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Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1

Lisa J Matthias1, Patricia T W Yam, Xing-Mai Jiang

  • 1Centre for Thrombosis and Vascular Research, School of Medical Sciences, University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, NSW 2052, Australia.

Nature Immunology
|June 29, 2002
PubMed

Insights

Redox changes in the CD4 D2 domain, regulated by thioredoxin, are crucial for HIV-1 entry. Targeting these redox states offers a novel strategy for developing HIV-1 entry inhibitors.

Area of Science:

  • Immunology
  • Virology
  • Biochemistry

Background:

  • CD4 is a key receptor for HIV-1 entry, mediating cell-cell interactions in the immune system.
  • The extracellular region of CD4 comprises four immunoglobulin-like domains (D1-D4), with disulfide bonds in D1, D2, and D4.

Purpose of the Study:

  • To investigate the role of redox activity in CD4 domains, specifically the D2 disulfide bond, concerning HIV-1 entry.
  • To identify potential targets for novel HIV-1 entry inhibitors.

Main Methods:

  • Analysis of the redox activity of the CD4 D2 disulfide bond.
  • Investigating the regulation of CD4 redox state by thioredoxin secreted from CD4(+) T cells.
  • Utilizing a hydrophilic trivalent arsenical to lock CD4 and thioredoxin dithiols in a reduced state.

Main Results:

  • The disulfide bond in the D2 domain of CD4 was found to be redox-active.
  • Thioredoxin, secreted by CD4(+) T cells, regulates the redox state of CD4.
  • Inhibiting the reduced dithiol state of CD4 D2 with an arsenical compound blocked HIV-1 entry into cells.

Conclusions:

  • Redox modifications in the CD4 D2 domain are critical for HIV-1 viral entry.
  • The CD4 D2 redox state represents a new therapeutic target for developing inhibitors of HIV-1 entry.

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