Reduced monomeric CD4 is the preferred receptor for HIV.
CD4 is a co-receptor for binding of T cells to antigen-presenting cells and the primary receptor for the human immunodeficiency virus type 1 (HIV). CD4 exists in three different forms on the cell surface defined by the state of the domain 2 cysteine residues: an oxidized monomer, a reduced monomer, and a covalent dimer linked through the domain 2 cysteines. The disulfide-linked dimer is the preferred immune co-receptor. The form of CD4 that is preferred by HIV was examined in this study. HIV entry and envelope-mediated cell-cell fusion were tested using cells expressing comparable levels of wild-type or disulfide bond mutant CD4 in which the domain 2 cysteines were mutated to alanine. Eliminating the domain 2 disulfide bond increased entry of HIV reporter viruses and enhanced HIV envelope-mediated cell-cell fusion 2-4-fold. These observations suggest that HIV enters susceptible cells preferably through monomeric reduced CD4, whereas dimeric CD4 is the preferred receptor for binding to antigen-presenting cells. Cleavage of the domain 2 disulfide bond is possibly involved in the conformational change in CD4 associated with fusion of the HIV and cell membranes.
Matthias
Lisa J
LJ
Lowy Cancer Research Centre and Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Azimi
Iman
I
Tabrett
Catherine A
CA
Hogg
Philip J
PJ
D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D053586:Virus Internalization
D015704:CD4 Antigens; D004220:Disulfides; D003545:Cysteine