Stanfield et. al (1999) Outline

Introduction

• HIV-1's exterior membrand is embedded with protein copes of gp120 and gp41. Viral cell entry --> gp120 binds to CD4 and another co receptor, gp41 then fusions the viral --> target cell membranes.
• CXCR4 and CCR5 serve as secondary viral receptors to T-tropic and M-tropic cells.
• Disulfide linked loop is the V3 domain of gp120, 40 amino acids have high degree of sequence diversity. V3=major immunogenic site of virus (termed principal neutralizing determinant.)
• V3 loop exposure varies. Increases when CD4-gp120 interaction. More sensitive to neutralize proteases and antibodies. T-tropic V3 seq. --> more basic charge than M-tropic, due to either side of GPGR tip being positivley charged.
• Examined 245 diff. HIV-1 V-3 loops
  • Some positions of aa are highly variable in aa composition.
  • Near tip of loop --> highly conserved
    • Suggests key fn. and structural role in virus infectivity.
• Disease progression = conversion of primary M-tropic to T-tropic strains. Knowing about conformational loops could help explain changes that take place and coreceptor usage when leading to disease progression.
• Antibodies were let against 40a.a V3 peptide RP70; showed that by preventing viral-cell membrane fusion, it neutralized the virus.
  • Previously thought that these antibodies do not interfere with CD4 binding. Using intact viral gp120 particles in recent studies, show that V3 neutralizing antibodies could prevent HIV-1 binding to CD4+ human cells.