It is estimated that over 33 million people worldwide are infected with HIV. Although the development of highly active anti-retroviral therapy (HAART) has transformed the course of HIV infection into a chronic disease, it cannot cure AIDS or eradicate the virus.Given that the majority of anti-HIV research is focused on drugs that interfere with viral replication, novel compounds are required that prohibit viral assembly and budding from infected cells. The objective of the EU-funded 'Targeting assembly of infectious HIV particles' (HIV ACE) project was to develop such antiviral drugs and target the interaction of viral proteins with host proteins. The advantage of this approach is that it disrupts the interaction rather than the viral enzymes, which are more prone to mutations.Among the HIV ACE objectives was the identification of inhibitors of the capsid assembly and Env protein incorporation. To this end, high-throughput screening was performed to single out small molecules that interfere with the interaction of both capsid CA and Env HIV proteins with cellular factors.Although pre-clinical testing in mice would be required to determine the efficacy of these compounds, these types of anti-HIV drugs would come as a novelty to existing strategies of targeting viral replication. Elucidation of the three-dimensional (3D) structures of target proteins as well as protein-inhibitor complexes aimed to improve future drug design.HIV ACE breakthroughs included the delineation of the mechanism by which the HIV Vpu protein counteracts the CD137/BST2 infection restrictive factor and facilitates virus infection. Other novel results included the discovery that the Rab7a protein was instrumental to the formation of fully infectious virion particles, alongside the detailed characterisation of the virion assembly process within living cells.HIV ACE work generated unprecedented knowledge regarding HIV virus assembly, interaction with host proteins and restriction factors. Through the development of drugs to inhibit these processes, it demonstrated the feasibility of targeting protein–protein interactions as a means of restricting HIV spread.
Targeting assembly of infectious HIV particles
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6 July 2020