Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State

Abstract

Dendritic cells (DCs) are professional antigen-presenting cells whose functions are dependent on their degree of differentiation. In their immature state, DCs capture pathogens and migrate to the lymph nodes. During this process, DCs become resident mature cells specialized in antigen presentation. DCs are characterized by a highly limiting environment for human immunodeficiency virus type 1 (HIV-1) replication due to the expression of restriction factors such as SAMHD1 and APOBEC3G. However, uninfected DCs capture and transfer viral particles to CD4 lymphocytes through a trans-enhancement mechanism in which chemokines are involved. We analyzed changes in gene expression with whole-genome microarrays when immature DCs (IDCs) or mature DCs (MDCs) were productively infected using Vpx-loaded HIV-1 particles. Whereas productive HIV infection of IDCs induced expression of interferon-stimulated genes (ISGs), such induction was not produced in MDCs, in which a sharp decrease in ISG-and CXCR3-binding chemokines was observed, lessening trans-infection of CD4 lymphocytes. Similar patterns of gene expression were found when DCs were infected with HIV-2 that naturally expresses Vpx. Differences were also observed under conditions of restrictive HIV-1 infection, in the absence of Vpx. ISG expression was not modified in IDCs, whereas an increase of ISG-and CXCR3-binding chemokines was observed in MDCs. Overall these results suggest that sensing and restriction of HIV-1 infection are different in IDCs and MDCs. We propose that restrictive infection results in increased virulence through different mechanisms. In IDCs avoidance of sensing and induction of ISGs, whereas in MDCs increased production of CXCR3-binding chemokines, would result in lymphocyte attraction and enhanced infection at the immune synapse.

The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection

“…There are two possible reasons for this phenomenon: On the one hand, pDCs that are persistently stimulated by IFN-I express low levels of migration receptors and regulatory factors, such as CCR7, CD40, and CD86. These pDCs produce IFN-I since pathogenic nucleic acid traffics to the endosome ( 72 , 73 ), which induces apoptosis to these out-of-control cells mediated by the TNF-related apoptosis-inducing ligand (TRAIL) ( 74 ). On the other hand, IFN-I activates the non-canonical NF-κB signaling in pDCs.…”

Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals

“…We evaluated the infection in human dendritic cells (DCs) and macrophages, because CAV1 is the major coat protein responsible for caveolae assembly and is highly expressed in these cell types [24]. Primary cells were generated and cultured as previously described [25].…”

“…Briefly, HeLaeP4 cells, macrophages or DCs were seeded into 24-well plates and 100 ng of siRNAs and 3 mL of HiPerfect were used for each transfection. Immunoblotting, immunofluorescence, detection of HIV-1 core antigens by flow cytometry and the measurement of luciferase activity were carried out as previously described [25]. The antibodies employed for these experiments were a mouse anti-UBXN6 antibody (5C3-1, Abcam Inc.), a rabbit anti-Caveolin-1 antibody (N20, sc-894, Santa Cruz Biotechnology) and a FITCconjugated human anti-Gag/p24 (KC57, Beckman Coulter).…”

Dendritic Cells, the Double Agent in the War Against HIV-1

“…On the contrary, in the case of mDCs, productive HIV-1 infection decreased expression of interferon-stimulated genes CXCR3-binding chemokines, suggesting a diminished trans-infection of CD4 lymphocytes. Paradoxically, restrictive HIV-1 infection had the opposite effect on mDCs, increasing the aforementioned gene expression, which would result in lymphocyte attraction and enhanced trans-infection (161).…”