PMID- 28148784 OWN - NLM STAT- MEDLINE DCOM- 20170515 LR - 20181202 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 91 IP - 8 DP - 2017 Apr 15 TI - Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State. LID - 10.1128/JVI.01379-16 [doi] LID - e01379-16 AB - 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.IMPORTANCE In this work we describe for the first time the activation of a different genetic program during HIV-1 infection depending on the state of maturation of DCs. This represents a breakthrough in the understanding of the restriction to HIV-1 infection of DCs. The results show that infection of DCs by HIV-1 reprograms their gene expression pattern. In immature cells, productive HIV-1 infection activates interferon-related genes involved in the control of viral replication, thus inducing an antiviral state in surrounding cells. Paradoxically, restriction of HIV-1 by SAMHD1 would result in lack of sensing and IFN activation, thus favoring initial HIV-1 escape from the innate immune response. In mature DCs, restrictive infection results in HIV-1 sensing and induction of ISGs, in particular CXCR3-binding chemokines, which could favor the transmission of HIV to lymphocytes. Our data support the hypothesis that genetic DC reprograming by HIV-1 infection favors viral escape and dissemination, thus increasing HIV-1 virulence. CI - Copyright (c) 2017 American Society for Microbiology. FAU - Calonge, Esther AU - Calonge E AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain. FAU - Bermejo, Mercedes AU - Bermejo M AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain. FAU - Diez-Fuertes, Francisco AU - Diez-Fuertes F AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain. FAU - Mangeot, Isabelle AU - Mangeot I AD - Inserm, U1184, Paris, France. AD - Universite Paris Sud 11, UMR1184, Orsay, France. AD - CEA, Department of Immunology of Viral Infections and Autoimmune Diseases, IDMIT Infrastructure, iMETI/DSV, Fontenay-aux-Roses, France. FAU - Gonzalez, Nuria AU - Gonzalez N AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain. FAU - Coiras, Mayte AU - Coiras M AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain. FAU - Jimenez Tormo, Laura AU - Jimenez Tormo L AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain. FAU - Garcia-Perez, Javier AU - Garcia-Perez J AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain. FAU - Dereuddre-Bosquet, Nathalie AU - Dereuddre-Bosquet N AD - Inserm, U1184, Paris, France. AD - Universite Paris Sud 11, UMR1184, Orsay, France. AD - CEA, Department of Immunology of Viral Infections and Autoimmune Diseases, IDMIT Infrastructure, iMETI/DSV, Fontenay-aux-Roses, France. FAU - Le Grand, Roger AU - Le Grand R AD - Inserm, U1184, Paris, France. AD - Universite Paris Sud 11, UMR1184, Orsay, France. AD - CEA, Department of Immunology of Viral Infections and Autoimmune Diseases, IDMIT Infrastructure, iMETI/DSV, Fontenay-aux-Roses, France. FAU - Alcami, Jose AU - Alcami J AD - AIDS Immunopathogenesis Unit, Instituto de Salud Carlos III, Majadahonda, Spain ppalcami@isciii.es. LA - eng PT - Journal Article DEP - 20170329 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Cytokines) RN - 9008-11-1 (Interferons) SB - IM MH - CD4-Positive T-Lymphocytes/virology MH - *Cell Differentiation MH - Cells, Cultured MH - Cytokines/metabolism MH - Dendritic Cells/*immunology/physiology/*virology MH - Gene Expression Profiling MH - *Gene Expression Regulation MH - HIV-1/*immunology MH - HIV-2/immunology MH - Humans MH - Interferons/*metabolism MH - Microarray Analysis PMC - PMC5375683 OTO - NOTNLM OT - HIV-1 OT - immature dendritic cells OT - interferon-stimulated genes OT - mature dendritic cells EDAT- 2017/02/06 06:00 MHDA- 2017/05/16 06:00 PMCR- 2017/09/29 CRDT- 2017/02/03 06:00 PHST- 2016/08/17 00:00 [received] PHST- 2017/01/20 00:00 [accepted] PHST- 2017/02/06 06:00 [pubmed] PHST- 2017/05/16 06:00 [medline] PHST- 2017/02/03 06:00 [entrez] PHST- 2017/09/29 00:00 [pmc-release] AID - JVI.01379-16 [pii] AID - 01379-16 [pii] AID - 10.1128/JVI.01379-16 [doi] PST - epublish SO - J Virol. 2017 Mar 29;91(8):e01379-16. doi: 10.1128/JVI.01379-16. Print 2017 Apr 15.