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

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 beenproposed that viral deletion mutants that conditionally self-renew at the expense of the wild-type virus (i.e., Defective Interfering Particles, DIPs 1 ) could constitute a longterm intervention that circumvents adherence challenges and has a high genetic barrier to resistance, echoing recent approaches 2 . Theories predict 3,4 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-ofconcept for a class of biologic with the potential to circumvent significant barriers to HIV-1 control.Despite the availability of effective antiretroviral therapy regimens, 37 million people are currently living with HIV-1/AIDS (hereafter HIV) and ~2 million new HIV infections occur each year, largely in the developing world 5 . Epidemiological models 6 project that epidemic control in sub-Saharan Africa using conventional approaches may be exceptionally

Conditionally Replicating Vectors Mobilize Chimeric Antigen Receptors against HIV

“…Earlier studies with conditionally replicating vectors have demonstrated mobilization of small interfering particles and RNAs. 14 , 33 The observations presented here demonstrate not only the mobilization of a large transgene, but the spread of CAR function by the mobilization of the anti-HIV CAR. Such an observation is impacting because it suggests that a single lentiviral vector treatment strategy to cure HIV infection is theoretically feasible.…”

“…Furthermore, only crLV-derived CAR T cells, when compared with LV-derived CAR or mock-transduced T cells, had a higher CD4 percentage ( Figure 4 C), suggesting that crLV-derived CARs can protect CD4 + T cells ex vivo . Indeed, previous studies have found that conditionally replicating vectors add a level of protection to uninfected cells by diluting the amount of active free virus, 12 , 14 , 33 although such a notion was not assessed here.…”

Library-based analysis reveals segment and length dependent characteristics of defective influenza genomes

“…However, clinical sequencing has revealed that they are a common component of viral infections and can be associated with disease outcome ( Felt et al, 2021 ; Saira et al, 2013 ; Vasilijevic et al, 2017 ). Their potential ability to modulate the course of disease has now sparked a renewed interest in their therapeutic potential ( Rezelj et al, 2021 ; Rand et al, 2021 ; Tanner et al, 2019 ; Dimmock and Easton, 2014 ).…”

Competition between social cheater viruses is driven by mechanistically different cheating strategies

“…Much interest has recently arisen in DIPs since they may be considered as therapeutic agents: By competing over resources with the pathogenic WT viruses, they markedly reduce the infectious load while stimulating both adaptive and innate immunity (3)(4)(5)(6)(7). DIPs also represent a form of an ecological interaction between two viruses.…”