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bioRxiv · 10.1101/820456

Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral

Tanner, E. J.·Jung, S.-Y.·Glazier, J. J.·Thompson, C. E.·Zhou, Y.·Martin, B.·Son, H.-I.·Riley, J. L.·Weinberger, L. S.
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Abstract

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.

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Tanner, E. J., Jung, S.-Y., Glazier, J. J., Thompson, C. E., Zhou, Y., Martin, B., Son, H.-I., Riley, J. L., Weinberger, L. S.. 2019-10-30. Discovery and Engineering of a Therapeutic Interfering Particle (TIP): a combination self-renewing antiviral. https://doi.org/10.1101/820456

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