Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors

Lin, Zheng‐Zhe; Cantone, Joseph L.; Lü, Hao; Nowicka-Sans, Beata; Protack, Tricia; Tian, Yuan; Yang, Hong; Liu, Zheng; Drexler, Dieter M.; Regueiro‐Ren, Alicia; Meanwell, Nicholas A.; Cockett, Mark I.; Krystal, Mark; Lataillade, Max; Dicker, Ira B.

doi:10.1371/journal.ppat.1005990

Cited by 20 publications

(35 citation statements)

References 55 publications

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“…While we (19) and others (42,43) observed an increase in CA-SP1 processing kinetics for the SP1-A1V mutant, other BVM-resistant mutants displayed CA-SP1 processing kinetics indistinguishable from, or in some cases slower than, those of the WT (19). A recent study (40) used an in vitro CA-SP1 processing assay to confirm that the SP1-A1V mutation markedly increases the kinetics of CA-SP1 processing. This study also observed moremodest effects of other CA-SP1 region polymorphisms on CA-SP1 processing, leading to the suggestion that increased CA-SP1 cleavage kinetics were a major contributor to MI resistance.…”

Section: Hiv-1 Maturation Inhibitor Resistancesupporting

confidence: 44%

“…13). However, other mutations/polymorphisms that induce MI resistance display only small increases, or no increases, in the kinetics of CA-SP1 processing (19,40,42,43) (Fig. 13) or, in the case of CA-V230M, significantly impair CA-SP1 processing.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple mechanisms appear to contribute to the ability of mutations and naturally occurring polymorphisms in CA and SP1 to confer MI resistance. (i) It has been suggested that increased rates of CA-SP1 processing can lead to MI resistance (40,42). Because the putative inhibitor binding site spans the CA-SP1 junction in the assembled immature virus-like particle (VLP), and CA-SP1 processing prevents binding (10,14,21,42), faster CA-SP1 processing would interfere with MI binding.…”

Section: Discussionmentioning

confidence: 99%

“…Because the putative inhibitor binding site spans the CA-SP1 junction in the assembled immature virus-like particle (VLP), and CA-SP1 processing prevents binding (10,14,21,42), faster CA-SP1 processing would interfere with MI binding. This mechanism may contribute to MI resistance in the case of SP1-A1V, which exhibits a significantly enhanced rate of CA-SP1 processing (19,40,42,43) (Fig. 13).…”

Section: Discussionmentioning

confidence: 99%

“…The CA-SP1 processing rate does not always correlate with MI resistance. A possible model to explain MI resistance is that resistance mutations increase the kinetics of CA-SP1 processing, allowing the virus to overcome the effect of the compound on cleavage at this site (40,42). We previously investigated the possibility that BVM resistance correlates with increased rates of CA-SP1 processing.…”

Section: Hiv-1 Maturation Inhibitor Resistancementioning

confidence: 99%

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Resistance to Second-Generation HIV-1 Maturation Inhibitors

Urano

Timilsina

Kaplan

et al. 2019

J Virol

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A betulinic acid-based compound, bevirimat (BVM), inhibits HIV-1 maturation by blocking a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. Previous studies showed that mutations conferring resistance to BVM cluster around the CA-SP1 cleavage site. Single amino acid polymorphisms in the SP1 region of Gag and the C terminus of CA reduced HIV-1 susceptibility to BVM, leading to the discontinuation of BVM’s clinical development. We recently reported a series of “second-generation” BVM analogs that display markedly improved potency and breadth of activity relative to the parent molecule. Here, we demonstrate that viral clones bearing BVM resistance mutations near the C terminus of CA are potently inhibited by second-generation BVM analogs. We performedde novoselection experiments to identify mutations that confer resistance to these novel compounds. Selection experiments with subtype B HIV-1 identified an Ala-to-Val mutation at SP1 residue 1 and a Pro-to-Ala mutation at CA residue 157 within the major homology region (MHR). In selection experiments with subtype C HIV-1, we identified mutations at CA residue 230 (CA-V230M) and SP1 residue 1 (SP1-A1V), residue 5 (SP1-S5N), and residue 10 (SP1-G10R). The positions at which resistance mutations arose are highly conserved across multiple subtypes of HIV-1. We demonstrate that the mutations confer modest to high-level maturation inhibitor resistance. In most cases, resistance was not associated with a detectable increase in the kinetics of CA-SP1 processing. These results identify mutations that confer resistance to second-generation maturation inhibitors and provide novel insights into the mechanism of resistance.IMPORTANCEHIV-1 maturation inhibitors are a class of small-molecule compounds that block a late step in the viral protease-mediated processing of the Gag polyprotein precursor, the viral protein responsible for the formation of virus particles. The first-in-class HIV-1 maturation inhibitor bevirimat was highly effective in blocking HIV-1 replication, but its activity was compromised by naturally occurring sequence polymorphisms within Gag. Recently developed bevirimat analogs, referred to as “second-generation” maturation inhibitors, overcome this issue. To understand more about how these second-generation compounds block HIV-1 maturation, here we selected for HIV-1 mutants that are resistant to these compounds. Selections were performed in the context of two different subtypes of HIV-1. We identified a small set of mutations at highly conserved positions within the capsid and spacer peptide 1 domains of Gag that confer resistance. Identification and analysis of these maturation inhibitor-resistant mutants provide insights into the mechanisms of resistance to these compounds.

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