The new issue of the Journal of Immunology features a paper from Ashley Haase’s group looking at lymphoid tissue gene expression in HIV infection. The study, led by Qingsheng Li, uses microarray technology to investigate gene expression changes during the acute, asymptomatic and late (AIDS) stages of disease compared to healthy uninfected individuals. The analyses reveal that the expression of 46 genes is significantly altered (in most cases upregulated) at all stages of infection; half of these genes have known functions in immunity, particularly immune activation. Examples include CD38 (the well-known immune activation marker that predicts the pace of disease progression in HIV infection), CCR5, pro-apoptotic genes and nine different interferon-related genes.
Acute infection is associated with altered expression of another 358 unique genes, more than any other stage of infection. Again, in most cases (81%) these genes are upregulated and a large proportion are related to immune activation (e.g. proinflammatory cytokines, signal transduction molecules, activators of cell proliferation, mediators of cell cycle progression and the pro-apoptotic Fas-Fas pathway). However, there are also increases in the expression of genes associated with dampening the immune response such as IDO, an enzyme with powerful immune-suppressing properties. A suite of additional genes involved in innate immunity are also upregulated during acute infection, including the toll-like receptors TLR7 and TLR8 and numerous components of the interferon pathway.
The asymptomatic stage of infection is associated with a dramatic shift in gene expression, with levels returning to baseline in most cases. In addition to the 46 genes with altered expression at all stages of infection, only 18 genes are uniquely altered in asymptomatic individuals. The majority relate to immune activation and lymphoid tissue remodeling and repair.
In people with AIDS, 183 genes are uniquely altered and - in contrast to the other stages of infection - most of these genes (84%) are downregulated. Examples include genes involved in immune activation, apoptosis, and tissue remodeling and repair. A substantial proportion of the genes belong to the CD28 T cell co-stimulatory pathway, consistent with the accumulation of dysfunctional CD28-negative T cells that occurs over the course of HIV infection. The researchers also note that at this stage of disease “decreased expression could be due to loss of cells expressing these genes, decreased expression in a particular cell type, or both.”
In the discussion section of the paper, the authors conclude: “the major finding of this study is that there are stage-specific transcriptional signatures in lymphoid tissues during HIV-1 infection.” The results set the stage for additional investigations into the consequences of the documented changes in gene expression using a comprehensive systems biology approach. The ultimate aim is “not only to better understand viral pathogenesis during the various stages of HIV-1 disease but also to identify adjunctive approaches to improving treatment and immune reconstitution.”
FIGURE 2. In human LT of HIV-1-infected subjects, the general functional categories of genes with altered expression (1.7 times the level at baseline, p < 0.05). A, Common to all stages (C1); B, unique to the acute stage (S1); C, unique to the asymptomatic stage (S2); and D, unique to the AIDS stage (S3). Green and red letters indicate, respectively, decreased and increased expression. The size of each sector in a pie diagram is proportional to the number of genes in its category (in parentheses). All genes and their names derived from abbreviations can be found in supplemental Table I.
CREDIT: The Journal of Immunology, 2009, doi:10.4049/jimmunol.0803222
The Journal of Immunology, 2009, doi:10.4049/jimmunol.0803222
Published online July 13, 2009
Qingsheng Li2,*, Anthony J. Smith2,*, Timothy W. Schacker, John V. Carlis, Lijie Duan*, Cavan S. Reilly and Ashley T. Haase3,*
*Department of Microbiology Division of Infectious Diseases, Department of Medicine, Medical School Department of Computer Science and Engineering, Institute of Technology, and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455
Untreated HIV-1 infection progresses through acute and asymptomatic stages to AIDS. Although each of the three stages has well-known clinical, virologic, and immunologic characteristics, much less is known of the molecular mechanisms underlying each stage. In this study, we report lymphatic tissue microarray analyses, revealing for the first time stage-specific patterns of gene expression during HIV-1 infection. We show that although there is a common set of key genes with altered expression throughout all stages, each stage has a unique gene expression signature. The acute stage is most notably characterized by increased expression of hundreds of genes involved in immune activation, innate immune defenses (e.g., RIG-1, MDA-5, TLR7 and TLR8, PKR, APOBEC3B, 3F, 3G), adaptive immunity, and in the proapoptotic Fas-Fas ligand pathway. Yet, quite strikingly, the expression of nearly all acute stage genes return to baseline levels in the asymptomatic stage, accompanying partial control of infection. This transition from acute to asymptomatic stage is tied to increased expression of a diverse array of immunosuppressive genes (e.g., CLEC12B, ILT4, galectin-3, CD160, BCMA, FGL2, LAG3, GPNMB). In the AIDS stage, decreased expression of numerous genes involved in T cell signaling identifies genes contributing to T cell dysfunction. These common and stage-specific gene expression signatures identify potential molecular mechanisms underlying the host response and the slow, natural course of HIV-1 infection.
Comments