Pleiotropic Nature of HIV‐1 Integrase Mutations

Engelman, Alan

doi:10.1002/9781118015377.ch6

Cited by 17 publications

(26 citation statements)

References 202 publications

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“…Missense mutations throughout the IN coding region can elicit the class II mutant viral phenotype (31,32), and 12 representative proteins that we and others had previously analyzed under simplified integration reaction conditions were selected for study. The mutant INs harbored amino acid substitutions in the CCD (E69R, V165A, R166A, D167K, Q168A, K186Q, and R199A), the CTD (R228A, K258A, and K264E), or the CCD-CTD interdomain linker (Q214L/Q216L and K215A/K219A) (72) ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The most common pleiotropic defect associated with the class II IN mutant viral phenotype occurs at reverse transcription (32). IN and RT proteins have accordingly been shown to directly interact and, under certain conditions, stimulate each other's in vitro activities (28,55).…”

Section: Interactions With Heterologous Binding Partners (I) Ledgf/ mentioning

confidence: 99%

“…Due to the specific block, a hallmark of class I IN mutant viral infection is transient accumulation of unintegrated nuclear vDNA (2,38,61,67,79,84,105,124), akin to the phenotype observed for wild-type (WT) HIV-1 in the presence of IN strand transfer inhibitors (INSTIs) (54). Reverse transcription is the most common pleiotropic defect associated with class II IN mutant viruses (31,32).…”

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confidence: 99%

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Correlation of Recombinant Integrase Activity and Functional Preintegration Complex Formation during Acute Infection by Replication-Defective Integrase Mutant Human Immunodeficiency Virus

Koh

Engelman

2012

J Virol

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Previous studies characterized two types of replication-defective human immunodeficiency virus type 1 (HIV-1) integrase mutants: class I, which are specifically blocked at the integration step, and class II, which harbor additional virion production and/or reverse transcription defects. Class I mutant enzymes supported little if any metal ion-dependent 3=-processing and DNA strand transfer activities in vitro, whereas class II enzymes displayed partial or full catalytic function in studies with simplified assay designs, suggesting that defective interaction(s) with heterologous integrase binding proteins might underlie the class II mutant viral phenotype. To address this hypothesis, class I and II mutant enzymes were interrogated under expanded sets of in vitro conditions. The majority failed to catalyze the concerted integration of two viral DNA ends into target DNA, highlighting defective integrase function as the root cause of most class II in addition to all class I mutant virus infection defects. One mutant protein, K264E, in contrast, could support the wild-type level of concerted integration activity. After accounting for its inherent reverse transcription defect, HIV-1 K264E moreover formed preintegration complexes that supported the efficient integration of endogenous viral DNA in vitro and normal levels and sequences of 2-long terminal repeat-containing circle junctions during acute infection. K264E integrase furthermore efficiently interacted in vitro with two heterologous binding partners, LEDGF/p75 and reverse transcriptase. Our results underscore the physiological relevance of concerted integration assays for tests of integrase mutant function and suggest that the K264E mutation disrupts an interaction with an intranuclear integrase binding partner that is important for HIV-1 integration.

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Section: Resultsmentioning

confidence: 99%

Section: Interactions With Heterologous Binding Partners (I) Ledgf/ mentioning

confidence: 99%

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confidence: 99%

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Correlation of Recombinant Integrase Activity and Functional Preintegration Complex Formation during Acute Infection by Replication-Defective Integrase Mutant Human Immunodeficiency Virus

Koh

Engelman

2012

J Virol

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“…IN is a central player in the viral life cycle, as is evident from the pleiotropic effects that various IN mutations have on viral replication [35]. Some of these mutant viruses display replication blocks at stages as diverse as virion assembly and budding or reverse transcription.…”

Section: Inhibitors Of In-viral Protein Interactionsmentioning

confidence: 99%

“…Some of these mutant viruses display replication blocks at stages as diverse as virion assembly and budding or reverse transcription. Concerning the last case, it comes as no surprise that IN was found to physically interact with RT and that this interaction seems to be essential for virus replication [35]. Wilkinson et al employed NMR and SPR analyses to map the IN side of the interaction to various residues around V250 in the IN CTD [36].…”

Section: Inhibitors Of In-viral Protein Interactionsmentioning

confidence: 99%

Fueling HIV-1 integrase drug design with structural insights

Demeulemeester

Christ

Maeyer

et al. 2012

Drug Discovery Today: Technologies

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HIV-1 Integrase Multimerization as a Therapeutic Target

Feng

Larue

Slaughter

et al. 2015

Current Topics in Microbiology and Immunology

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Multimeric HIV-1 integrase (IN) plays an essential, multifunctional role in virus replication and serves as an important therapeutic target. Structural and biochemical studies have revealed the importance of the ordered interplay between IN molecules for its function. In the presence of viral DNA ends, individual IN subunits assemble into a tetramer and form a stable synaptic complex (SSC), which mediates integration of the reverse transcribed HIV-1 genome into chromatin. Cellular chromatin-associated protein LEDGF/p75 engages the IN tetramer in the SSC and directs HIV-1 integration into active genes. A mechanism to deregulate the productive interplay between IN subunits with small molecule inhibitors has recently received considerable attention. Most notably, allosteric IN inhibitors (ALLINIs) have been shown to bind to the IN dimer interface at the LEDGF/p75 binding pocket, stabilize interacting IN subunits, and promote aberrant, higher order IN multimerization. Consequently, these compounds impair formation of the SSC and associated LEDGF/p75-independent IN catalytic activities as well as inhibit LEDGF/p75 binding to the SSC in vitro. However, in infected cells, ALLINIs more potently impaired correct maturation of virus particles than the integration step. ALLINI treatments induced aberrant, higher order IN multimerization in virions and resulted in eccentric, non-infectious virus particles. These studies have suggested that the correctly ordered IN structure is important for virus particle morphogenesis and highlighted IN multimerization as a plausible therapeutic target for developing new inhibitors to enhance treatment options for HIV-1-infected patients.

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Pleiotropic Nature of HIV‐1 Integrase Mutations

Cited by 17 publications

References 202 publications

Correlation of Recombinant Integrase Activity and Functional Preintegration Complex Formation during Acute Infection by Replication-Defective Integrase Mutant Human Immunodeficiency Virus

Correlation of Recombinant Integrase Activity and Functional Preintegration Complex Formation during Acute Infection by Replication-Defective Integrase Mutant Human Immunodeficiency Virus

Fueling HIV-1 integrase drug design with structural insights

HIV-1 Integrase Multimerization as a Therapeutic Target

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