HIV Mutation Detail Information

Virus Mutation HIV Mutation Y173A


Basic Characteristics of Mutations
Mutation Site Y173A
Mutation Site Sentence To confirm the role of the V2 loop tyrosines in maintaining the HIV-1 trimer in a closed, antibody-protected configuration, we tested the sensitivity of the double-alanine mutant HIV-1 BaL Y173A Y177A to neutralization by a larger panel of weakly or nonneutralizing antibodies directed against diverse Env antigenic regions, including non-glycan-dependent V2 loop epitopes, the tip of the V3 loop, the CD4-BS, and the coreceptor-binding site.
Mutation Level Amino acid level
Mutation Type Nonsynonymous substitution
Gene/Protein/Region Env
Standardized Encoding Gene Env  
Genotype/Subtype HIV-1 B;A;E
Viral Reference "BG505, CM244, JR-FL and JR-CSF"
Functional Impact and Mechanisms
Disease Acquired Immunodeficiency Syndrome    
Immune Y
Target Gene -
Clinical and Epidemiological Correlations
Clinical Information -
Treatment -
Location USA
Literature Information
PMID 30538178
Title Structural Constraints at the Trimer Apex Stabilize the HIV-1 Envelope in a Closed, Antibody-Protected Conformation
Author Guzzo C,Zhang P,Liu Q,Kwon AL,Uddin F,Wells AI,Schmeisser H,Cimbro R,Huang J,Doria-Rose N,Schmidt SD,Dolan MA,Connors M,Mascola JR,Lusso P
Journal mBio
Journal Info 2018 Dec 11;9(6):e00955-18
Abstract The human immunodeficiency virus type 1 (HIV-1) envelope (Env) trimer evades antibody recognition by adopting a closed prefusion conformation. Here, we show that two conserved tyrosines (Y173, Y177) within the second variable (V2) loop of the gp120 Env glycoprotein are key regulators of the closed, antibody-protected state of the trimer by establishing intramolecular interaction with the base of the third variable (V3) loop. Mutation of Y177 and/or Y173 to phenylalanine or alanine dramatically altered the susceptibility of diverse HIV-1 strains to neutralization, increasing sensitivity to weakly and nonneutralizing antibodies directed against diverse Env regions, consistent with the adoption of an open trimer configuration. Conversely, potent broadly neutralizing antibodies (bNAbs) against different supersites of HIV-1 vulnerability exhibited reduced potency against V2 loop tyrosine mutants, consistent with their preferential targeting of the closed trimer. Mutation of V3 loop residues predicted to interact with the V2 loop tyrosines yielded a similar neutralization phenotype. Sera from chronically HIV-1-infected patients contained very high titers of antibodies capable of neutralizing V2 loop tyrosine mutants but not wild-type viruses, indicating that the bulk of antibodies produced in infected hosts are unable to penetrate the protective shield of the closed trimer. These results identify the tyrosine-mediated V2-V3 loop complex at the trimer apex as a key structural constraint that facilitates HIV-1 evasion from the bulk of host antibodies.IMPORTANCE The extraordinary ability of human immunodeficiency virus type 1 (HIV-1) to evade host immunity represents a major obstacle to the development of a protective vaccine. Thus, elucidating the mechanisms whereby HIV-1 protects its external envelope (Env), which is the sole target of virus-neutralizing antibodies, is an essential step toward vaccine design. We identified a key structural element that maintains the HIV-1 Env trimer in a closed, antibody-resistant conformation. A major role is played by two conserved tyrosines at the apex of the Env spike, whose mutation causes a global opening of the trimer structure, exposing multiple concealed targets for neutralizing antibodies. We also found that HIV-infected individuals produce very large amounts of antibodies that neutralize the open Env form; however, the bulk of these antibodies are unable to penetrate the tight defensive shield of the native virus. This work may help to devise new strategies to overcome the viral defensive mechanisms and facilitate the development of an effective HIV-1 vaccine.
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.