HIV-1 Maturation: Lessons Learned from Inhibitors

Abstract

Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus. However, to combat the growing rates of virologic failure and toxicity associated with long-term therapy, it is important to diversify our repertoire of HIV-1 treatments by identifying compounds that block additional steps not targeted by current drugs. Most of the available therapeutics disrupt early events in the replication cycle, with the exception of the protease (PR) inhibitors, which act at the virus maturation step. HIV-1 maturation consists of a series of biochemical changes that facilitate the conversion of an immature, noninfectious particle to a mature infectious virion. These changes include proteolytic processing of the Gag polyprotein by the viral protease (PR), structural rearrangement of the capsid (CA) protein, and assembly of individual CA monomers into hexamers and pentamers that ultimately form the capsid. Here, we review the development and therapeutic potential of maturation inhibitors (MIs), an experimental class of anti-HIV-1 compounds with mechanisms of action distinct from those of the PR inhibitors. We emphasize the key insights into HIV-1 biology and structure that the study of MIs has provided. We will focus on three distinct groups of inhibitors that block HIV-1 maturation: (1) compounds that block the processing of the CA-spacer peptide 1 (SP1) cleavage intermediate, the original class of compounds to which the term MI was applied; (2) CA-binding inhibitors that disrupt capsid condensation; and (3) allosteric integrase inhibitors (ALLINIs) that block the packaging of the viral RNA genome into the condensing capsid during maturation. Although these three classes of compounds have distinct structures and mechanisms of action, they share the ability to block the formation of the condensed conical capsid, thereby blocking particle infectivity.

Interactions of HIV-1 Capsid with Host Factors and Their Implications for Developing Novel Therapeutics

“…The CA-NTD contains seven α-helices (α1–α7), a characteristic extended cyclophilin A (CypA)-binding loop and a β-hairpin, whereas CA-CTD consists of four α-helices (α8–α11), a short 3 10 -helix, and the major homology region (MHR). The assembly and stability of the capsid shell is driven by three sets of intermolecular protein–protein interactions between CA subunits: (1) intra-hexameric NTD-NTD contacts between individual CA molecules stabilize the hexamers and pentamers that function as the building blocks of the capsid, as well as form a central pore gated by the β-hairpin, (2) intra-hexameric NTD-CTD contacts between adjacent CA molecules further stabilize the individual hexamers and pentamers, and (3) inter-hexameric CTD-CTD contacts participate in dimeric and trimeric interactions to link the individual hexamers and pentamers [ 34 , 35 , 36 ] ( Figure 2 D). Therefore, the capsid core not only shields the viral genome but also provides expansive and diverse interfaces for cellular protein interactions.…”

Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs—First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor

“…Every CA-binding inhibitor that has been studied extensively to date results in rapid development of resistant variants upon selection in vitro [ 22 ], including the two highly potent but broadly acting small molecules GS-CA1 and GS-6027 [ 77 , 80 ]. Similarly, the first and second generation maturation inhibitors, a different class of small molecules that inhibit Gag cleavage, also select for resistance mutations in vitro (reviewed in [ 81 ]).…”

Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

“…Based on the accumulated evidence suggesting that viral replication and infectivity are dependent on the appropriate function and assembly of the capsid, there has been a flurry of research investigating the effect of small molecules on this process. Inhibitors include those targeted at the CA-SP1 junction in the immature particle (termed maturation inhibitors), but also small molecules which bind the NTD-CTD interface within the capsomere of the mature viral particle [ 9 , 98 , 99 ]. Further, there is a host-derived small molecule, inositol hexakisphosphate, which has recently been shown to be important for the appropriate construction of new viral particles [ 100 ].…”