HIV Mutation Detail Information

Virus Mutation HIV Mutation M66I


Basic Characteristics of Mutations
Mutation Site M66I
Mutation Site Sentence Structural and mechanistic bases for resistance of the M66I capsid variant to lenacapavir.
Mutation Level Amino acid level
Mutation Type Nonsynonymous substitution
Gene/Protein/Region CA
Standardized Encoding Gene Gag  
Genotype/Subtype HIV-1
Viral Reference -
Functional Impact and Mechanisms
Disease HIV Infections    
Immune -
Target Gene -
Clinical and Epidemiological Correlations
Clinical Information -
Treatment lenacapavir
Location -
Literature Information
PMID 40231850
Title Structural and mechanistic bases for resistance of the M66I capsid variant to lenacapavir
Author Briganti L,Annamalai AS,Bester SM,Wei G,Andino-Moncada JR,Singh SP,Kleinpeter AB,Tripathi M,Nguyen B,Radhakrishnan R,Singh PK,Greenwood J,Schope LI,Haney R,Huang S-W,Freed EO,Engelman AN,Francis AC,Kvaratskhelia M
Journal mBio
Journal Info 2025 May 14;16(5):e0361324
Abstract Lenacapavir (LEN) is the first-in-class viral capsid protein (CA) targeting antiretroviral for treating multi-drug-resistant HIV-1 infection. Clinical trials and cell culture experiments have identified resistance-associated mutations (RAMs) in the vicinity of the hydrophobic CA pocket targeted by LEN. The M66I substitution conferred by far the highest level of resistance to the inhibitor compared to other RAMs. Here we investigated structural and mechanistic bases for how the M66I change affects LEN binding to CA and viral replication. The high-resolution X-ray structure of the CA(M66I) hexamer revealed that the beta-branched side chain of Ile66 induces steric hindrance specifically to LEN, thereby markedly reducing the inhibitor binding affinity. By contrast, the M66I substitution did not affect the binding of Phe-Gly (FG)-motif-containing cellular cofactors CPSF6, NUP153, or SEC24C, which engage the same hydrophobic pocket of CA. In cell culture, the M66I variant did not acquire compensatory mutations. Analysis of viral replication intermediates revealed that HIV-1((M66I CA)) predominantly formed correctly matured viral cores, which were more stable than their wild-type counterparts. The mutant cores stably bound to the nuclear envelope but failed to penetrate inside the nucleus. Furthermore, the M66I substitution markedly altered HIV-1 integration targeting. Taken together, our findings elucidate mechanistic insights into how the M66I change confers remarkable resistance to LEN and affects HIV-1 replication. Moreover, our structural findings provide a powerful means for future medicinal chemistry efforts to rationally develop second-generation inhibitors with a higher barrier to resistance.IMPORTANCELenacapavir (LEN) is a highly potent and long-acting antiretroviral that works by a unique mechanism of targeting the viral capsid protein. The inhibitor is used in combination with other antiretrovirals to treat multi-drug-resistant HIV-1 infection in heavily treatment-experienced adults. Furthermore, LEN is in clinical trials for preexposure prophylaxis (PrEP) with interim results indicating 100% efficacy to prevent HIV-1 infections. However, one notable shortcoming is a relatively low barrier of viral resistance to LEN. Clinical trials and cell culture experiments identified emergent resistance mutations near the inhibitor binding site on capsid. The M66I variant was the most prevalent capsid substitution identified in patients receiving LEN to treat multi-drug-resistant HIV-1 infections. The studies described here elucidate the underlying mechanism by which the M66I substitution confers a marked resistance to the inhibitor. Furthermore, our structural findings will aid future efforts to develop the next generation of capsid inhibitors with enhanced barriers to resistance.
Sequence Data -
Mutation Information
Note
Basic Characteristics of Mutations
  • Mutation Site: The specific location in a gene or protein sequence where a change occurs.
  • Mutation Level: The level at which a mutation occurs, including the nucleotide or amino acid level.
  • Mutation Type: The nature of the mutation, such as missense mutation, nonsense mutation, synonymous mutation, etc.
  • Gene/Protein/Region: Refers to the specific region of the virus where the mutation occurs. Including viral genes, viral proteins, or a specific viral genome region. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main
  • Gene/Protein/Region studied in the article is marked.
  • Genotype/Subtype: Refers to the viral genotype or subtype where the mutation occurs. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main Genotype/Subtype studied in the article is marked.
  • Viral Reference: Refers to the standard virus strain used to compare and analyze viral sequences.
Functional Impact and Mechanisms
  • Disease: An abnormal physiological state with specific symptoms and signs caused by viral infection.
  • Immune: The article focuses on the study of mutations and immune.
  • Target Gene: Host genes that viral mutations may affect.
Clinical and Epidemiological Correlations
  • Clinical Information: The study is a clinical or epidemiological study and provides basic information about the population.
  • Treatment: The study mentioned a certain treatment method, such as drug resistance caused by mutations. If the study does not specifically indicate the relationship between mutations and their correspondence treatment, the main treatment studied in the article is marked.
  • Location: The source of the research data.
Literature Information
  • Sequence Data: The study provides the data accession number.