Biomedical subjects

Rémi Cheynier

Publications and source records attributed to Rémi Cheynier.

9 recordsLinked to original sources

PubMed2006

IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy.

Despite efficient antiretroviral therapy (ART), CD4+ T cell counts often remain low in HIV-1-infected patients. This has led to IL-7, a crucial cytokine involved in both thymopoiesis and peripheral T cell homeostasis, being suggested as an additional therapeutic strategy. We investigated whether recombinant simian IL-7-treatment enhanced the T cell renewal initiated by ART in rhesus macaques chronically infected with SIVmac251. Six macaques in the early chronic phase of SIV infection received antiretroviral treatment. Four macaques also received a 3-wk course of IL-7 injections. Viral load was unaffected by IL-7 treatment. IL-7 treatment increased the number of circulating CD4+ and CD8+ memory T cells expressing activation (HLA-DR+, CD25+) and proliferation (Ki-67+) markers. It also increased naive (CD45RAbrightCD62L+) T cell counts by peripheral proliferation and enhanced de novo thymic production. The studied parameters returned to pretreatment values by day 29 after the initiation of treatment, concomitantly to the appearance of anti-IL-7 neutralizing Abs, supporting the need for a nonimmunogenic molecule for human treatment. Thus, IL-7, which increases T cell memory and de novo renewal of naive T cells may have additional benefits in HIV-infected patients receiving ART.

Animals↗

PubMed2006

Naive T-cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy.

The reasons for poor CD4+ T-cell recovery in some human immunodeficiency virus (HIV)-infected subjects despite effective highly active antiretroviral therapy (HAART) remain unclear. We recently reported that CXCR4-using (X4) HIV-1 could be gradually selected in cellular reservoirs during sustained HAART. Because of the differential expression of HIV-1 coreceptors CCR5 and CXCR4 on distinct T-cell subsets, the residual replication of R5 and X4 viruses could have different impacts on T-cell homeostasis during immune reconstitution on HAART. We examined this hypothesis and the mechanisms of CD4+ T-cell restoration by comparing the virological and immunological features of 15 poor and 15 good immunological responders to HAART. We found a high frequency of X4 viruses in the poor immunological responders. But the levels of intrathymic proliferation of the two groups were similar regardless of whether they were infected by R5 or X4 virus. The frequency of recent thymic emigrants in the poor immunological responders was also similar to that found in the good immunological responders, despite their reduced numbers of naïve CD4+ T cells. Our data, rather, suggest that the naïve T-cell compartment is drained by a high rate of mature naïve cell loss in the periphery due to bystander apoptosis or activation-induced differentiation. X4 viruses could play a role in the depletion of naïve T cells in poor immunological responders to HAART by triggering persistent T-cell activation and bystander apoptosis via gp120-CXCR4 interactions.

Adult↗

PubMed2005

The majority of human immunodeficiency virus type 1 particles present within splenic germinal centres are produced locally.

In most stages of human immunodeficiency virus (HIV) infection, cell-free viral particles can be detected in germinal centres (GCs) that are principally retained, in the form of immune complexes, on the surface of follicular dendritic cells (FDCs). The source of this virus remains unknown, although it is agreed that the FDCs themselves are not infected productively. By sequencing HIV viral DNA, genomic RNA and spliced mRNA isolated from individual splenic white pulps, it was shown here that the majority of HIV-1 viral particles are produced locally within the supporting lymphoid structure and do not result from trapping of circulating viruses or immune complexes. These findings underline the exquisite spatial organization of HIV-1 replication in vivo, suggesting a local origin for viruses trapped in splenic GCs.

DNA, Viral↗

PubMed2005

Antigenic stimulation specifically reactivates the replication of archived simian immunodeficiency virus genomes in chronically infected macaques.

Human immunodeficiency virus/simian immunodeficiency virus (SIV) diversification is a direct consequence of viral replication and occurs principally in secondary lymphoid organs where CD4(+) T cells are activated and proliferate. However, the evolution of viral quasispecies may also be driven by various nonexclusive mechanisms, including adaptation to specific immune responses and modification of viral fitness. Analysis of viral quasispecies in SIV-infected macaques subjected to repeated antigenic stimulations allowed us to demonstrate transient expansions of SIV populations that were highly dependent upon activation of antigen-specific T cells. T-cell clones expanded in response to a particular antigen were infected by a specific viral population and persisted for prolonged periods. Upon a second stimulation by encounter with the same antigen, these specific genomes were at the origin of a new burst of replication, leading to rapid but transient replacement of the viral quasispecies in blood. Finally, longitudinal analysis of SIV sequence variation during and between antigenic stimulations revealed that viral evolution is mostly constrained to periods of strong immunological activity.

Amino Acid Sequence↗

PubMed2004

HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation.

The supply of naive T cells by the thymus normally requires precursor T cell proliferation within the thymus and would be particularly important in the setting of HIV infection when both naive and memory T cells are progressively depleted. As a robust, quantitative index of intrathymic proliferation, the ratio of different T cell receptor excision circles (TRECs), molecular markers of distinct T cell receptor rearrangements occurring at different stages of thymocyte development, was measured in peripheral blood-mononuclear cells (PBMCs). This ratio has the virtue that it is a "signature" of thymic emigrants throughout their entire life and, thus, can be measured in peripheral cell populations that are easy to obtain. Using the new assay, we evaluated the effect of HIV infection on intrathymic precursor T cell proliferation by longitudinal analysis of PBMCs from recently infected individuals. Our findings reveal a substantial reduction in intrathymic proliferation. The analysis also indicates the existence of a compensatory mechanism acting to sustain the numbers of recent thymic emigrants (RTEs) in the periphery.

Aging↗

PubMed2003

Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation (AHSCT) leads to a prolonged state of immunodeficiency characterized by low peripheral naive T-cell counts. To identify the mechanisms leading to this defect we quantitatively and qualitatively analyzed thymic function through quantification of T-cell receptor excision circle (TREC) frequencies (both the signal-joint TREC [sjTREC] and 6 different DbetaJbeta TRECs, by-products of T-cell receptor [TCR] alpha and beta gene rearrangement, respectively), in conjunction with immunophenotype and spectratype analyses in a cohort of patients sampled from 1 to 10 years following AHSCT. In this cohort, reduced thymic function was associated only with ongoing clinical chronic graft-versus-host disease (cGVHD). Nonetheless, the diversity of thymic production remained unchanged irrespective of the patient's cGVHD status. Interestingly, increased homeostatic proliferation was found in the naive T-cell compartment of cGVHD- patients who underwent transplantation. However, reduced expression of both the interleukin-7 receptor alpha (IL-7Ralpha) (CD127) chain and the antiapoptotic protein Bcl-2 was observed. Taken together, these data indicate that the inability to reconstitute the naive T-cell compartment for several years after AHSCT, in the absence of cGVHD, is a consequence of impaired naive T-cell survival rather than thymic dysfunction.

Adult↗

PubMed2002

Phylogeny derived from coding retroviral genome organization.

When divergence between viral species is large, the analysis and comparison of nucleotide or protein sequences are dependent on mutation biases and multiple substitutions per site leading, among other things, to the underestimation of branch lengths in phylogenetic trees. To avoid the problem of multiply substituted sites, a method not directly based on the nucleic or protein sequences has been applied to retroviruses. It consisted of asking questions about genome structure or organization, and gene function, the series of answers creating coded sequences analyzed by phylogenic software. This method recovered the principal retroviral groups such as the lentiviruses and spumaviruses and highlighted questions and answers characteristic of each group of retroviruses. In general, there was reasonable concordance between the coded genome methodology and that based on conventional phylogeny of the integrase protein sequence, indicating that integrase was fixing mutations slowly enough to marginalize the problem of multiple substitutions at sites. To a first approximation, this suggests that the acquisition of novel genetic features generally parallels the fixation of amino acid substitutions.

Genome, Viral↗

PubMed2001

Insertion/deletion frequencies match those of point mutations in the hypervariable regions of the simian immunodeficiency virus surface envelope gene.

A method for encoding insertions and deletions (indels) has been developed and adapted to the SplitsTree program. Following phylogenetic reconstruction, the relative frequencies of indels were estimated for a large number of in vivo sequence sets corresponding to the env V1 hypervariable region of the simian immunodeficiency virus SIVmac251. The method allowed recovery of many point mutations hitherto lost due to gap stripping. Deletions were as frequent as transversions and were 4- to 8-fold more frequent than insertions, invariably duplications. The high proportion of deletions among mutation events suggests that lentivirus vectors may readily delete parts of their cargo.

Base Sequence↗

PubMed2001

Phylogenetic reconstruction of intrapatient evolution of human immunodeficiency virus type 1: predominance of drift and purifying selection.

The intra-host evolution of 73 human immunodeficiency virus type 1 quasispecies was analysed by split decomposition analysis. Non-synonymous and synonymous nucleotide substitutions were counted along the shortest path connecting all sequences and compared with the numbers expected under the assumption of a random model of mutation. For the majority of substitutions, drift and negative selection seemed to prevail.

Biological Evolution↗