RT Journal Article
SR Electronic
T1 Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 820456
DO 10.1101/820456
A1 Elizabeth J Tanner
A1 Seung-Yong Jung
A1 Joshua Glazier
A1 Cassandra Thompson
A1 Yuqi Zhou
A1 Benjamin Martin
A1 Hye-In Son
A1 James L Riley
A1 Leor S Weinberger
YR 2019
UL http://biorxiv.org/content/early/2019/10/30/820456.abstract
AB Population-level control of HIV-1 faces recognized challenges, including the evolution of viral resistance and adherence issues in resource-limited settings. It has long been proposed that viral deletion mutants that conditionally self-renew at the expense of the wild-type virus (i.e., Defective Interfering Particles, DIPs1) could constitute a long-term intervention that circumvents adherence challenges and has a high genetic barrier to resistance, echoing recent approaches2. Theories predict3, 4 that DIPs could be engineered into a therapy for HIV-1 (i.e., Therapeutic interfering particles or ‘TIPs’) provided they stably persist in patients (R0>1) by spreading to new cells during active infection (hence, a self-replenishing antiviral). To date, DIPs amenable to such engineering have remained elusive for HIV-1. Here we report the discovery of an HIV-1 DIP and its subsequent engineering into a TIP. The TIP interferes with HIV-1 replication at multiple stages of the viral lifecycle, including genome packaging, virion maturation, and reverse transcription, essentially acting as a combination antiviral. In humanized mice, the TIP suppressed HIV-1 replication by ten-fold and significantly protected CD4+ T cells from HIV-1 mediated depletion. These data provide proof-of-concept for a class of biologic with the potential to circumvent significant barriers to HIV-1 control.