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. 2008 Jan;82(1):538-45.
doi: 10.1128/JVI.01449-07. Epub 2007 Oct 24.

Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration

Sumathi Sankaran  1 , Michael D George, Elizabeth Reay, Moraima Guadalupe, Jason Flamm, Thomas Prindiville, Satya Dandekar
Affiliations

Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration

Sumathi Sankaran et al. J Virol. 2008 Jan.

Abstract

Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is a site for severe CD4(+) T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4(+) T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4(+) T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability to control viral replication and repair and regenerate intestinal mucosal tissues.

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Figures

FIG. 1.
FIG. 1.
Quantitation of viral loads and localization of HIV-infected cells in GALT during primary-stage HIV infection. (A) Viral RNA levels, measured by B-DNA assay, ranged between 4 and 6 logs per ml of plasma. (B) At corresponding time points, viral burden was detected in GALT biopsy samples, varying between 1 and 4 log copies per μg of total RNA. (C) Viral p24 was localized to both lymphocytes and macrophages. CD3+ T cells appear red, macrophages pink, and HIV p24 yellow. Double staining in a p24-positive lymphocyte results in a green cell, while double staining in a p24-positive macrophage appears blue.
FIG. 2.
FIG. 2.
Disruption in T-cell homeostasis in GALT during primary-stage HIV infection. (A) CD4+ T-cell percentages in GALT were markedly decreased in all four primary-stage patients, with the largest depletion occurring in patients at 6 and 8 weeks postinfection. (B) The vast majority of CD4+ depletion in GALT appears to occur early in the primary stage, leading to the disruption of T-cell homeostasis, similarly to observations in chronic-stage patients but in striking contrast to LTNP patients, who maintain natural control over viral replication and disease progression.
FIG. 3.
FIG. 3.
Modulation of host gene expression in GALT during primary HIV infection. Genes whose transcription was altered by HIV infection in the intestinal mucosa were identified through microarray analysis of jejunal biopsy samples and subjected to hierarchical clustering to identify common patterns of up and down regulation. Pathways statistically overrepresented were identified through functional analysis of the genes in each subcluster. Up regulated genes were predominated by defense response factors, cell cycle mediators, and apoptosis regulators, while genes associated with a broad range of metabolic pathways and tissue regeneration were down modulated, highlighting a pathogenic shift in the normal physiological balance within the GALT microenvironment.
FIG. 4.
FIG. 4.
(A to F) Immunohistochemistry-based detection of RANTES and activated caspase 3 in GALT. Increased levels of caspase 3 were observed in GALT during primary HIV infection (B) compared to an uninfected healthy control (A). Caspase 3 (dark pink) signal also overlapped substantially with the epithelial marker Ber EP4 (green), appearing as a light pink stain (×40 magnification in panel C and ×100 magnification in panel D). RANTES expression was also increased (light blue punctuate stain) in primary-stage infections (F) compared to that in uninfected controls (E). (G) Gene expression profile of host immune responses in GALT during primary HIV infection. n-fold increases over uninfected controls in the expression of genes controlling various host response pathways in GALT during primary-stage infection were determined for patients E116, E134, and E154. A broad range of antiviral, cytotoxic, antimicrobial, and humoral response mediators were significantly up regulated. Stronger levels of interferon induction and cytoxic responses correlated with high levels of local viral replication (E154), while lower viral burden was associated with dampened immune responses and increased transcription of cytoprotective genes (E116).
FIG. 5.
FIG. 5.
(A) Suppression of HIV replication is linked to induction of genes with cytoprotective and regenerative function. Genes encoding mucins and trefoil factors were substantially up regulated in the primary-stage HIV patient that displayed the lowest viral burden (E116). The cumulative level of increase was similar to those observed for elite long-term HIV controllers and in contrast to those observed for chronic-stage patients as well as E134 and E154, suggesting a potential link between primary-stage control of enteropathy and effective suppression of disease progression. (B) Repressed expression of metabolic factors, growth mediators, and cellular differentiation markers in primary-stage HIV patients. mRNA levels for a broad range of genes controlling lipid, carbohydrate, and xenobiotic metabolism, organogenesis, and cellular differentiation were repressed in essentially all primary-stage HIV patients tested, indicating that impairment of tissue growth and regeneration may have contributed to the early development of enteropathy. Patient E154, with elevated mucosal viral loads, showed the lowest expression of genes involved in epithelial growth and differentiation (e.g., Wnt pathway genes). (C) RT-PCR-based analysis of immune activation and lipid metabolism-associated gene expression. TaqMan validation of microarray results demonstrated similar patterns of up regulation of immune activation-associated genes CCR5, STAT1, IFN9-27, and MIG and a down regulation of lipid metabolism-associated transcription (FABP2). Error bars indicate standard deviations.
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