Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development
Copyright policy )Rare twin cysteine residues in the HIV-1 envelope variable region 1 link to neutralization escape and breadth development
Identifying HIV-1 envelope (Env) traits associated with neutralization cross-reactivity is crucial for vaccine design. Variable loops 1 and 2 (V1V2), positioned at the Env trimer apex, are key regions linked to neutralization. We describe non-canonical cysteine (Cys) residues in V1 that are enriched in individuals with elite neutralization breadth. Analyzing over 65,000 V1 sequences from the CATNAP database, AMP trials, and longitudinal HIV-1 cohorts (SHCS, ZPHI, and CAPRISA), we found that Env variants with extra V1 Cys are present at low levels and fluctuate over time. Extra V1 Cys associate with elite plasma neutralization, and two additional Cys are preferred, suggesting stabilization through disulfide bonds. Among 34 broadly neutralizing antibody (bnAb)-inducer Envs, 17.6% had elongated V1 regions with extra Cys. These extra Cys moderately increased neutralization resistance and altered bnAb epitope accessibility. Collectively, altering epitope exposure alongside Env stabilization renders the V1 twin Cys motif a promising feature for HIV-1 bnAb immunogens.
- University of Geneva Switzerland
- Los Alamos National Laboratory United States
- University of KwaZulu-Natal South Africa
- National Health Laboratory Service South Africa
- University Hospital of Lausanne Switzerland
AIDS Vaccines, elite neutralizers, HIV vaccine, broadly neutralizing antibodies, env Gene Products, Human Immunodeficiency Virus, envelope glycoprotein, HIV Infections, HIV Antibodies, Cross Reactions, HIV Envelope Protein gp120, Antibodies, Neutralizing, Epitopes, HIV-1/immunology; HIV-1/genetics; Humans; Cysteine/genetics; Cysteine/immunology; Cysteine/chemistry; HIV Antibodies/immunology; HIV Infections/immunology; HIV Infections/virology; Antibodies, Neutralizing/immunology; Epitopes/immunology; Epitopes/genetics; env Gene Products, Human Immunodeficiency Virus/immunology; env Gene Products, Human Immunodeficiency Virus/genetics; env Gene Products, Human Immunodeficiency Virus/chemistry; Cross Reactions; HIV Envelope Protein gp120/immunology; HIV Envelope Protein gp120/genetics; HIV Envelope Protein gp120/chemistry; Env stabilization; HIV vaccine; V1V2; broadly neutralizing antibodies; elite neutralizers; envelope glycoprotein, HIV-1, Humans, V1V2, Cysteine, Immune Evasion, Env stabilization
AIDS Vaccines, elite neutralizers, HIV vaccine, broadly neutralizing antibodies, env Gene Products, Human Immunodeficiency Virus, envelope glycoprotein, HIV Infections, HIV Antibodies, Cross Reactions, HIV Envelope Protein gp120, Antibodies, Neutralizing, Epitopes, HIV-1/immunology; HIV-1/genetics; Humans; Cysteine/genetics; Cysteine/immunology; Cysteine/chemistry; HIV Antibodies/immunology; HIV Infections/immunology; HIV Infections/virology; Antibodies, Neutralizing/immunology; Epitopes/immunology; Epitopes/genetics; env Gene Products, Human Immunodeficiency Virus/immunology; env Gene Products, Human Immunodeficiency Virus/genetics; env Gene Products, Human Immunodeficiency Virus/chemistry; Cross Reactions; HIV Envelope Protein gp120/immunology; HIV Envelope Protein gp120/genetics; HIV Envelope Protein gp120/chemistry; Env stabilization; HIV vaccine; V1V2; broadly neutralizing antibodies; elite neutralizers; envelope glycoprotein, HIV-1, Humans, V1V2, Cysteine, Immune Evasion, Env stabilization
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