TY - JOUR
T1 - CD4 receptor diversity in chimpanzees protects against SIV infection
AU - Bibollet-Ruche, Frederic
AU - Russell, Ronnie M
AU - Liu, Weimin
AU - Stewart-Jones, Guillaume B.E.
AU - Sherrill-Mix, Scott
AU - Li, Yingying
AU - Learn, Gerald H
AU - Smith, Andrew G
AU - Gondim, Marcos V.P.
AU - Plenderleith, Lindsey J
AU - Decker, Julie M.
AU - Easlick, Juliet L.
AU - Wetzel, Katherine S.
AU - Collman, Ronald G.
AU - Ding, Shilei
AU - Finzi, Andrés C.
AU - Ayouba, Ahidjo
AU - Peeters, Martine
AU - Leendertz, Fabian H.
AU - van Schijndel, Joost
AU - Goedmakers, Annemarie
AU - Ton, Els
AU - Boesch, Christophe
AU - Kuehll, Hjalmar
AU - Arandjelovic, Mimi
AU - Dieguez, Paula
AU - Murai, Mizuki
AU - Colin, Christelle
AU - Koops, Kathelijne
AU - Speede, Sheri
AU - Gonder, Mary K.
AU - Muller, Martin N.
AU - Sanz, Crickette M.
AU - Morgan, David B.
AU - Atencia, Rebecca
AU - Cox, Debby
AU - Piel, Alex K.
AU - Stewart, Fiona A.
AU - Ndjango, Jean-Bosco N.
AU - Mjungu, Deus
AU - Lonsdorf, Elizabeth V.
AU - Pusey, Anne E.
AU - Kwong, Peter D.
AU - Sharp, Paul M.
AU - Shaw, George M.
AU - Hahn, Beatrice H
PY - 2019/2/4
Y1 - 2019/2/4
N2 - Human and simian immunodeficiency viruses (HIV/SIV) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4+ T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In-silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained to protect chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.
AB - Human and simian immunodeficiency viruses (HIV/SIV) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)-CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4+ T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In-silico modeling and site-directed mutagenesis identified charged residues at the CD4-Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained to protect chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.
KW - CD4
KW - SIV
KW - chimpanzee
KW - envelope glycoprotein
KW - glycan restriction
U2 - 10.1073/pnas.1821197116
DO - 10.1073/pnas.1821197116
M3 - Article
C2 - 30718403
SN - 0027-8424
JO - Proceedings of the National Academy of Sciences (PNAS)
JF - Proceedings of the National Academy of Sciences (PNAS)
ER -