Lineage-specific differences between human and simian immunodeficiency virus regulation of gp120 trimer association and CD4 binding.
Metastable conformations of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) must be maintained in the unliganded state of the envelope glycoprotein trimer. Binding of gp120 to the primary receptor, CD4, triggers the transition to an open conformation of the trimer, promoting interaction with the CCR5 chemokine receptor and ultimately leading to gp41-mediated virus-cell membrane fusion and entry. Topological layers in the gp120 inner domain contribute to gp120-trimer association in the unliganded state and to CD4 binding. Here we describe similarities and differences between HIV-1 and SIVmac gp120. In both viruses, the gp120 N/C termini and the inner domain β-sandwich and layer 2 support the noncovalent association of gp120 with the envelope glycoprotein trimer. Layer 1 of the SIVmac gp120 inner domain contributes more to trimer association than the corresponding region of HIV-1 gp120. On the other hand, layer 1 plays an important role in stabilizing the CD4-bound conformation of HIV-1 but not SIVmac gp120 and thus contributes to HIV-1 binding to CD4. In SIVmac, CD4 binding is instead enhanced by tryptophan 375, which fills the Phe 43 cavity of gp120. Activation of SIVmac by soluble CD4 is dependent on tryptophan 375 and on layer 1 residues that determine a tight association of gp120 with the trimer. Distinct biological requirements for CD4 usage have resulted in lineage-specific differences in the HIV-1 and SIV gp120 structures that modulate trimer association and CD4 binding.
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Andrés
A
Finzi
Beatriz
B
Pacheco
Shi-Hua
SH
Xiang
Marie
M
Pancera
Alon
A
Herschhorn
Liping
L
Wang
Xing
X
Zeng
Anik
A
Desormeaux
Peter D
PD
Kwong
Joseph
J
Sodroski
D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D019070:Cell Lineage; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus