these results suggest that virus-specific CTL can persist for the life span of the host as memory cells.

Animals↗

PubMed1988

T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells.

This study documents the curing of a congenitally acquired chronic viral infection and the acquisition of T-cell competence by a previously tolerant host. Infection of mice with lymphocytic choriomeningitis virus (LCMV) is a classic model of viral persistence and antigen-specific T-cell unresponsiveness. Mice infected at birth or in utero become lifelong carriers with no detectable virus-specific cytotoxic T lymphocyte (CTL) responses. This chronic infection can be eliminated by adoptive transfer of Lyt-2+ T cells from LCMV-immune mice. To determine whether these cured carriers were capable of generating their own LCMV-specific CTL response, mice congenic at the Thy-1 locus (Thy-1.1 and Thy-1.2) were used in the adoptive transfer experiments. Host-derived T-cell responses were checked after treating the cured carriers with a monoclonal antibody to deplete the immune donor T cells. Such cured carrier mice were able to generate a host-derived virus-specific CTL response and resisted a second LCMV challenge in the absence of any donor T cells. In addition, bone marrow cells from these cured carriers could functionally reconstitute irradiated mice. Thus this report demonstrates the acquisition of LCMV-specific T-cell competence by previously unresponsive carrier mice infected in utero. These results show that exposure to a virus even during embryonic life does not cause a permanent deletion of specific T cells. These findings are of significance to the understanding of tolerance mechanisms and have implications for the treatment of chronic viral infections.

Animals↗

PubMed1987

Immune therapy of a persistent and disseminated viral infection.

The mechanism of viral clearance was studied by using the mouse model of chronic infection with lymphocytic choriomeningitis virus. Distinct patterns of viral clearance and histopathology were observed in different organs after adoptive immune therapy of persistently infected (carrier) mice. Clearance from the liver occurred within 30 days and was accompanied by extensive mononuclear cell infiltrates and necrosis of hepatocytes. Infectious virus and viral antigen were eliminated concurrently. This pattern of viral clearance was also seen in most other tissues (i.e., lung, spleen, lymph nodes, pancreas, etc.). In contrast, a different pattern of clearance was observed in the brain. Infectious virus was eliminated within 30 days, but viral antigen persisted in the central nervous systems of treated carrier mice for up to 90 days. The urinary system was the most resistant to immune therapy. Elimination of infectious virus and viral antigen from the kidney took greater than 200 days and even then was not complete; trace levels of infectious virus were still present in the kidneys of some treated carrier mice. After immune therapy, viral antigen in the kidney was located within renal tubules that costained for intracellular mouse immunoglobulin G. This unusual staining pattern, coupled with the observation of large numbers of plasma cells within the kidney, suggests that virus-immunoglobulin G complexes found in the tubules may represent in situ immune complex formation as opposed to deposition of circulating immune complexes. In conclusion, these results suggest that the site (organ) of viral persistence is an important consideration in developing treatment strategies for controlling chronic viral infections.

Animals↗

PubMed1987

Effective clearance of a persistent viral infection requires cooperation between virus-specific Lyt2+ T cells and nonspecific bone marrow-derived cells.

The lifelong chronic lymphocytic choriomeningitis virus (LCMV) infection established in neonatally or congenitally infected mice can be eliminated by adoptive transfer of lymphoid cells from LCMV-immune mice. In this study, we have identified the effector cells mediating the clearance of persistent and disseminated LCMV infection. Using mice that are recombinant in the H-2 region and by selective depletion of lymphocyte subpopulations, we show that viral clearance was mediated by LCMV-specific Lyt2+ L3T4- T cells that are restricted to the class I genes of the major histocompatibility complex. In addition, our results show a requirement for host-derived bone marrow cells for the effective elimination of virus from the liver. These studies emphasize the importance of virus-specific T cells and an intact bone marrow function in viral clearance.

Animals↗

PubMed1978

Driving offenders and the defensive driving course--an archival study.

Two hundred and seventy-five drivers who had been required by court order to attend a Defensive Driving Course (DDC) were compared on six posttreatment driving measures obtained from archival data with 275 drivers who also had had a court appearance and standard treatment. The DDC group showed greater reductions in serious and accident-promoting convictions but no greater reduction in accidents when compared with the standard treatment comparison group.

Accidents, Traffic↗

PubMed1972