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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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HIV-1 virus production from New World monkey PBMCs. Approximately 100,000 RT cpm of wild-type NL4–3 HIV-1 strain or the NL4–3 virus pseudotyped with the VSV G protein (NL4–3 (G)) were incubated with human CEMx174 cells as a positive control and rhesus macaque (MM) PBMCs as a negative control (A), PBMCs from three different squirrel monkey (SS) donors (B), or PBMCs from three different common marmoset (CJ) donors (C). Cells were washed at 16 h and RT units were measured in duplicate cultures at 24-h time points. Virus production on day 2, which for the primary monkey cells represents the peak value, is shown for each cell type in the bar graphs on the left. Equivalent RT units of virus produced from each culture were added to CEMx174 target cells to assay for their infectivity (line graphs on right). Where no detectable virus was produced after the round of initial infection (e.g., wild-type NL4–3 infection of New World monkey PBMCs), the entire supernatant was added. Target cells were washed at 16 h and RT units were measured at 24-h time points.
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fig1: HIV-1 virus production from New World monkey PBMCs. Approximately 100,000 RT cpm of wild-type NL4–3 HIV-1 strain or the NL4–3 virus pseudotyped with the VSV G protein (NL4–3 (G)) were incubated with human CEMx174 cells as a positive control and rhesus macaque (MM) PBMCs as a negative control (A), PBMCs from three different squirrel monkey (SS) donors (B), or PBMCs from three different common marmoset (CJ) donors (C). Cells were washed at 16 h and RT units were measured in duplicate cultures at 24-h time points. Virus production on day 2, which for the primary monkey cells represents the peak value, is shown for each cell type in the bar graphs on the left. Equivalent RT units of virus produced from each culture were added to CEMx174 target cells to assay for their infectivity (line graphs on right). Where no detectable virus was produced after the round of initial infection (e.g., wild-type NL4–3 infection of New World monkey PBMCs), the entire supernatant was added. Target cells were washed at 16 h and RT units were measured at 24-h time points.

Mentions: CEMx174 cells supported the production of the NL4–3 and NL4–3 (VSV G) viruses, which peaked on the second day after inoculation (Fig. 1 A, left). The viruses produced from the CEMx174 cells were able to initiate subsequent rounds of infection in CEMx174 cells (Fig. 1 A, right). In parallel experiments, the NL43 NL4–3 (VSV G) virus produced in 293T cells was incubated with the PBMCs from two rhesus macaques, an Old World monkey that restricts HIV-1 replication at a post-entry stage. Little or no virus was produced from the rhesus macaque PBMCs and supernatants from these Old World monkey cells were not able to initiate detectable infection of CEMx174 cells (Fig. 1 A).


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)

HIV-1 virus production from New World monkey PBMCs. Approximately 100,000 RT cpm of wild-type NL4–3 HIV-1 strain or the NL4–3 virus pseudotyped with the VSV G protein (NL4–3 (G)) were incubated with human CEMx174 cells as a positive control and rhesus macaque (MM) PBMCs as a negative control (A), PBMCs from three different squirrel monkey (SS) donors (B), or PBMCs from three different common marmoset (CJ) donors (C). Cells were washed at 16 h and RT units were measured in duplicate cultures at 24-h time points. Virus production on day 2, which for the primary monkey cells represents the peak value, is shown for each cell type in the bar graphs on the left. Equivalent RT units of virus produced from each culture were added to CEMx174 target cells to assay for their infectivity (line graphs on right). Where no detectable virus was produced after the round of initial infection (e.g., wild-type NL4–3 infection of New World monkey PBMCs), the entire supernatant was added. Target cells were washed at 16 h and RT units were measured at 24-h time points.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: HIV-1 virus production from New World monkey PBMCs. Approximately 100,000 RT cpm of wild-type NL4–3 HIV-1 strain or the NL4–3 virus pseudotyped with the VSV G protein (NL4–3 (G)) were incubated with human CEMx174 cells as a positive control and rhesus macaque (MM) PBMCs as a negative control (A), PBMCs from three different squirrel monkey (SS) donors (B), or PBMCs from three different common marmoset (CJ) donors (C). Cells were washed at 16 h and RT units were measured in duplicate cultures at 24-h time points. Virus production on day 2, which for the primary monkey cells represents the peak value, is shown for each cell type in the bar graphs on the left. Equivalent RT units of virus produced from each culture were added to CEMx174 target cells to assay for their infectivity (line graphs on right). Where no detectable virus was produced after the round of initial infection (e.g., wild-type NL4–3 infection of New World monkey PBMCs), the entire supernatant was added. Target cells were washed at 16 h and RT units were measured at 24-h time points.
Mentions: CEMx174 cells supported the production of the NL4–3 and NL4–3 (VSV G) viruses, which peaked on the second day after inoculation (Fig. 1 A, left). The viruses produced from the CEMx174 cells were able to initiate subsequent rounds of infection in CEMx174 cells (Fig. 1 A, right). In parallel experiments, the NL43 NL4–3 (VSV G) virus produced in 293T cells was incubated with the PBMCs from two rhesus macaques, an Old World monkey that restricts HIV-1 replication at a post-entry stage. Little or no virus was produced from the rhesus macaque PBMCs and supernatants from these Old World monkey cells were not able to initiate detectable infection of CEMx174 cells (Fig. 1 A).

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