Geneviève Martin

Human Immunodeficiency Virus Type 1-Associated CD40 Ligand Transactivates B Lymphocytes and Promotes Infection of CD4+ T Cells

ABSTRACT Abnormal activation of B lymphocytes is a feature commonly seen in human immunodeficiency virus type 1 (HIV-1)-infected persons. However, the mechanism(s) responsible for this dysfunction is still poorly understood. Having recently shown that CD40L, the ligand for CD40, is inserted within emerging HIV-1 particles, we hypothesized that the contact between virus-anchored host CD40L and CD40 on the surface of B lymphocytes might result in the activation of this cell type. We report here that CD40L-bearing viruses, but not isogenic virions lacking host-derived CD40L, can induce immunoglobulin G and interleukin-6 production. Furthermore, such viral entities were found to induce B-cell homotypic adhesion. These effects were paralleled at the intracellular level by the nuclear translocation of the ubiquitous transcription factor NF-κB. The presence of host-derived CD40L within virions resulted in an increased virus attachment to B cells and a more-efficient B-cell-mediated transfer of HIV-1 to autologous CD4+ T lymphocytes. All the above processes were independent of the virus-encoded envelope glycoproteins. Altogether, the data gathered from this series of investigations suggest that the incorporation of host-encoded CD40L in HIV-1 is likely to play a role in the B-cell abnormalities that are seen in infected individuals.

The importance of virus-associated host ICAM-1 in human immunodeficiency virus type 1 dissemination depends on the cellular context

The primary objective of this study was to define whether the nature of virion‐bound host cell membrane proteins influenced the process of human immunodeficiency virus 1 (HIV‐1) capture and transmission. We pulsed cells of monocytoid lineage (established and primary) and CD4‐ negative epithelial cells transiently expressing DC‐SIGN or LFA‐1 with isogenic HIV‐1 particles either devoid or bearing host‐derived ICAM‐1 or ICAM‐3 before incubation with an indicator cell line. To our surprise, the ICAM‐1/LFA‐1 association was a more efficient transmission factor than the combined gp120/DC‐SIGN and ICAM‐3/DC‐SIGN interactions. The involvement of the association between virus‐bound ICAM‐1 and its natural ligand LFA‐1 in virus binding and carriage was confirmed when using more physiological cellular targets, i.e., human lymphoid tissues cultured ex vivo. However, the contribution of virus‐anchored host ICAM‐1 to the process of retention and transmission of HIV‐1 could not be confirmed when using primary human cells of macrophage/dendritic lineage as transmitter cells and autologous CD4+ T lymphocytes as targets. Altogether these data underscore the complexity of factors participating in virus‐cell contact and efficient dissemination of HIV‐1 to target cells.

A novel virus capture assay reveals a differential acquisition of host HLA-DR by clinical isolates of human immunodeficiency virus type 1 expanded in primary human cells depending on the nature of producing cells and the donor source.

Previous findings indicated that HLA-DR is probably one of the most abundant cellular constituents incorporated within the human immunodeficiency virus type 1 (HIV-1) envelope. Given that the life-cycle of HIV-1 has been reported to be modulated by virion-bound host HLA-DR, an improved version of a virus capture technique was developed to assess the degree of HLA-DR incorporation in several clinical isolates of HIV-1 derived from primary human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDM). Analysis of virus stocks purified from PBMCs and MDM indicated that primary isolates of HIV-1 bearing distinct tropism (i.e. T-, macrophage-, and dual-tropic) all incorporate host cell membrane HLA-DR protein. The amount of incorporated HLA-DR varies among the primary HIV-1 isolates tested. Propagation of some clinical HIV-1 isolates in either autologous PBMCs or MDM resulted in differential incorporation of virion-bound cellular HLA-DR depending on the nature of the virus producer cells. Differences in the degree of HLA-DR incorporation were also noticed when macrophage-tropic isolates of HIV-1 were produced in MDM from different donors. Altogether these data show that the efficiency of HLA-DR incorporation into the envelope of primary isolates of HIV-1 is a multifactorial phenomenon since it is affected by the virus isolate itself, the nature of host cells (i.e. PBMCs or MDM) and the donor source.

Acquisition of Host-Derived CD40L by HIV-1 In Vivo and Its Functional Consequences in the B-Cell Compartment

ABSTRACT Aberrant activation of the B-cell compartment and hypergammaglobulinemia were among the first recognized characteristics of HIV-1-infected patients in the early 1980s. It has been demonstrated previously that HIV-1 particles acquire the costimulatory molecule CD40L when budding from activated CD4+ T cells. In this paper, we confirmed first that CD40L-bearing virions are detected in the plasma from untreated HIV-1-infected individuals. To define the biological functions of virus-associated CD40L and fully characterize its influence on the activation state of B cells, we conducted a large-scale gene expression analysis using microarray technology on B cells isolated from human tonsillar tissue. Comparative analyses of gene expression profiles revealed that CD40L-bearing virions induce a highly similar response to the one observed in samples treated with a CD40 agonist, indicating that virions bearing CD40L can efficiently activate B cells. Among modulated genes, many cytokines/chemokines (CCL17, CCL22), surface molecules (CD23, CD80, ICAM-1), members of the TNF superfamily (FAS, A20, TNIP1, CD40, lymphotoxin alpha, lymphotoxin beta), transcription factors and associated proteins (NFKB1, NFKBIA, NFKBIE), second messengers involved in CD40 signaling (TRAF1, TRAF3, MAP2K1, phosphatidylinositol 3-kinase), and the activation-induced cytidine deaminase (AID) were identified. Moreover, we show that soluble factors induced upon the exposure of B cells to CD40L-bearing virions can exert chemoattractant properties toward CD4+ T cells. We thus propose that a positive feedback loop involving CD40L-bearing HIV-1 particles issued from CD4+ T cells productively infected with HIV-1 play a role in the virus-induced dysfunction of humoral immunity by chronically activating B cells through sustained CD40 signaling.

HIV Type 1 Can Act as an APC upon Acquisition from the Host Cell of Peptide-Loaded HLA-DR and CD86 Molecules

It is well documented that a wide range of host-derived cell surface constituents is inserted within HIV type 1 (HIV-1) and located on the exterior of the virion. Although no virus-associated protein of host origin has been shown to be absolutely required for virus replication, studies have revealed that many of these proteins are functional and can affect several steps of the virus life cycle. In this study, we found that HIV-1 acquires peptide-loaded class II MHC (MHC-II) and the costimulatory CD86 molecules from the host cell. Moreover, we present evidence that virions bearing such peptide-loaded MHC-II and CD86 proteins can lead to activation of the transcription factors NF-κB and NF-AT in an Ag-specific human T cell line. A linear correlation was found between activation of NF-κB and the amount of peptide-loaded MHC-II molecules inserted within HIV-1. Finally, transcription of unintegrated and integrated HIV-1 DNA was promoted upon exposure of peptide-specific human T cells to viruses bearing both peptide-loaded MHC-II and CD86 proteins. These data suggest that HIV-1 can operate as an APC depending on the nature of virus-anchored host cell membrane components. It can be proposed that HIV-1 can manipulate one of its primary targets through the process of incorporation of host-derived proteins.

Activité physique, santé et vieillissement chez des femmes francophones de l'Ontario

This article discusses qualitative research conducted in minority Francophone communites in Ontario. The perceptions of and participation in physical activity by some thirty women are analysed with respect to sociological foundations and current views on aging. These views apply to individual responsibility for health; to the links between health, beauty, and aging; to participation in sports; to perceptions of masculinity and femininity; and, finally, to the obligation to remain physically active at all stages of life. The results of the study among women grouped into three age brackets reveal that, although these women have adopted a view of individual responsibility for health and the prevention of the harmful effects of aging through regular physical exercise, they may also be seen as subjects who find strategies in their daily lives to avoid falling prey to the pressures of health and beauty standards regarding aging, to face limitations, and to develop a healthy way of experiencing the aging process.