13th Conference on Retroviruses and Opportunistic Infections Denver, Colorado - February 5-8, 2006

Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 20

Seema Desai, A Chaparro, H Liu, G Scott, P Haslett, R Pahwa, and S Pahwa
Univ of Miami, Miller Sch of Med, FL, US

BACKGROUND: Defects of myeloid (m) dendritic cells (DC) and plasmacytoid (p) DC have been described in HIV infection. Following potent ART, mDC become normal but pDC defects persist. The status of DC in perinatally HIV-infected subjects who have survived into late childhood and adolescence with ART is unknown. We hypothesized that persistent pDC defects could be associated with impaired immune reconstitution or virologic failure on ART.

METHODS: Subjects with perinatal HIV infection (n=18, median age 13.2 years), of whom 14 were on ART for >5 years (median 9.9 years), and 4 for <5 years (median 2.5 years), were classified as immunologic responders (IR+; CD4 >25%), or virologic responders (VR+; plasma HIV RNA <400 copies/mL). As controls, 5 healthy age-matched subjects were studied. DC were defined as (Lin 1­, HLA DR+) and subtyped as mDC (CD11c+) or pDC (CD123+). Short-term stimulation (3 hours) of mDC and pDC was performed through ligation of their toll-like receptors (TLR) with a TLR7/8 agonist (Resiquomod). DC maturation markers CD83, CD80, lymph node homing receptor CCR7, and intracellular cytokines tumor necrosis factor-α (TNF-α) and interferon-α (IFN-α), were evaluated by flow cytometry in a whole blood assay. Spearman correlation and Student’s t tests were used as statistical tools.

RESULTS: Upon TLR ligation, both subsets of DC showed marked up-regulation of CD83, and moderate increase in CD80 (mDC> pDC) in all study subjects. CCR7 up-regulation and IFN-α response occurred primarily in pDC, and TNF-α response was more pronounced in mDC than in pDC. A selective impairment in up-regulation of pDC CCR7 was observed in patients classified as IR­ and VR­ as compared with subjects who were classified as IR+VR+ (mean CCR7: 5.6% vs 43.3%, respectively; p=0.0002). Levels of pDC CCR7 were intermediate (mean 22.8%) in the IR+VR­ patient group. CCR7 expression correlated strongly with percentage of CD4 counts (p=0.002). The pDC IFN-α response was markedly reduced in 2 subjects with >30,000 HIV RNA copies with almost absent CCR7 following Resiquomod stimulation. No defects in mDC were observed in patients.

CONCLUSIONS: The most striking finding was a reduced expression of CCR7 in TLR-stimulated pDC of HIV-infected children who have poor immunologic response or ongoing, active viral replication while on ART. A defect in homing of the pDC to lymph nodes could break the link between innate and adaptive immune response to HIV.

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2006-02-05
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