Inhibiting Early-Stage Events in HIV-1 Replication by Small-Molecule Targeting of the HIV-1 Capsid

Kortagere, Sandhya; Madani, Navid; Mankowski, Marie K.; Schön, Arne; Zentner, Isaac; Swaminathan, Gokul; Princiotto, Amy M.; Anthony, Kevin; Oza, Apara; Sierra, Luz Jeannette; Passic, Shendra; Wang, Xiaozhao; Jones, David M.; Stavale, Eric; Krebs, Fred C.; Martín-García, Julio; Freire, Ernesto; Ptak, Roger G.; Sodroski, Joseph; Simon, Chantal; Smith, Amos B.

doi:10.1128/jvi.05006-11

Cited by 70 publications

(69 citation statements)

References 45 publications

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“…The effect of ebselen on CA assembly was measured by monitoring the turbidity at 350 nm, as previously described (51). Briefly, 75 l of NaCl solution (2 ml of 5 M NaCl mixed with 1 ml of 200 mM sodium phosphate, pH 8) containing increasing concentrations of ebselen, PF74, raltegravir (used as a negative control), or DMSO was placed into a 96-well plate.…”

Section: Tr-fretmentioning

confidence: 99%

Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

Thenin-Houssier

Vera

Pedró-Rosa

et al. 2016

Antimicrob Agents Chemother

102

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Section: Tr-fretmentioning

confidence: 99%

Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

Thenin-Houssier

Vera

Pedró-Rosa

et al. 2016

Antimicrob Agents Chemother

102

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“…Additionally, compounds and peptides that prevent formation of the mature, functional viral capsid can inhibit HIV-1 replication. Examples include CAP-1 and NYAD-1, among others (29)(30)(31). Unfortunately, none of these inhibitors has advanced to clinical studies.…”

mentioning

confidence: 99%

Inhibition of HIV-1 Maturation via Small-Molecule Targeting of the Amino-Terminal Domain in the Viral Capsid Protein

Wang

Zhou

Halambage

et al. 2017

J Virol

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The human immunodeficiency virus type 1 (HIV-1) capsid protein is an attractive therapeutic target, owing to its multifunctionality in virus replication and the high fitness cost of amino acid substitutions in capsids to HIV-1 infectivity. To date, small-molecule inhibitors have been identified that inhibit HIV-1 capsid assembly and/or impair its function in target cells. Here, we describe the mechanism of action of the previously reported capsid-targeting HIV-1 inhibitor, BoehringerIngelheim compound 1 (C1). We show that C1 acts during HIV-1 maturation to prevent assembly of a mature viral capsid. However, unlike the maturation inhibitor bevirimat, C1 did not significantly affect the kinetics or fidelity of Gag processing. HIV-1 particles produced in the presence of C1 contained unstable capsids that lacked associated electron density and exhibited impairments in early postentry stages of infection, most notably reverse transcription. C1 inhibited assembly of recombinant HIV-1 CA in vitro and induced aberrant cross-links in mutant HIV-1 particles capable of spontaneous intersubunit disulfide bonds at the interhexamer interface in the capsid lattice. Resistance to C1 was conferred by a single amino acid substitution within the compound-binding site in the N-terminal domain of the CA protein. Our results demonstrate that the binding site for C1 represents a new pharmacological vulnerability in the capsid assembly stage of the HIV-1 life cycle. IMPORTANCEThe HIV-1 capsid protein is an attractive but unexploited target for clinical drug development. Prior studies have identified HIV-1 capsid-targeting compounds that display different mechanisms of action, which in part reflects the requirement for capsid function at both the efferent and afferent phases of viral replication. Here, we show that one such compound, compound 1, interferes with assembly of the conical viral capsid during virion maturation and results in perturbations at a specific protein-protein interface in the capsid lattice. We also identify and characterize a mutation in the capsid protein that confers resistance to the inhibitor. This study reveals a novel mechanism by which a capsid-targeting small molecule can inhibit HIV-1 replication.

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“…The relationship between uncoating and reverse transcription has been investigated most extensively. Accelerated uncoating resulting from capsid changes, restriction by TRIM5␣, or destabilizing drugs has been associated with failure to initiate and/or complete reverse transcription (3,4,7,9,11,17,19). Conversely, blocking reverse transcription was reported to inhibit functional uncoating (51).…”

Section: Discussionmentioning

confidence: 99%

“…For example, some HIV-1 CA mutants fail to negotiate passage through the nuclear pore complex and do not access the nuclear chromatin (6). Both SIV and HIV-1 utilize karyophilic host proteins to shuttle their preintegration complexes into the nucleus of the target cell (3,4,7,9,11,17,19). The A87E and A87D SIV CA mutants can form true 2-LTR circles in the presence of an integrase inhibitor, raltegravir.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Enhanced Autointegration in Hyperstable Simian Immunodeficiency Virus Capsid Mutants Blocked after Reverse Transcription

Tipper

Sodroski

2013

J Virol

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cAfter entering a host cell, retroviruses such as simian immunodeficiency virus (SIV) uncoat, disassembling the viral capsid. Rates of uncoating that are too high and too low can be detrimental to the efficiency of infection. Rapid uncoating typically leads to blocks in reverse transcription, but the basis for replication defects associated with slow uncoating is less clear. Here we characterize the phenotypes of two SIVmac239 mutants with changes, A87E and A87D, in the helix 4/5 loop of the capsid protein. These mutant viruses exhibited normal capsid morphology but were significantly attenuated for infectivity. The infectivity of wild-type and mutant SIVmac239 was not decreased by aphidicolin-induced growth arrest of the target cells. In the cytosol of infected cells, the A87E and A87D capsids remained in particulate form longer than the wild-type SIVmac239 capsid, suggesting that the mutants uncoat more slowly than the wild-type capsid. Both mutants exhibited much higher levels of autointegrated DNA forms than wild-type SIVmac239. Thus, some changes in the helix 4/5 loop of the SIVmac239 capsid protein result in capsid hyperstability and an increase in autointegration.

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Inhibiting Early-Stage Events in HIV-1 Replication by Small-Molecule Targeting of the HIV-1 Capsid

Cited by 70 publications

References 45 publications

Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1 Replication

Inhibition of HIV-1 Maturation via Small-Molecule Targeting of the Amino-Terminal Domain in the Viral Capsid Protein

Enhanced Autointegration in Hyperstable Simian Immunodeficiency Virus Capsid Mutants Blocked after Reverse Transcription

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