PolyICLC Exerts Pro- and Anti-HIV Effects on the DC-T Cell Milieu In Vitro and In Vivo.
Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection outcomes will inform HIV prevention and treatment strategies. The long double-stranded RNA (dsRNA) viral mimic, polyinosinic polycytidylic acid (polyIC, PIC) potently stimulates DCs to focus Th1 responses, triggers direct antiviral activity in vitro, and boosts anti-HIV responses in vivo. Stabilized polyICLC (PICLC) is being developed for vaccine adjuvant applications in humans, making it critical to understand how mDC sensing of PICLC influences HIV infection. Using the monocyte-derived DC (moDC) model, we sought to describe how PICLC (vs. other dsRNAs) impacts HIV infection within DCs and DC-T cell mixtures. We extended this work to in vivo macaque rectal transmission studies by administering PICLC with or before rectal SIVmac239 (SIVwt) or SIVmac239ΔNef (SIVΔNef) challenge. Like PIC, PICLC activated DCs and T cells, increased expression of α4β7 and CD169, and induced type I IFN responses in vitro. The type of dsRNA and timing of dsRNA exposure differentially impacted in vitro DC-driven HIV infection. Rectal PICLC treatment similarly induced DC and T cell activation and pro- and anti-HIV factors locally and systemically. Importantly, this did not enhance SIV transmission in vivo. Instead, SIV acquisition was marginally reduced after a single high dose challenge. Interestingly, in the PICLC-treated, SIVΔNef-infected animals, SIVΔNef viremia was higher, in line with the importance of DC and T cell activation in SIVΔNef replication. In the right combination anti-HIV strategy, PICLC has the potential to limit HIV infection and boost HIV immunity.
Center for Biomedical Research, Population Council, New York, NY, United States of America.
Meropi
M
Aravantinou
Center for Biomedical Research, Population Council, New York, NY, United States of America.
Ines
I
Frank
Center for Biomedical Research, Population Council, New York, NY, United States of America.|Linköping University, Linköping, Sweden.
Magnus
M
Hallor
Center for Biomedical Research, Population Council, New York, NY, United States of America.
Rachel
R
Singer
Center for Biomedical Research, Population Council, New York, NY, United States of America.
Hugo
H
Tharinger
Center for Biomedical Research, Population Council, New York, NY, United States of America.
Jessica
J
Kenney
Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY, United States of America.
Agegnehu
A
Gettie
Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA, United States of America.
Brooke
B
Grasperge
Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA, United States of America.
James
J
Blanchard
Oncovir, Inc., Washington, DC, United States of America.
Andres
A
Salazar
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD, United States of America.
Michael
M
Piatak
AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD, United States of America.
Jeffrey D
JD
Lifson
Center for Biomedical Research, Population Council, New York, NY, United States of America.
Melissa
M
Robbiani
Center for Biomedical Research, Population Council, New York, NY, United States of America.
Nina
N
Derby
D000818:Animals; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000628:therapy* / Q000635:transmission; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008251:Macaca / Q000276:immunology / Q000821:virology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D011070:Poly I-C / Q000008:administration & dosage / Q000235:genetics*; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000235:genetics; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000235:genetics*; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
D007370:Interferon Type I; D012330:RNA, Double-Stranded; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C