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Blockade of HIV-1 infection of New World monkey cells occurs primarily at the stage of virus entry.

LaBonte JA, Babcock GJ, Patel T, Sodroski J - J. Exp. Med. (2002)

Bottom Line: Efficient HIV-1 entry typically requires binding of the viral envelope glycoproteins and host cell receptors, CD4 and either CCR5 or CXCR4 chemokine receptors.A marmoset CD4 variant, in which residues 48 and 59 were altered to the amino acids found in human CD4, supported HIV-1 entry efficiently.Directed adaptation of the HIV-1 envelope glycoproteins to common marmoset receptors might allow the development of New World monkey models of HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Immunology & AIDS, JFB 824, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

ABSTRACT
HIV-1 naturally infects chimpanzees and humans, but does not infect Old World monkeys because of replication blocks that occur after virus entry into the cell. To understand the species-specific restrictions operating on HIV-1 infection, the ability of HIV-1 to infect the cells of New World monkeys was examined. Primary cells derived from common marmosets and squirrel monkeys support every phase of HIV-1 replication with the exception of virus entry. Efficient HIV-1 entry typically requires binding of the viral envelope glycoproteins and host cell receptors, CD4 and either CCR5 or CXCR4 chemokine receptors. HIV-1 did not detectably bind or utilize squirrel monkey CD4 for entry, and marmoset CD4 was also very inefficient compared with human CD4. A marmoset CD4 variant, in which residues 48 and 59 were altered to the amino acids found in human CD4, supported HIV-1 entry efficiently. The CXCR4 molecules of both marmosets and squirrel monkeys supported HIV-1 infection, but the CCR5 proteins of both species were only marginally functional. These results demonstrate that the CD4 and CCR5 proteins of New World monkeys represent the major restriction against HIV-1 replication in these primates. Directed adaptation of the HIV-1 envelope glycoproteins to common marmoset receptors might allow the development of New World monkey models of HIV-1 infection.

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Predicted amino acid alignment of Ig domains 1 and 2 of New World monkey CD4 proteins. PCR primers specific for the 5′ and 3′ untranslated regions were used to amplify CD4 from cDNA generated from squirrel monkey or marmoset PBMCs. (A) The predicted amino acid sequences of these cloned CD4 molecules are aligned to the previously identified sequences of human, rhesus macaque, and murine CD4. The shaded boxes designate Ig domains 1 and 2. The solid line identifies the signal sequence, which is cleaved from the mature protein. Dots (.) denote residues identical to the human sequence and minus signs (−) denote deletions. Gray arrows denote residues that differ from the published squirrel monkey CD4 allele D86588. GenBank/EMBL/DDBJ accession nos. for the sequences are as follows: human, M12807; rhesus, D63347; squirrel monkey, AF452617; common marmoset, AF452616; mouse, NM_013488. (B) The region of human CD4 that makes important contacts with the HIV-1 gp120 glycoprotein is aligned with the analogous region of squirrel monkey and common marmoset CD4 proteins. Phenylalanine 43 and arginine 59 (arrows) are particularly important residues for gp120 binding (references 45, 77, and 79). Changes introduced into the squirrel monkey and common marmoset CD4 molecules in this study are shown in bold.
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fig2: Predicted amino acid alignment of Ig domains 1 and 2 of New World monkey CD4 proteins. PCR primers specific for the 5′ and 3′ untranslated regions were used to amplify CD4 from cDNA generated from squirrel monkey or marmoset PBMCs. (A) The predicted amino acid sequences of these cloned CD4 molecules are aligned to the previously identified sequences of human, rhesus macaque, and murine CD4. The shaded boxes designate Ig domains 1 and 2. The solid line identifies the signal sequence, which is cleaved from the mature protein. Dots (.) denote residues identical to the human sequence and minus signs (−) denote deletions. Gray arrows denote residues that differ from the published squirrel monkey CD4 allele D86588. GenBank/EMBL/DDBJ accession nos. for the sequences are as follows: human, M12807; rhesus, D63347; squirrel monkey, AF452617; common marmoset, AF452616; mouse, NM_013488. (B) The region of human CD4 that makes important contacts with the HIV-1 gp120 glycoprotein is aligned with the analogous region of squirrel monkey and common marmoset CD4 proteins. Phenylalanine 43 and arginine 59 (arrows) are particularly important residues for gp120 binding (references 45, 77, and 79). Changes introduced into the squirrel monkey and common marmoset CD4 molecules in this study are shown in bold.

Mentions: Of the three receptors, the New World monkey CD4 molecules diverge the most from their human counterpart, displaying 80.3 and 81% sequence identity to human CD4 for the SS and CJ molecules, respectively. An alignment of the SS and CJ CD4 sequence to the human and rhesus monkey proteins, which support HIV-1 infection, and to murine CD4, which does not support HIV-1 infection, is shown in Fig. 2 A. Of the four immunoglobulin-like extracellular domains of CD4, the NH2-terminal domain is the most important for HIV-1 binding and entry. Phenylalanine 43 and arginine 59 of human CD4 make particularly important contacts with the HIV-1 gp120 glycoprotein (66–68). Both SS and CJ CD4 glycoproteins possess a phenylalanine residue at position 43, but exhibit numerous differences from human CD4 in the adjacent regions of the protein. For example, the CJ CD4 has a glutamine at residue 59.


Blockade of HIV-1 infection of New World monkey cells occurs primarily at the stage of virus entry.

LaBonte JA, Babcock GJ, Patel T, Sodroski J - J. Exp. Med. (2002)

Predicted amino acid alignment of Ig domains 1 and 2 of New World monkey CD4 proteins. PCR primers specific for the 5′ and 3′ untranslated regions were used to amplify CD4 from cDNA generated from squirrel monkey or marmoset PBMCs. (A) The predicted amino acid sequences of these cloned CD4 molecules are aligned to the previously identified sequences of human, rhesus macaque, and murine CD4. The shaded boxes designate Ig domains 1 and 2. The solid line identifies the signal sequence, which is cleaved from the mature protein. Dots (.) denote residues identical to the human sequence and minus signs (−) denote deletions. Gray arrows denote residues that differ from the published squirrel monkey CD4 allele D86588. GenBank/EMBL/DDBJ accession nos. for the sequences are as follows: human, M12807; rhesus, D63347; squirrel monkey, AF452617; common marmoset, AF452616; mouse, NM_013488. (B) The region of human CD4 that makes important contacts with the HIV-1 gp120 glycoprotein is aligned with the analogous region of squirrel monkey and common marmoset CD4 proteins. Phenylalanine 43 and arginine 59 (arrows) are particularly important residues for gp120 binding (references 45, 77, and 79). Changes introduced into the squirrel monkey and common marmoset CD4 molecules in this study are shown in bold.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196058&req=5

fig2: Predicted amino acid alignment of Ig domains 1 and 2 of New World monkey CD4 proteins. PCR primers specific for the 5′ and 3′ untranslated regions were used to amplify CD4 from cDNA generated from squirrel monkey or marmoset PBMCs. (A) The predicted amino acid sequences of these cloned CD4 molecules are aligned to the previously identified sequences of human, rhesus macaque, and murine CD4. The shaded boxes designate Ig domains 1 and 2. The solid line identifies the signal sequence, which is cleaved from the mature protein. Dots (.) denote residues identical to the human sequence and minus signs (−) denote deletions. Gray arrows denote residues that differ from the published squirrel monkey CD4 allele D86588. GenBank/EMBL/DDBJ accession nos. for the sequences are as follows: human, M12807; rhesus, D63347; squirrel monkey, AF452617; common marmoset, AF452616; mouse, NM_013488. (B) The region of human CD4 that makes important contacts with the HIV-1 gp120 glycoprotein is aligned with the analogous region of squirrel monkey and common marmoset CD4 proteins. Phenylalanine 43 and arginine 59 (arrows) are particularly important residues for gp120 binding (references 45, 77, and 79). Changes introduced into the squirrel monkey and common marmoset CD4 molecules in this study are shown in bold.
Mentions: Of the three receptors, the New World monkey CD4 molecules diverge the most from their human counterpart, displaying 80.3 and 81% sequence identity to human CD4 for the SS and CJ molecules, respectively. An alignment of the SS and CJ CD4 sequence to the human and rhesus monkey proteins, which support HIV-1 infection, and to murine CD4, which does not support HIV-1 infection, is shown in Fig. 2 A. Of the four immunoglobulin-like extracellular domains of CD4, the NH2-terminal domain is the most important for HIV-1 binding and entry. Phenylalanine 43 and arginine 59 of human CD4 make particularly important contacts with the HIV-1 gp120 glycoprotein (66–68). Both SS and CJ CD4 glycoproteins possess a phenylalanine residue at position 43, but exhibit numerous differences from human CD4 in the adjacent regions of the protein. For example, the CJ CD4 has a glutamine at residue 59.

Bottom Line: Efficient HIV-1 entry typically requires binding of the viral envelope glycoproteins and host cell receptors, CD4 and either CCR5 or CXCR4 chemokine receptors.A marmoset CD4 variant, in which residues 48 and 59 were altered to the amino acids found in human CD4, supported HIV-1 entry efficiently.Directed adaptation of the HIV-1 envelope glycoproteins to common marmoset receptors might allow the development of New World monkey models of HIV-1 infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Immunology & AIDS, JFB 824, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

ABSTRACT
HIV-1 naturally infects chimpanzees and humans, but does not infect Old World monkeys because of replication blocks that occur after virus entry into the cell. To understand the species-specific restrictions operating on HIV-1 infection, the ability of HIV-1 to infect the cells of New World monkeys was examined. Primary cells derived from common marmosets and squirrel monkeys support every phase of HIV-1 replication with the exception of virus entry. Efficient HIV-1 entry typically requires binding of the viral envelope glycoproteins and host cell receptors, CD4 and either CCR5 or CXCR4 chemokine receptors. HIV-1 did not detectably bind or utilize squirrel monkey CD4 for entry, and marmoset CD4 was also very inefficient compared with human CD4. A marmoset CD4 variant, in which residues 48 and 59 were altered to the amino acids found in human CD4, supported HIV-1 entry efficiently. The CXCR4 molecules of both marmosets and squirrel monkeys supported HIV-1 infection, but the CCR5 proteins of both species were only marginally functional. These results demonstrate that the CD4 and CCR5 proteins of New World monkeys represent the major restriction against HIV-1 replication in these primates. Directed adaptation of the HIV-1 envelope glycoproteins to common marmoset receptors might allow the development of New World monkey models of HIV-1 infection.

Show MeSH
Related in: MedlinePlus