Long-Term Cultures of HTLV-III—Infected T Cells: a Model of Cytopathology of T-Cell Depletion in AIDS

Zagury, Daniel; Bernard, Jacky; Leonard, Reid J.; Cheynier, Rémi; Feldman, Michaël; Sarin, P. S.; Gallo, Rosella

doi:10.1126/science.2418502

Cited by 517 publications

(214 citation statements)

References 22 publications

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“…Based on these observations, our experiments suggest that T cell activation may render the cell susceptible for HIV entry due to an increased expression of cell surface CD4. Indeed, previous studies have shown that activation of T cells strongly contributes to HIV replication (73)(74)(75)(76)(77). Up to now, however, these findings have been explained by an interplay of viral and host regulatory proteins, such as Tat, Rev, Nef, NF-B, and NF-AT.…”

Section: Discussionmentioning

confidence: 71%

Glucocorticoids Regulate TCR-Induced Elevation of CD4: Functional Implications

Wiegers

Stec

Klinkert

et al. 2000

The Journal of Immunology

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CD4 serves as a coreceptor during Ag recognition by the TCR. This interaction results in a marked increase in the sensitivity of a T cell to Ag presented by MHC class II molecules. Here we report that activation of T cells either by plate-bound mAb (anti-TCR, anti-CD3) or soluble activators (staphylococcal enterotoxin A, Con A) is associated with an (up to 3-fold) increase in CD4 cell surface expression on CD25+ cells, which was maximal after 72–96 h. Incubation with the glucocorticoid hormone corticosterone (CORT) shifted the enhancement of CD4 expression to a point about 24 h earlier than that observed in control cultures. In parallel, the proliferative response of these CORT-treated cells was profoundly enhanced. An involvement of increased CD4 expression in this enhanced proliferative response was evidenced by the observation that T cell proliferation in CORT-treated cultures was much less sensitive to inhibition by an inhibitory, nondepleting anti-CD4 mAb than that in control cultures. TCR down-regulation was, however, not affected by CORT. Thus, based on this study and previous reports we propose that both TCR-mediated signals and glucocorticoids are important physiological regulators of CD4 expression. In addition, these findings may be of significance for the sensitivity of CD4+ cells to HIV infection upon T cell activation, as the efficacy of primary patient HIV entry depends on the level of surface CD4.

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Section: Discussionmentioning

confidence: 71%

Glucocorticoids Regulate TCR-Induced Elevation of CD4: Functional Implications

Wiegers

Stec

Klinkert

et al. 2000

The Journal of Immunology

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“…The human immunodeficiency virus (HIV) infects helper T cells by binding the gpl20 virus envelope glycoprotein to CD4+ molecules (1). The selective infection and death of CD4+ T cells provides a simple explanation for the impairment of the immune system (2,3). This explanation, however, is widely debated (4)(5)(6)(7).…”

mentioning

confidence: 93%

Diversity and virulence thresholds in AIDS

Boer¹,

Boerlijst²

1996

Models for Infectious Human Diseases

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We propose a model for the interaction between human immunodeficiency virus and the immune system. Two differential equations describe the interactions between one strain of virus and one clone of T lymphocytes. We use the model to generalize earlier results pertaining to the AIDS diversity threshold [Nowak, M. A., Anderson, R. M., McLean The development of AIDS is associated with the selective depletion of the most crucial cell type of the immune system: the CD4+ helper T cell. The human immunodeficiency virus (HIV) infects helper T cells by binding the gpl20 virus envelope glycoprotein to CD4+ molecules (1). The selective infection and death of CD4+ T cells provides a simple explanation for the impairment of the immune system (2, 3). This explanation, however, is widely debated (4-7).One hallmark of HIV infection is the long and variable incubation period. Although the processes of infection and immune activation have a short time scale, a typical time scale for the incubation period is 10 years (8). Another hallmark of HIV is its enormous genetic diversity. The dominant surface antigen for the immune response is the V3 loop of gpl20 (9,10). This V3 loop is hypervariable: virus isolates from one infected individual have genetically different V3 loops (11, 12). Since HIV accumulates one point mutation per genome during an average replication cycle (12,13), the genetic variability will grow exponentially. However, antigenic variability is not unique to HIV: several pathogens possess antigenic variability which lets them "run ahead" of the immune response.A recent model (14-17) combines these two hallmarks of AIDS in that it attributes the long and variable incubation period to genetic variability. The authors of the model coinedThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. the term "diversity threshold" for the critical variability beyond which the immune system is no longer capable of controlling the virus. The diversity threshold emerges mathematically from their simple and quite reasonable model. The diversity threshold (14-17) is a generic property of a wide variety of models. (See refs. 17 and 18 for recent reviews of mathematical models for the various pathogenic effects of HIV.)The virus quasispecies (19) not only increases in diversity but also evolves physiologically different strains. Virus strains evolve different replication rates, cytotrophisms, and antigenicities (20)(21)(22). Here we develop a model that allows us to study the relation between the diversity of the virus quasispecies and the "virulence" of each virus strain. We derive a dimensionless virulence parameter and show that it is involved in well-known local and global bifurcations. Models of the Immune Response to HIVOur models describe the interactions between one strain of virus vj, where j is the strain number, and the clone(s) of CD4+ T cells tj that recognizes thi...

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“…One possibility is co-infection with other viruses, especially herpesviruses. Several studies have demonstrated the ability of secondary infectious agents to trigger HIV growth in vitro (Gendelman et al, 1986;Zagury et al, 1986;Mosca et al, 1987;Rando et al, 1987;Horvat et al, 1989). Clinical findings have served to focus attention on human cytomegalovirus (HCMV), an opportunistic pathogen that has been detected in a number of different immunodeficiency syndromes, including AIDS (Macher et al, 1983;Mintz et al, 1983) and HCMV viraemia parallels the progression of AIDS symptoms (Fiala et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

Reciprocal Enhancement of Gene Expression and Viral Replication Between Human Cytomegalovirus and Human immunodeficiency Virus Type 1

Harouse

Rando

et al. 1990

Journal of General Virology

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Biological interactions between human cytomegalovirus (HCMV) and the human immunodeficiency virus type 1 (HIV-1) were analysed in transfection and infection experiments, carried out in a human osteogenic sarcoma cell line (HOS) and in the same cell line chronically infected with HCMV (E155). When HOS and E155 cells were transfected with recombinant plasmids containing the HIV long terminal repeat (LTR) linked to the bacterial chloramphenicol acetyltransferase (CAT) gene, LTR-directed CAT expression was 20 times higher in E155 cells than in HOS cells. HOS cells co-infected with HCMV and HIV-1 showed enhanced production of the HIV-1 p24 antigen. In reciprocal experiments, an increase in HCMV immediate early gene expression was observed when HCMVinfected HOS cells and E155 cells were either transfected with a recombinant plasmid containing the HIV transactivator gene (pTAT), or when infected with HIV-1. DNA hybridization analysis of E155 and HCMV-infected HOS cells revealed higher levels of HCMV DNA in cells transfected with pTAT than in ceils transfected with other non-specific recombinant plasmids. E155 cells transfected with pTAT also produced higher titres of infectious HCMV than control cultures of E155 cells transfected with other recombinant plasmids, including pMTAT carrying a mutant tat gene. The functional reciprocity in vitro between HCMV and HIV is discussed with respect to its possible implications for the clinical development of AIDS.

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Long-Term Cultures of HTLV-III—Infected T Cells: a Model of Cytopathology of T-Cell Depletion in AIDS

Cited by 517 publications

References 22 publications

Glucocorticoids Regulate TCR-Induced Elevation of CD4: Functional Implications

Glucocorticoids Regulate TCR-Induced Elevation of CD4: Functional Implications

Diversity and virulence thresholds in AIDS

Reciprocal Enhancement of Gene Expression and Viral Replication Between Human Cytomegalovirus and Human immunodeficiency Virus Type 1

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