Abstract - Steven Bloom

Anti-Packaging Peptides (APPs) as New Antiretroviral Drugs for HIV-1

The Human Immunodeficiency Virus 1 (HIV-1), the causative agent of AIDS, is a widespread and deadly virus affecting millions of people worldwide.  The virus infects and depletes the body of healthy T-lymphocytes, crippling the immune system, and leaving the body defenseless against opportunistic infections.  Enormous effort has been made to develop anti-HIV drugs, but the propensity for HIV-1 to adopt resistance conferring mutations continually limits their efficacy.  One way to avoid HIV-drug resistance would be to introduce new drugs that target conserved aspects of the viral life cycle that cannot tolerate mutations.  ψRNA (psi-RNA), specifically its Stem-loop 3 (SL3) hairpin, directs the selective packaging of the HIV-1 genome (gRNA) through its obligatory interaction with the nucleocapsid protein (NCp7) of the viral Gag-polyprotein.  Mutations in SL3 greatly impede the ability of NCp7 to correctly select for gRNA, and this leads to new daughter virions that package incorrect RNAs and are not able to replicate.  Thus, SL3 RNA stands out as a prime target for designing a mutation-resistant antiretroviral drug.

Recent work has shown that the high-fidelity interaction between NCp7 and SL3 is governed by a series of single-stranded guanosines located in the stem of SL3 that serve as high-affinity recognition sites for NCp7 binding.  Drugs that specifically target the stem of SL3 and impede NCp7 binding could offer a new way to combat HIV-1 in ways that viral mutations could not overcome, but no such drugs exist. In the quest for an effective NCp7-SL3 inhibitor we used in-silico modeling and synthetic peptide chemistry to design a brand-new peptide inhibitor.  Preliminary in vitro testing revealed that our novel peptide greatly diminished the infectivity of two major strains of HIV-1 and did not inhibit viral particle release or other stages of the HIV-1 life cycle, consistent with its potential anti-packaging activity.