497-M.
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Mucosal Cytokines/Chemokines are Increased by as much as 75-fold in HAART-Treated Subjects with Detectable Plasma Viral Loads Compared to Those with Fully Suppressed Viremia
J. Elliott1, W.J. Boscardin1, M. Poles2, I. McGowan1, M. Fuerst1, P. Taing1, and P. Anton*1
1Univ. of California AIDS Inst., Los Angeles and 2New York Univ. Sch. of Med., New York
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Background: The normal gut mucosa expresses levels of chemokines/cytokines that maintain low-level inflammation. Increased expression of pro-inflammatory cytokine mRNA is seen in the mucosa of untreated HIV-infected patients. These cytokines up-regulate HIV replication, contribute to apoptosis, and recruit additional target cells to tissue. We asked if mucosal cytokine mRNA differs in suppressed versus unsuppressed subjects on HAART.
Methods: Banked rectosigmoid biopsies from 15 HIV-positive men on HAART with CD4 counts >100 cells/mm3 were retrospectively evaluated for mucosal cytokine mRNA. 6 subjects had undetectable plasma HIV-1 RNA (<50 copies/mL) and undetectable mucosal HIV RNA viral load (<10 copies/upsilong; 9 subjects had detectable plasma HIV-1 RNA (mean 4.5 log, range 3.7-5.5 log) and high mucosal HIV RNA viral load (mean 4.1 log, range 3.7-5.0 log). Total RNA was isolated from 3 pooled biopsies and amplified using primers specific for beta-actin, IL-1beta, IL-2, IL-6, IL-10, IL-12,TNF-alpha, gamma-IFN, and RANTES using real-time PCR. Results were normalized for beta-actin mRNA content and expressed as a ratio.
Results: Subjects with detectable plasma and mucosal HIV RNA express significantly increased levels of mucosal mRNA for gamma-IFN (75-fold; p=0.001), RANTES (25-fold; p=0.002); TNF-alpha (14-fold; p=0.01), IL-2 (19.5-fold; p=0.001), IL-1 (9-fold; p=0.02), IL-10 (9-fold; p=0.004) when compared to subjects with undetectable plasma and mucosal HIV RNA. No significant differences were observed with IL-12 and IL-6. Years of infection (mean=12), duration of HAART, and CD4 levels did not differ. Plasma phenotypic resistance panels are pending.
Conclusions: Mucosal cytokine profiles are significantly increased in subjects with detectable plasma and mucosal viral burden compared to those effectively suppressed in plasma. Increases do not simply reflect a change in Th1/Th2 ratios but were detected in pro-inflammatory (TNF-alpha, IL-1) and Th1 (IL-2, gamma-IFN) as well as Th2 (IL-10) and chemokine (RANTES) mRNA. These data identify a subgroup with mucosal hyperactivity that correlates with incomplete responsiveness to HAART and identifies new adjunctive targets for therapy as well as potential mechanisms for mucosal apoptosis.
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