HIV-1 gp41 antibody
Description
Early Immune Responses
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Non-neutralizing dominance: Initial antibodies post-transmission bind gp41 but fail to control viremia due to polyreactivity with host/bacterial antigens (e.g., gut flora) .
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Somatic hypermutation: gp41-reactive antibodies in acute HIV-1 infection exhibit mutation frequencies (7–10%) resembling secondary immune responses, suggesting activation of pre-existing memory B cells .
Vaccine Trials and gp41 Immunogenicity
Vaccines incorporating gp41 components show mixed outcomes:
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HVTN 505: DNA/rAd5 regimen induced gp41-reactive IgG, but baseline anti-gp41 antibodies did not correlate with reduced HIV-1 risk .
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RV144: Partial efficacy linked to gp120 V1V2 antibodies; gp41 transmembrane domain included but not immunodominant .
Neutralizing Antibodies and gp41
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MPER-targeting bNAbs: Antibodies like 4E10 bind conserved MPER epitopes but are rare due to structural accessibility challenges .
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Q563R mutation: A gp41 HR1 mutation disrupts six-helix bundle formation, increasing sensitivity to MPER bNAbs while reducing infectivity. Host antibodies restore infectivity by stabilizing Env .
Clinical and Research Implications
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Vaccine design: gp41 immunogens risk diverting immune focus from gp120, reducing neutralizing antibody development .
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Diagnostic utility: Early gp41 antibody detection aids acute HIV-1 diagnosis but does not predict disease control .
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Therapeutic potential: MPER-targeting bNAbs remain promising for passive immunization despite elicitation challenges .
Future Directions
Product Specs
Q&A
Basic Research Questions
What experimental methods are used to assess antibody responses against gp41 in clinical studies?
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ELISA: Soluble GST-gp41 fusion proteins (e.g., GST-gp41-30, -64, -100) enable quantification of antibody reactivity in patient sera .
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Neutralization assays: Measure breadth/potency using pseudoviruses or TZM-bl cells. Patients with stronger anti-MPER responses show broader neutralization .
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Epitope mapping: Overlapping peptides spanning gp41 regions (e.g., MPER, HR1) identify antibody binding sites .
Which gp41 regions are critical for antibody-mediated neutralization?
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MPER (Membrane-Proximal External Region): Targeted by broadly neutralizing antibodies (bNAbs) 2F5 and 4E10. Structural studies show MPER’s conformational plasticity enables antibody evasion .
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HR1 (Heptad Repeat 1): Contains a hydrophobic pocket bound by antibodies like D5. Mutations here confer resistance to neutralization .
What factors influence inter-patient variability in anti-gp41 antibody efficacy?
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Epitope accessibility: MPER’s membrane-proximal location restricts antibody access .
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Viral diversity: gp41 sequence variation reduces antibody cross-reactivity .
Advanced Research Challenges
How do gp41 conformational states impact antibody binding?
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Prefusion vs. postfusion states: Crystal structures reveal gp41 adopts asymmetric arrangements of fusion peptides (FP) and transmembrane domains (TM) during fusion .
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Intermediate states: Anti-MPER antibodies trap gp41 in a prehairpin intermediate, blocking membrane fusion .
| Conformational State | Key Features | Antibody Targets |
|---|---|---|
| Prefusion (metastable) | FP buried, gp120-associated | Rarely targeted |
| Prehairpin intermediate | FP exposed, HR1/HR2 separated | HR1 (D5), MPER (2F5/4E10) |
| Postfusion | Six-helix bundle formed | Non-neutralizing epitopes |
Why do pre-existing anti-gp41 antibodies occur in uninfected individuals?
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Cross-reactivity: Anti-gp41 IgG correlates with gut microbiota proteins (e.g., bacterial RNA polymerase) .
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Stability: Pre-vaccine anti-gp41 levels remain consistent over 26–52 weeks in placebo groups .
How can structural biology address gp41 vaccine design challenges?
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Crystallography: Resolve antibody-gp41 complexes (e.g., MPER-bound 2F5 at 2.4 Å) .
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Molecular dynamics (MD): Simulate transitions between gp41 conformations to identify druggable states .
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Rational immunogen design: Stabilize prehairpin intermediates using MPER-specific bNAbs as templates .
Methodological Insights
How to resolve contradictory data on gp41 immunodominance?
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Controlled antigen exposure: Use gp41 truncations (e.g., GST-gp41-172 vs. -30) to isolate epitope-specific responses .
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Longitudinal studies: Track antibody durability in vaccine trials lacking gp41 immunogens (e.g., HVTN 111) .
What techniques validate gp41 antibody specificity?
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Competition assays: Test antibody inhibition by HR1 pocket-forming peptides (e.g., N17) .
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Mutagenesis: Introduce point mutations (e.g., L565A in HR1) to confirm epitope reliance .
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2D NMR: Map antibody interactions with gp41 peptides (e.g., 5-helix bundle) .
Key Data Trends
Product Science Overview
HIV-1 gp41 is a transmembrane glycoprotein that plays a crucial role in the fusion of the HIV-1 virus with host cells. It is a subunit of the envelope protein complex of the virus, which also includes gp120. Together, gp41 and gp120 form the envelope spike complex, which is essential for the virus’s ability to infect host cells .
Structure and Function:
- Gp41 is coded along with gp120 as a single precursor protein, gp160, by the env gene of HIV. This precursor is then glycosylated and cleaved by a host protease called furin .
- The gp41 protein has three main regions: the ectodomain, the transmembrane domain, and the cytoplasmic domain . The ectodomain contains the fusion peptide region, the helical N-terminal heptad repeat (NHR), and the C-terminal heptad repeat (CHR) .
- The fusion peptide region is critical for the fusion of the viral envelope with the host cell membrane . This process is initiated when gp120 binds to the CD4 receptor and a co-receptor (CCR5 or CXCR4) on the host cell .
- Gp41 undergoes significant conformational changes during the fusion process, forming a six-helix bundle that brings the viral and cellular membranes into close proximity, facilitating their fusion .
Importance in HIV Research:
Mouse antibodies are antibodies derived from mice and are commonly used in research and therapeutic applications. These antibodies are produced by immunizing mice with an antigen, which stimulates the production of specific antibodies against that antigen .
Types and Uses:
- There are five antibody isotypes in mice: IgA, IgD, IgE, IgG, and IgM . Each isotype has a different heavy chain and plays a distinct role in the immune response.
- Mouse antibodies are used extensively in preclinical studies to understand biological mechanisms and evaluate therapeutic targets . They are particularly valuable in cancer research, immunology, and infectious disease studies.
Human Anti-Mouse Antibody (HAMA) Response:
- One challenge with using mouse antibodies in humans is the potential for a HAMA response. This occurs when the human immune system recognizes the mouse antibodies as foreign and mounts an immune response against them . This can reduce the effectiveness of the treatment and cause adverse reactions.
- To mitigate this issue, researchers have developed methods to humanize mouse antibodies, reducing their immunogenicity while retaining their specificity and efficacy .
In the context of HIV-1 research, mouse antibodies targeting gp41 are valuable tools for studying the mechanisms of viral entry and for developing potential therapeutic interventions. These antibodies can be used to:
- Neutralize the virus: By binding to gp41, mouse antibodies can prevent the conformational changes required for membrane fusion, thereby inhibiting viral entry .
- Study immune responses: Mouse antibodies can help researchers understand how the immune system recognizes and responds to gp41, providing insights into vaccine development .
