Ljubljana/Strategy

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)