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. 1999 Jan;73(1):684-94.
doi: 10.1128/JVI.73.1.684-694.1999.

Enhancement of human immunodeficiency virus type 1 infection by the CC-chemokine RANTES is independent of the mechanism of virus-cell fusion

C J Gordon  1 , M A Muesing, A E Proudfoot, C A Power, J P Moore, A Trkola
Affiliations

Enhancement of human immunodeficiency virus type 1 infection by the CC-chemokine RANTES is independent of the mechanism of virus-cell fusion

C J Gordon et al. J Virol. 1999 Jan.

Abstract

We have studied the effects of CC-chemokines on human immunodeficiency virus type 1 (HIV-1) infection, focusing on the infectivity enhancement caused by RANTES. High RANTES concentrations increase the infectivity of HIV-1 isolates that use CXC-chemokine receptor 4 for entry. However, RANTES can have a similar enhancing effect on macrophagetropic viruses that enter via CC-chemokine receptor 5 (CCR5), despite binding to the same receptor as the virus. Furthermore, RANTES enhances the infectivity of HIV-1 pseudotyped with the envelope glycoprotein of murine leukemia virus or vesicular stomatitis virus, showing that the mechanism of enhancement is independent of the route of virus-cell fusion. The enhancing effects of RANTES are not mediated via CCR5 or other known chemokine receptors and are not mimicked by MIP-1alpha or MIP-1beta. The N-terminally modified derivative aminooxypentane RANTES (AOP-RANTES) efficiently inhibits HIV-1 infection via CCR5 but otherwise mimics RANTES by enhancing viral infectivity. There are two mechanisms of enhancement: one apparent when target cells are pretreated with RANTES (or AOP-RANTES) for several hours, and the other apparent when RANTES (or AOP-RANTES) is added during virus-cell absorption. We believe that the first mechanism is related to cellular activation by RANTES, whereas the second is an increase in virion attachment to target cells.

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Figures

FIG. 1
FIG. 1
Effects of RANTES and AOP-RANTES on infection of different target cells by HIV-1 ADA pseudotypes. Cells were infected with HIV-1 ADA pseudotypes in the presence or absence of the indicated concentrations of RANTES (a to c, ■) or AOP-RANTES (d to f, □). Unbound virus was removed after a 2-h incubation, and cultures were replenished with medium containing the same concentration of CC-chemokine. Luciferase expression was measured on day 3 postinfection and presented as percentage of control (no RANTES, considered 100%). a and d, HeLa-CD4-CCR5 cells; b and e, HOS-CD4-CCR5 cells; c and f, U87MG-CD4-CCR5 cells.
FIG. 2
FIG. 2
Effects of CC- and CXC-chemokines on infection of different target cells by HIV-1 pseudotypes. Cells were infected with pseudotyped viruses in the presence or absence of indicated concentrations of chemokines. Unbound virus was removed after a 2-h incubation, and cultures were replenished with medium containing the same concentration of chemokine. Luciferase expression was measured on day 3 postinfection and presented as percentage of control (no chemokine, considered 100%). (a) HeLa-CD4 cells were infected with HIV-1 HxB2-pseudotyped in the presence of 2.5 μg of RANTES, MIP-1α, MIP-1β, MCP-1, MCP-3, or SDF-1α per ml or with no added chemokine. (b to g) The cells were incubated with the indicated concentrations of RANTES (■), AOP-RANTES (□), MIP-1β (•), or SDF-1α (▾). The target cells were HeLa-CD4 (a, b, d, f, and g) and HeLa-CD4-CCR5 (c and e). The Env pseudotypes were HIV-1 HxB2 (a, b, c, and f) MuLV (d and g), and HIV-1 ADA (e). Viral inocula were the equivalents of 5 ng (a, b, and d), 1.5 ng (c), 3.5 ng (e), 30 ng (f), and 4 ng (g) of p24 antigen.
FIG. 3
FIG. 3
RANTES enhances infection of nonhuman cells by MuLV pseudotypes. Murine 3T3-CD4 cells (5 × 104 per well of a 24-well plate) (a) and simian COS-CD4 cells (104 per well of a 96-well plate) (b) were infected with MuLV Env-pseudotyped HIV-1 in the presence or absence of the indicated concentrations of RANTES. Viral inocula were the equivalents of 200 ng of HIV-1 p24 antigen for the 3T3-CD4 cells 11 ng for the COS-CD4 cells. Unbound virus was removed after a 2-h incubation, and cultures were replenished with medium containing the same concentration of RANTES. Luciferase expression was measured on day 3 postinfection and presented as percentage of control (no RANTES, considered 100%).
FIG. 4
FIG. 4
RANTES enhances the infectivity of both VSV and MuLV pseudotypes. HeLa-CD4 cells were infected with various concentrations of MuLV-pseudotyped (a) and VSV-G-pseudotyped (b) viruses in the presence (■) or absence (▴) of 5 μg of RANTES per ml. Unbound virus was removed after a 2-h incubation, and cultures were replenished with medium containing the same concentration of RANTES.
FIG. 5
FIG. 5
Time of addition affects the extent of RANTES-mediated infectivity enhancement. RANTES (2.5 μg/ml) was added to HeLa-CD4 cells at the indicated times before, during, or after infection with MuLV (a) or HIV-1 HxB2 (b) Env pseudotypes. Viral inocula were the equivalents of 3 ng (a) and 5.8 ng (b) of HIV-1 p24 antigen. The infection period, defined as the time when the virus inoculum was in contact with the cells, lasted 2 h. For the pretreatment time points, RANTES was added to the cells at the indicated time before infection was initiated, and then the RANTES-containing medium was removed immediately before the addition of virus. RANTES was absent for the 2-h infection period and subsequently. For the “infection” time point, RANTES was added during the 2-h infection period but was not present before or after this time. For the time point marked “post infection,” RANTES was added to the cells immediately after the virus inoculum had been removed at the end of the 2-h infection period. For all other postinfection time points, RANTES was added at the indicated times after removal of the viral inoculum. For all postinfection time points, RANTES remained in the cultures until the end of the experiment. Luciferase expression was measured on day 3 postinfection and presented as percentage of control (no RANTES, considered 100%).
FIG. 6
FIG. 6
AOP-RANTES mimics RANTES by enhancing viral infectivity. For design of the experiment, see the legend to Fig. 5. RANTES (a) or AOP-RANTES (b), each at 2.5 μg/ml, was added to HeLa-CD4 cells at various times prior to or during infectivity with MuLV Env pseudotypes (3.5 ng of p24 antigen per ml). Note that the scales on the abscissa differ in the two panels, reflecting the lesser enhancement of infectivity caused by AOP-RANTES.
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