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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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Binding of soluble gp120 glycoprotein to New World monkey CD4 molecules. 293T cells were transfected with plasmids encoding human, marmoset (CJ), or mutant marmoset CD4 molecules and assayed for binding to soluble purified gp120 by flow cytometry. The concentration of the gp120 envelope glycoprotein used in the assay is shown on the x-axis, and the mean fluorescence associated with detection of bound gp120 is on the y-axis. SS CD4 showed no binding to gp120 molecules at any concentration and was used as a negative control.
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fig8: Binding of soluble gp120 glycoprotein to New World monkey CD4 molecules. 293T cells were transfected with plasmids encoding human, marmoset (CJ), or mutant marmoset CD4 molecules and assayed for binding to soluble purified gp120 by flow cytometry. The concentration of the gp120 envelope glycoprotein used in the assay is shown on the x-axis, and the mean fluorescence associated with detection of bound gp120 is on the y-axis. SS CD4 showed no binding to gp120 molecules at any concentration and was used as a negative control.

Mentions: The ability of the gp120 envelope glycoprotein from the ADA, JR-FL, and YU2 HIV-1 strains to bind 293T cells expressing the wild-type and variant New World monkey CD4 proteins was tested. The HIV-1 gp120 glycoproteins bound cells expressing human CD4 more efficiently than cells expressing common marmoset CD4 (Fig. 8) . Approximate differences of 20-fold and 100-fold in affinity for the two CD4 molecules were observed for the ADA and JR-FL gp120 glycoproteins, respectively. A smaller difference in affinity was observed for the YU2 gp120 glycoprotein; the YU2 gp120 bound the CJ CD4 with an apparent Kd of ∼100 nM, a significantly higher affinity than was seen for the ADA or JR-FL gp120 glycoproteins. Thus, the gp120 glycoproteins from different HIV-1 strains apparently bind the CJ CD4 with a range of affinities. The CJ CD4 mutants Q48P and Q59R bound the gp120 glycoproteins of all three HIV-1 strains with an affinity that was better than that associated with the wild-type CJ CD4 protein. The double mutant CJ CD4 Q48P/Q59R bound the gp120 glycoproteins comparably to the human CD4 protein. Thus, the differences between the abilities of common marmoset and human CD4 to bind HIV-1 gp120 can be largely attributed to species-specific differences in CD4 residues 48 and 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)

Binding of soluble gp120 glycoprotein to New World monkey CD4 molecules. 293T cells were transfected with plasmids encoding human, marmoset (CJ), or mutant marmoset CD4 molecules and assayed for binding to soluble purified gp120 by flow cytometry. The concentration of the gp120 envelope glycoprotein used in the assay is shown on the x-axis, and the mean fluorescence associated with detection of bound gp120 is on the y-axis. SS CD4 showed no binding to gp120 molecules at any concentration and was used as a negative control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196058&req=5

fig8: Binding of soluble gp120 glycoprotein to New World monkey CD4 molecules. 293T cells were transfected with plasmids encoding human, marmoset (CJ), or mutant marmoset CD4 molecules and assayed for binding to soluble purified gp120 by flow cytometry. The concentration of the gp120 envelope glycoprotein used in the assay is shown on the x-axis, and the mean fluorescence associated with detection of bound gp120 is on the y-axis. SS CD4 showed no binding to gp120 molecules at any concentration and was used as a negative control.
Mentions: The ability of the gp120 envelope glycoprotein from the ADA, JR-FL, and YU2 HIV-1 strains to bind 293T cells expressing the wild-type and variant New World monkey CD4 proteins was tested. The HIV-1 gp120 glycoproteins bound cells expressing human CD4 more efficiently than cells expressing common marmoset CD4 (Fig. 8) . Approximate differences of 20-fold and 100-fold in affinity for the two CD4 molecules were observed for the ADA and JR-FL gp120 glycoproteins, respectively. A smaller difference in affinity was observed for the YU2 gp120 glycoprotein; the YU2 gp120 bound the CJ CD4 with an apparent Kd of ∼100 nM, a significantly higher affinity than was seen for the ADA or JR-FL gp120 glycoproteins. Thus, the gp120 glycoproteins from different HIV-1 strains apparently bind the CJ CD4 with a range of affinities. The CJ CD4 mutants Q48P and Q59R bound the gp120 glycoproteins of all three HIV-1 strains with an affinity that was better than that associated with the wild-type CJ CD4 protein. The double mutant CJ CD4 Q48P/Q59R bound the gp120 glycoproteins comparably to the human CD4 protein. Thus, the differences between the abilities of common marmoset and human CD4 to bind HIV-1 gp120 can be largely attributed to species-specific differences in CD4 residues 48 and 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