Poly-ICLC, a TLR3 agonist, induces transient innate immune responses in patients with treated HIV-infection: A randomized double-blinded placebo controlled trial

Mansi Saxena, Rachel L. Sabado, Melissa La Mar, Hiroshi Mohri, Andres M. Salazar, Hanqing Dong, Joel Correa Da Rosa, Martin Markowitz, Nina Bhardwaj, Elizabeth Miller

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Objective: Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. Design: This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants (n = 15) were randomized 3:1 to receive two consecutive daily doses of PolyICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Methods: Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4+ T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Results: Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4+ T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. Conclusions: These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV+ subjects indicating promise as an adjuvant for HIV therapeutic vaccines.

Original languageEnglish
Article number725
JournalFrontiers in Immunology
Volume10
Issue numberAPR
DOIs
StatePublished - 2019

Keywords

  • Adjuvant
  • HIV-1
  • Poly-ICLC
  • Toll-like receptor ligand
  • Vaccine

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