PLoS One. 2010 Feb 25;5(2):e9436.

Increased alpha-defensins 1-3 production by dendritic cells in HIV-infected individuals is associated with slower disease progression.

Rodríguez-García M, Climent N, Oliva H, Casanova V, Franco R, Leon A, Gatell JM, García F, Gallart T.

Source

Service of Immunology, Hospital Clínic de Barcelona, Barcelona, Spain.

Abstract

BACKGROUND:

Defensins are natural endogenous antimicrobial peptides with potent anti-HIV activity and immuno-modulatory effects. We recently demonstrated that immature dendritic cells (DC) produce alpha-defensins1-3 and that alpha-defensins1-3 modulate DC generation and maturation. Since DC-HIV interaction plays a critical role during the first steps of HIV infection, we investigated the possible impact of alpha-defensins1-3 production by DC on disease progression.

METHODOLOGY/PRINCIPAL FINDINGS:

Monocyte-derived DC (MDDC) were analyzed comparatively in healthy controls (HC) and HIV-infected patients, including untreated "elite" and "viremic" controllers, untreated viremic non-controllers and antiretroviral-treated patients. We found that production of alpha-defensins1-3 was significantly increased in MDDC from HIV-infected patients versus HC, and this increase was mainly due to that observed in controllers, while in non-controllers the increase was not statistically significant (controllers vs. HC, p<0.005; controllers vs. non-controllers p<0.05). Secreted alpha-defensins1-3 by immature MDDC positively correlated with CD4 T cell counts in controllers, but not in non-controllers. Moreover, independently of their clinical classification, HIV-infected patients with higher alpha-defensins1-3 secretion by immature MDDC showed slower disease progression, measured as no decrease in the number of CD4+ T-cells below 350 cell/mm(3), lower increase of plasma viral load and no initiation of treatment over time. Plasma alpha-defensins1-3 levels lacked any relationship with immunologic and virologic parameters.

CONCLUSIONS/SIGNIFICANCE:

High production of alpha-defensins1-3 by immature DCs appears as a host protective factor against progression of HIV-1 infection, suggesting potential diagnostic, therapeutic and preventive implications. This protective effect may arise from the activity of alpha-defensins1-3 to damage the virions prior and/or after their internalization by immature DC, and hence favoring a more efficient viral processing and presentation to HIV-specific CD4+ T cells, without or with a minor rate of transmission of infectious HIV-1 virions.

PMID:: 20195543; [PubMed - indexed for MEDLINE]
PMCID:: PMC2828484

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Figure 1

Production of α-defensins 1-3 by immature (im) and mature (m) MDDCs.

(A) Immature and mature MDDC immunophenotype from one representative healthy control individual and one HIV-infected subject. X-axis represents HLA-DR expression and Y-axis represents the surface markers indicated. The percentage of positive cells are shown in each quadrant. (B) Relative expression of α-defensins 1-3 mRNA by real time RT-PCR in healthy control individuals (n = 15; open circles) and HIV-infected subjects (n = 39; open rhombus). Dots represent each patient and horizontal lines represent median ± interquartile ranges. Undetectable samples from mMMDC in HC and HIV-infected patients are not represented in the figure. (C) Levels of α-defensins 1-3 detected in MDDC culture supernatants from healthy non-infected controls (n = 15; white boxes) and HIV-infected subjects (n = 39; grey boxes). Boxes represent interquartile ranges, horizontal lines inside each box indicate the median and whiskers indicate maximum and minimum values. (D) Intracellular staining and flow cytometry analysis of α-defensins 1-3 in immature MDDCs. MDDCs were treated with monensin for 8h and double-stained for CD40 and α-defensins 1-3. CD40 positive cells were selected and the histogram corresponds to positive cells for intracellular α-defensins 1-3. Histogram represents the isotype control (dots line), healthy control (open line) and HIV-infected subject (filled histogram). Numbers indicate the percent of positive cells for healthy control (normal number) or HIV-infected patient (bold numbers). Representative result of four different healthy controls and four HIV-infected patients. (E) Geometric mean fluorescence intensity for intracellular α-defensins 1-3 in non-infected individuals (n = 4; white box) and HIV-infected subjects (n = 4; grey box). Boxes represent interquartile ranges, horizontal lines inside each box indicate the median and whiskers indicate maximum and minimum values.

Increased α-Defensins 1-3 Production by Dendritic Cells in HIV-Infected Individuals Is Associated with Slower Disease Progression

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Increased alpha-defensins 1-3 production by dendritic cells in HIV-infected individuals is associated with slower disease progression.

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