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.
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