Blood dendritic cells in chronically HIV-1 infected individuals in South Africa: Phenotype, function and immune modulation

[摘要] ENGLISH ABSTRACT :HIV-1 infection detrimentally affects CD4 T lymphocytes as well as the blood plasmacytoid (pDC) andmyeloid dendritic cell (mDC) compartment. DCs act as innate sensors and as initiators and directors ofantigen-specific immune responses. Whereas, mDCs have the unique ability to prime naïve T-lymphocytesand activate adaptive immune responses, pDCs are primary producers of type 1 interferons (IFNs), playing apivotal role in anti-viral immunity. In the current study both pDCs and mDCs from chronically HIV-1 infectedSouth African individuals (on or naïve for ARV therapy) as well as with and without concurrent TB disease,were compared to matched uninfected controls. Similar to CD4 T lymphocytes, bothpDCs and mDCs, weresignificantly depleted during HIV-1 infection, (reduction of pDC, mDC and CD4 T lymphocyte was 63% (p 0.001), 80% (p 0.001) and 31% (p 0.01), respectively). In parallel, significantly higher levels ofgeneralised immune activation and exhaustion (CD38+CD8+, PD-1+CD8+ and CD38+PD-1+CD8+ Tlymphocytes) were observed. ARV treatment (1 year) did not result in DC number recovery despite asignificant increase of CD4 T lymphocytes numbers (CD4 T lymphocyte number gain of 89% (p 0.01), it fellshort of full recovery).TB co-infection did not exacerbate number loss. Phenotypic characterisation of DCpopulations in circulation during HIV-1 infection may indicate the underlying reasons for the loss fromcirculation. Phenotypic profiling by multiparameter flow cytometry included: markers of activation (CD86,CD80 and CD62L), maturation (CD83), apoptosis (TNF-R2, FAS, FASL and TRAIL R1-R4) and chemotaxis(CCR5, CCR7, CCR9 and CXCR6). HIV-infection was associated with a significantly higher percentage ofCD86+mDCs which may be indicative of early maturation or transition to secondary lymphoid tissue. Thefrequency of the CD86+mDCs subset normalised upon ARV therapy. Also, HIV-1 infection influenced thedistribution of TNF-R2+pDCs and TNF-R2+mDCs. Increased TNF-R2 expression in both subsets, may attestto enhanced survival function. Functionally, DCs of HIV-1 infected individuals were reactive to TLR-Lstimulation and in some cases showed enhanced responses compared to uninfected individuals. Asignificantly higher frequency of TNF-R2+pDCs, IFN- +pDCs, and TNF +mDCs was observed in whole bloodTLR cultures of HIV-1 infected individuals (TNF-R2+pDCs: LPS (p = 0.002) and R848 (p = 0.01), IFN- +pDCs: R848 (p = 0.04), TNF +mDCs: LPS (p = 0.003))s.In addition, whole blood TLR cultures of the ARVtreated study group generally showed normalisation of the responses, however; in certain cases ARVtherapy reduced responsiveness to levels significantly lower than the control study group (i.e.TNF-R2+pDCsand TNF-R2+mDCs in CpG ODN stimulation). In contrast, a significantly lower frequency of IL12p40+mDCswas observed during HIV-1 infection (p = 0.02). TLR-L cultures of the ARV treated study groups showednormalisation of IL12p40+mDCsfrequency. Notably, treatment with the immunomodulating peptide VIPinduced a decline in IL12p40+mDCs to levels lower than the control study group.The frequency ofTNF +pDCs in TLR-L whole blood cultures was similar between the healthy, untreated and treated HIV-1infected study groups, however, significantly reduced frequencies were observed in these study groups uponVIP treatment. These data indicate unique phenotypic and functional changes in DC subsets in chronic HIV-1 infection which may provide potential targets for immunotherapeutic intervention.

[发布机构] Stellenbosch University