Effects of natural sequence variation on recognition by monoclonal antibodies neutralize simian immunodeficiency virus infectivity.
The determinants of immune recognition by five monoclonal antibodies (KK5, KK9, KK17, Senv7.1, and Senv101.1) that neutralize simian immunodeficiency virus infectivity were analyzed. These five neutralizing monoclonal antibodies were generated to native SIVmac251 envelope glycoprotein expressed by a vaccinia virus recombinant vector. All five recognize conformational or discontinuous epitopes and require native antigen for optimal recognition. These monoclonal antibodies also recognize SIVmac239 gp120, but they do not recognize gp120 of two natural variants of SIVmac239, 1-12 and 8-22, which evolved during the course of persistent infection in vivo (D.P.W. Burns and R.C. Desrosiers, J. Virol. 65:1843-1854, 1991). Recombinant viruses which were constructed by exchanging variable regions between SIVmac239 and variant 1-12 were used to define domains important for recognition. Radioimmunoprecipitation analysis demonstrated that sequence changes in variable regions 4 and 5 (V4/V5) were primarily responsible for the loss of recognition of the 1-12 variant. Site-specific mutants were used to define precise changes that eliminate recognition by these neutralizing antibodies. Changing N-409 to D, deletion of KPKE, and deletion of KEQH in V4 each resulted in loss of recognition by all five monoclonal antibodies. SIVs with these natural sequence changes are still replication competent and viable. Changing A-417 to T or A/N-417/418 to TK in V4 or Q-477 to K in V5 did not alter recognition detectably. These results define specific, naturally occurring sequence changes in V4 of SIVmac that result in loss of recognition by one class of SIVmac neutralizing antibodies.
Choi
W S
WS
New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102.
Collignon
C
C
Thiriart
C
C
Burns
D P
DP
Stott
E J
EJ
Kent
K A
KA
Desrosiers
R C
RC
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology*; D000918:Antibody Specificity; D001483:Base Sequence; D015704:CD4 Antigens / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D000939:Epitopes; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009500:Neutralization Tests; D011487:Protein Conformation; D011994:Recombinant Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015704:CD4 Antigens; D017931:DNA Primers; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus