title: An ancestral HIV-2/simian immunodeficiency virus peptide with potent HIV-1 and HIV-2 fusion inhibitor activity.
abstract: OBJECTIVE
  To produce new fusion inhibitor peptides for HIV-1 and HIV-2 based on ancestral envelope sequences.
  
  
  METHODS
  HIV-2/simian immunodeficiency virus (SIV) ancestral transmembrane protein sequences were reconstructed and ancestral peptides were derived from the helical region 2 (HR2). The activity of one ancestral peptide (named P3) was examined against a panel of HIV-1 and HIV-2 primary isolates in TZM-bl cells and peripheral blood mononuclear cells and compared to T-20. Peptide secondary structure was analyzed by circular dichroism. Resistant viruses were selected and resistance mutations were identified by sequencing the env gene.
  
  
  RESULTS
  P3 has 34 residues and overlaps the N-terminal pocket-binding region and heptad repeat core of HR2. In contrast to T-20, P3 forms a typical α-helical structure in solution, binds strongly to the transmembrane protein, and potently inhibits both HIV-2 (mean IC50, 63.8 nmol/l) and HIV-1 (11 nmol/l) infection, including T-20-resistant isolates. The N43K mutation in the HR1 region of HIV-1 leads to 120-fold resistance to P3 indicating that the HR1 region in transmembrane glycoprotein is the target of P3. No HIV-2-resistant mutations could be selected by P3 suggesting that the genetic barrier to resistance is higher in HIV-2 than in HIV-1. HIV-1-infected patients presented significantly lower P3-specific antibody reactivity compared to T-20.
  
  
  CONCLUSIONS
  P3 is an HIV-2/SIV ancestral peptide with low antigenicity, high stability, and potent activity against both HIV-1, including variants resistant to T-20, and HIV-2. Similar evolutionary biology strategies should be explored to enhance the production of antiviral peptide drugs, microbicides, and vaccines.
authors: Unidade dos Retrovírus e Infecções Associadas, Centro de Patogénese Molecular (URIA-CPM), Faculdade de Farmácia da Universidade de Lisboa, Lisbon, Portugal.
authors: Pedro
authors: P
authors: Borrego
authors: Rita
authors: R
authors: Calado
authors: José M
authors: JM
authors: Marcelino
authors: Patrícia
authors: P
authors: Pereira
authors: Alexandre
authors: A
authors: Quintas
authors: Helena
authors: H
authors: Barroso
authors: Nuno
authors: N
authors: Taveira
mesh_terms: D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D015195:Drug Design; D024882:Drug Resistance, Viral; D005260:Female; D015752:Genes, env / Q000276:immunology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D015498:HIV-2 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000302:isolation & purification
chemical_list: D002352:Carrier Proteins; D023581:HIV Fusion Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C485059:peptide P3