Ljubljana/Strategy

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Strategy

HIV virus mutates at rates 1 per 3x105 nucleotides per replication cycle and with generation of 109 to 1010 virions every day it is clear that viral mutability has to be bypassed in order to develop an efficient antiviral therapy.

Requirements for the effective antiviral treatment:

  • should be BASED ON VIRAL FUNCTION and INSENSITIVE TO MUTATIONS
  • should be VERSATILE - allow activation of different effectors, e.g.
    - those that kill infected cells that spread infection (activation of apoptosis)
    - destroy virus (RNase, APOBEC3...)
    - activate human immune defense system (e.g. interferons, chemokines…)
  • system should be able to respond to low levels of activation – the RESPONSE SHOULD BE AMPLIFIED
  • avoid activation in noninfected cells


Considered approaches

  • use of siRNA - attractive but not suitable because of the mutations
  • antibodies (same problem)
  • use of viral LPR promoter - experimental evidence that transcription is "leaky"
  • use the chimeras with TLR3 intracellular domain, which activates the interferon beta signaling pathway - problem with active homodimers (tested, high constitutive activity)
  • use viral reverse transcriptase to integrate the effector into the genome (difficult, perhaps next time :-) )
  • use of viral protease activity (OK, works)
  • detect formation of CD4-CCR5 heterodimer (OK, works)