PMID- 31867020 OWN - NLM STAT- MEDLINE DCOM- 20201109 LR - 20240422 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - HSV-2 Cellular Programming Enables Productive HIV Infection in Dendritic Cells. PG - 2889 LID - 10.3389/fimmu.2019.02889 [doi] LID - 2889 AB - Genital herpes is a common sexually transmitted infection caused by herpes simplex virus type 2 (HSV-2). Genital herpes significantly enhances the acquisition and transmission of HIV-1 by creating a microenvironment that supports HIV infection in the host. Dendritic cells (DCs) represent one of the first innate cell types that encounter HIV-1 and HSV-2 in the genital mucosa. HSV-2 infection has been shown to modulate DCs, rendering them more receptive to HIV infection. Here, we investigated the potential mechanisms underlying HSV-2-mediated augmentation of HIV-1 infection. We demonstrated that the presence of HSV-2 enhanced productive HIV-1 infection of DCs and boosted inflammatory and antiviral responses. The HSV-2 augmented HIV-1 infection required intact HSV-2 DNA, but not active HSV-2 DNA replication. Furthermore, the augmented HIV infection of DCs involved the cGAS-STING pathway. Interestingly, we could not see any involvement of TLR2 or TLR3 nor suppression of infection by IFN-beta production. The conditioning by HSV-2 in dual exposed DCs decreased protein expression of IFI16, cGAS, STING, and TBK1, which is associated with signaling through the STING pathway. Dual exposure to HSV-2 and HIV-1 gave decreased levels of several HIV-1 restriction factors, especially SAMHD1, TREX1, and APOBEC3G. Activation of the STING pathway in DCs by exposure to both HSV-2 and HIV-1 most likely led to the proteolytic degradation of the HIV-1 restriction factors SAMHD1, TREX1, and APOBEC3G, which should release their normal restriction of HIV infection in DCs. This released their normal restriction of HIV infection in DCs. We showed that HSV-2 reprogramming of cellular signaling pathways and protein expression levels in the DCs provided a setting where HIV-1 can establish a higher productive infection in the DCs. In conclusion, HSV-2 reprogramming opens up DCs for HIV-1 infection and creates a microenvironment favoring HIV-1 transmission. CI - Copyright (c) 2019 Crisci, Svanberg, Ellegard, Khalid, Hellblom, Okuyama, Bhattacharya, Nystrom, Shankar, Eriksson and Larsson. FAU - Crisci, Elisa AU - Crisci E AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. FAU - Svanberg, Cecilia AU - Svanberg C AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. FAU - Ellegard, Rada AU - Ellegard R AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. FAU - Khalid, Mohammad AU - Khalid M AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. AD - Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia. FAU - Hellblom, Julia AU - Hellblom J AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. FAU - Okuyama, Kazuki AU - Okuyama K AD - Division of Experimental Haematology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. FAU - Bhattacharya, Pradyot AU - Bhattacharya P AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. FAU - Nystrom, Sofia AU - Nystrom S AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. FAU - Shankar, Esaki M AU - Shankar EM AD - Division of Infection Biology and Medical Microbiology, Department of Life Sciences, School of Life Sciences, Central University of Tamil Nadu, Thiruvarur, India. FAU - Eriksson, Kristina AU - Eriksson K AD - Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden. FAU - Larsson, Marie AU - Larsson M AD - Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden. LA - eng GR - R01 AI052731/AI/NIAID NIH HHS/United States GR - R37 AI052731/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191206 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (Membrane Proteins) RN - 0 (STING1 protein, human) RN - EC 2.7.7.- (Nucleotidyltransferases) RN - EC 2.7.7.- (cGAS protein, human) SB - IM MH - *Coinfection MH - Cytokines/metabolism MH - Dendritic Cells/immunology/metabolism MH - Disease Susceptibility MH - HIV Infections/*immunology/metabolism/*virology MH - HIV-1/*physiology MH - Herpes Genitalis/*immunology/metabolism/*virology MH - Herpesvirus 2, Human/*physiology MH - Host-Pathogen Interactions/immunology MH - Humans MH - Inflammation Mediators/metabolism MH - Membrane Proteins/metabolism MH - Nucleotidyltransferases/metabolism MH - Signal Transduction MH - *Symbiosis PMC - PMC6909011 OTO - NOTNLM OT - DNA sensors OT - HIV-1 OT - HSV-2 OT - HSV-2 and HIV-1 coinfection OT - dendritic cells OT - immune responses EDAT- 2019/12/24 06:00 MHDA- 2020/11/11 06:00 PMCR- 2019/01/01 CRDT- 2019/12/24 06:00 PHST- 2019/08/13 00:00 [received] PHST- 2019/11/25 00:00 [accepted] PHST- 2019/12/24 06:00 [entrez] PHST- 2019/12/24 06:00 [pubmed] PHST- 2020/11/11 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.02889 [doi] PST - epublish SO - Front Immunol. 2019 Dec 6;10:2889. doi: 10.3389/fimmu.2019.02889. eCollection 2019.