Dysregulation of multiple inflammatory molecules in lymph node and ileum of macaques during RT-SHIV infection with or without antiretroviral therapy

Abstract

Background: Pathogenic infection with human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) is characterized by a loss of CD4+ T cells and chronic lymphocyte activation even during suppressive antiretroviral therapy (ART).

Methods: Using NanoString, expression of >100 molecules associated with inflammation or immune activation was evaluated in mesenteric lymph nodes and ileum of macaques infected with a pathogenic SIV/HIV virus, RT-SHIV, during viremia or during suppressive ART and compared to uninfected controls.

Results: Of the 105 RNA species quantified in the tissues, expression of 33 genes was altered significantly in one or both tissues during viremia but returned to normal levels during ART. However, 29 additional genes were altered in expression levels in the tissues of both viremic and ART-suppressed macaques.

Conclusions: Identification of the mechanisms of chronic inflammation in specific cells and in different tissues may help determine whether early ART initiation or novel therapies can prevent it.

Keywords: HIV; inflammation; persistence; reservoirs.

Figure 1

(A) Plasma viral RNA detected at week 2 post-infection and necropsy from the uninfected animals, untreated RT-SHIV-infected animals, and ART-treated RT-SHIV-infected animals. The dotted line denotes the limit of detection of 30 viral RNA copies/ml. (B) Viral RNA detected in mesenteric LN and ileum samples of uninfected animals, untreated RT-SHIV-infected animals, and ART-treated RT-SHIV-infected animals is graphed per 100ng of total tissue RNA. Each bar represents the median of all samples in each group and error bars represent standard deviations.

Figure 2

(A) The proportion of the NanoString CodeSet in each category of gene products detected in the samples (total = 110). (B) Results are shown of a subset of inflammatory RNA molecules and all 5 housekeeping RNA molecules measured in mesenteric LN and ileum from all samples. The results were averaged per group and the fold difference between viremic (untreated infected) animals or ART-treated animals and uninfected controls. The dotted line denotes no difference or a fold change of 1.

Figure 3

CD4 RNA copies/100ng RNA in (A) mesenteric LN and (C) ileum and CD8 RNA copies/100ng RNA in (B) mesenteric LN and (D) ileum were plotted against SIV gag copies detected in the same samples. R² and p values were determined by Spearman correlation.

Figure 4

CD103, or integrin αE, RNA copies in (A) mesenteric LN and (C) ileum of uninfected, untreated RT-SHIV+, and ART-treated RT-SHIV+ macaques. Asterisks denote p values < 0.05 between groups determined by unpaired t tests. CD103 RNA copies/100ng RNA in (B) mesenteric LN and (D) ileum were plotted against SIV gag copies detected in all animals. (E) CD103 RNA copies/100ng RNA in ileum of only uninfected and untreated RT-SHIV+ macaques. R² and p values were determined by Spearman correlation.

Figure 5

PRKCB RNA copies in (A) mesenteric LN and (C) ileum of uninfected, untreated RTSHIV+, and ART-treated RT-SHIV+ macaques. Asterisks denote p values < 0.05 between groups determined by unpaired t tests.