PMID- 35204813 OWN - NLM STAT- MEDLINE DCOM- 20220408 LR - 20230721 IS - 2218-273X (Electronic) IS - 2218-273X (Linking) VI - 12 IP - 2 DP - 2022 Feb 15 TI - HIV-1 Trans Infection via TNTs Is Impeded by Targeting C5aR. LID - 10.3390/biom12020313 [doi] LID - 313 AB - Nonadjacent immune cells communicate through a complex network of tunneling nanotubes (TNTs). TNTs can be hijacked by HIV-1, allowing it to spread between connected cells. Dendritic cells (DCs) are among the first cells to encounter HIV-1 at mucosal sites, but they are usually efficiently infected only at low levels. However, HIV-1 was demonstrated to productively infect DCs when the virus was complement-opsonized (HIV-C). Such HIV-C-exposed DCs mediated an improved antiviral and T-cell stimulatory capacity. The role of TNTs in combination with complement in enhancing DC infection with HIV-C remains to be addressed. To this aim, we evaluated TNT formation on the surface of DCs or DC/CD4(+) T-cell co-cultures incubated with non- or complement-opsonized HIV-1 (HIV, HIV-C) and the role of TNTs or locally produced complement in the infection process using either two different TNT or anaphylatoxin receptor antagonists. We found that HIV-C significantly increased the formation of TNTs between DCs or DC/CD4(+) T-cell co-cultures compared to HIV-exposed DCs or co-cultures. While augmented TNT formation in DCs promoted productive infection, as was previously observed, a significant reduction in productive infection was observed in DC/CD4(+) T-cell co-cultures, indicating antiviral activity in this setting. As expected, TNT inhibitors significantly decreased infection of HIV-C-loaded-DCs as well as HIV- and HIV-C-infected-DC/CD4(+) T-cell co-cultures. Moreover, antagonizing C5aR significantly inhibited TNT formation in DCs as well as DC/CD4(+) T-cell co-cultures and lowered the already decreased productive infection in co-cultures. Thus, local complement mobilization via DC stimulation of complement receptors plays a pivotal role in TNT formation, and our findings herein might offer an exciting opportunity for novel therapeutic approaches to inhibit trans infection via C5aR targeting. FAU - Bertacchi, Giulia AU - Bertacchi G AD - Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria. FAU - Posch, Wilfried AU - Posch W AUID- ORCID: 0000-0001-8955-7654 AD - Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria. FAU - Wilflingseder, Doris AU - Wilflingseder D AUID- ORCID: 0000-0002-5888-5118 AD - Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria. LA - eng GR - P 33510/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220215 PL - Switzerland TA - Biomolecules JT - Biomolecules JID - 101596414 RN - 0 (C5AR1 protein, human) RN - 0 (Receptor, Anaphylatoxin C5a) RN - 9007-36-7 (Complement System Proteins) SB - IM MH - *Cell Communication MH - Complement System Proteins/metabolism MH - *Dendritic Cells MH - *HIV Infections MH - HIV-1/metabolism MH - Humans MH - *Receptor, Anaphylatoxin C5a/therapeutic use MH - *T-Lymphocytes PMC - PMC8868603 OTO - NOTNLM OT - HIV-1 OT - complement OT - trans infection OT - tunneling nanotubes (TNTs) COIS- The authors declare no conflict of interest. EDAT- 2022/02/26 06:00 MHDA- 2022/04/09 06:00 PMCR- 2022/02/15 CRDT- 2022/02/25 01:05 PHST- 2022/01/11 00:00 [received] PHST- 2022/02/03 00:00 [revised] PHST- 2022/02/10 00:00 [accepted] PHST- 2022/02/25 01:05 [entrez] PHST- 2022/02/26 06:00 [pubmed] PHST- 2022/04/09 06:00 [medline] PHST- 2022/02/15 00:00 [pmc-release] AID - biom12020313 [pii] AID - biomolecules-12-00313 [pii] AID - 10.3390/biom12020313 [doi] PST - epublish SO - Biomolecules. 2022 Feb 15;12(2):313. doi: 10.3390/biom12020313.