Title: Drug Discovery and Virus Characterization in HIV-1

Presenter: Dr. Pi-Han Lin

University: The National Taiwan University Hospital

Time: 10:00-11:00, January 22, 2016

Venue: Room A203, Institute of Microbiology, Chinese Academy of Sciences

HIV is a major global public health issue and many resistant virus strains were reported. It is urgent to develop new anti-HIV compounds through new mechanism. In addition, the relation between disease progression and circulating recombinant forms (CRFs) of HIV-1 is also an important issue. In our study, we try to discover new compounds on inhibiting HIV replication and characterize the disease progression related with virus in CRF07_BC virus. In the search of novel compounds in inhibiting Tat transactivity, BPRHIV001 was identified after screening 292 coumarin-derivatives. BPRHIV001 was shown to significantly inhibit Tat-mediated transactivation at nanomolar range. BPRHIV001 is likely to reduce the p300 protein level while the p300 mRNA level was unaffected. The decreased p300 protein level was possibly resulted from reducing the level of phosphorylated Akt, which was shown to be closely related with p300 stability. A concordant reduction of phosphorylated PDPK1, a well-known Akt activator was also observed. The docking analysis revealed that the reduced PDPK1 phosphorylation is likely resulted from the allosteric effect induced by interaction between BPRHIV001 and PDPK1. Finally, BPRHIV001 was shown to effectively inhibit HIV-1 replication in vitro and the 50% inhibitory concentration (IC50) of BPRHIV001 against HIV-1 was 1.3 nM. With strong synergistic effects with current reverse transcriptase inhibitors, BPRHIV001 has the potential to become a promising lead compound for the development of a novel therapeutic agent against HIV-1 infection. In the research of relations between virus and disease progression, HIV-1 circulating CRF07_BC has caused serious HIV-1 epidemics among injecting drug users (IDUs) in East Asia but little is known about the characteristics of the virus and its impact on disease progression among the infected individuals. We compared immunological progression between 423 IDUs infected with CRF07_BC and 194 men who have sex with men (MSM) with primary subtype B infection, we found that IDUs infected with CRF07_BC had significantly slower immunological progression in the Cox proportional hazards model (hazard ratio: 0.30; 95% confidence interval: 0.13–0.69; P=0.004). Furthermore, a representative full-length CRF07_BC molecular clone, pCRF07_BC, was constructed to characterize the virus. The constructed recombinant CRF07_BC viruses had a reduced processing of the Gag/Gag-Pol polyproteins, a decreased incorporation of Vpr in the virus particle, tethering virus particles on the plasma membrane and decreased virus growth kinetics. These phenotypes are related to the unique 7-amino acid deletion in the p6 of CRF07_BC, since complementation of the 7-amino acid in pCRF07_BC could improve the defective phenotypes. In summary, compared with MSM infected with HIV-1 subtype B, IDUs infected with CRF07_BC had slower immunological progression, which is likely correlated with interference of virus particle maturation by the 7-amino acid deletion in p6.