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. 2003 Feb;77(4):2762-7.
doi: 10.1128/jvi.77.4.2762-2767.2003.

Human immunodeficiency virus type 1 attachment, coreceptor, and fusion inhibitors are active against both direct and trans infection of primary cells

Thomas J Ketas  1 , Ines Frank, Per Johan Klasse, Brian M Sullivan, Jason P Gardner, Catherine Spenlehauer, Mirjana Nesin, William C Olson, John P Moore, Melissa Pope
Affiliations

Human immunodeficiency virus type 1 attachment, coreceptor, and fusion inhibitors are active against both direct and trans infection of primary cells

Thomas J Ketas et al. J Virol. 2003 Feb.

Abstract

Inhibitors of human immunodeficiency virus type 1 attachment (CD4-immunoglobulin G subclass 2), CCR5 usage (PRO 140), and fusion (T-20) were tested on diverse primary cell types that represent the major targets both for infection in vivo and for the inhibition of trans infection of target cells by virus bound to dendritic cells. Although minor cell-type-dependent differences in potency were observed, each inhibitor was active on each cell type and trans infection was similarly vulnerable to inhibition at each stage of the fusion cascade.

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Figures

FIG. 1.
FIG. 1.
Cell-type-specific variations in inhibitor activity. IC50s and IC90s were observed for CD4-IgG2 (A), PRO 140 (B), T-20 (C), and RANTES (D) against HIV-1JR-FL (open circles), HIV-1SF162 (filled squares), and HIV-1Case C 1/85 (filled triangles) on the indicated cell types. Overall mean log IC50s and IC90s for all assays are indicated with horizontal bars. Mean log ICs that differed significantly (P < 0.013) from the corresponding value for PBMC are indicated with an asterisk. (A) CD4-IgG2. The mean log IC90s and IC50s obtained for macrophages were significantly lower than those obtained for PBMC (P = 7.9 × 10−7 for both IC90 and IC50). Mean log ICs for CBMC were also lower than those for PBMC (P = 0.0039 and 0.0045 for IC90 and IC50, respectively). None of the other values were significantly different from those for PBMC. (For IC90s, P = 0.96 for immature DC and 0.78 for DC in trans. For IC50s, P = 0.91 for immature DC and 0.82 for DC in trans.) (B) PRO 140. The mean log IC90 for immature DC was significantly higher than that for PBMC (P = 5.7 × 10−4). None of the other mean log IC90s were different from those for PBMC (P = 0.63 for macrophages, 0.19 for CBMC, and 0.38 for DC in trans). None of the IC50s differed from that for PBMC (P = 0.33 for immature DC, 0.23 for macrophages, 0.94 for CBMC, and 0.89 for DC in trans). (C) T-20. Immature DC had an IC90 higher than that for PBMC (P = 8.8 × 10−4). No other cell types had IC90s different from those for PBMC (P = 0.47 for macrophages, 0.62 for CBMC, and 0.19 for DC in trans). No IC50s were different compared to those for PBMC (P = 0.17 for immature DC, 0.34 for macrophages, 0.32 for CBMC, and 0.76 for DC in trans). (D) RANTES. Macrophages had higher mean log ICs than did PBMC (P = 4.8 × 10−7 for IC90 and 2.9 × 10−4 for IC50). The IC90s for immature DC bordered on being significantly higher than those for PBMC (P = 0.013). No other cell types had ICs different from those for PBMC. (For IC90s, P = 0.43 for CBMC and 0.63 for DC in trans. For IC50s, P = 0.31 for immature DC, 0.96 for CBMC, and 0.21 for DC in trans.) Any higher ICs for immature DC may reflect the 10-fold greater virus doses used to detect production infection in these assays.
FIG. 1.
FIG. 1.
Cell-type-specific variations in inhibitor activity. IC50s and IC90s were observed for CD4-IgG2 (A), PRO 140 (B), T-20 (C), and RANTES (D) against HIV-1JR-FL (open circles), HIV-1SF162 (filled squares), and HIV-1Case C 1/85 (filled triangles) on the indicated cell types. Overall mean log IC50s and IC90s for all assays are indicated with horizontal bars. Mean log ICs that differed significantly (P < 0.013) from the corresponding value for PBMC are indicated with an asterisk. (A) CD4-IgG2. The mean log IC90s and IC50s obtained for macrophages were significantly lower than those obtained for PBMC (P = 7.9 × 10−7 for both IC90 and IC50). Mean log ICs for CBMC were also lower than those for PBMC (P = 0.0039 and 0.0045 for IC90 and IC50, respectively). None of the other values were significantly different from those for PBMC. (For IC90s, P = 0.96 for immature DC and 0.78 for DC in trans. For IC50s, P = 0.91 for immature DC and 0.82 for DC in trans.) (B) PRO 140. The mean log IC90 for immature DC was significantly higher than that for PBMC (P = 5.7 × 10−4). None of the other mean log IC90s were different from those for PBMC (P = 0.63 for macrophages, 0.19 for CBMC, and 0.38 for DC in trans). None of the IC50s differed from that for PBMC (P = 0.33 for immature DC, 0.23 for macrophages, 0.94 for CBMC, and 0.89 for DC in trans). (C) T-20. Immature DC had an IC90 higher than that for PBMC (P = 8.8 × 10−4). No other cell types had IC90s different from those for PBMC (P = 0.47 for macrophages, 0.62 for CBMC, and 0.19 for DC in trans). No IC50s were different compared to those for PBMC (P = 0.17 for immature DC, 0.34 for macrophages, 0.32 for CBMC, and 0.76 for DC in trans). (D) RANTES. Macrophages had higher mean log ICs than did PBMC (P = 4.8 × 10−7 for IC90 and 2.9 × 10−4 for IC50). The IC90s for immature DC bordered on being significantly higher than those for PBMC (P = 0.013). No other cell types had ICs different from those for PBMC. (For IC90s, P = 0.43 for CBMC and 0.63 for DC in trans. For IC50s, P = 0.31 for immature DC, 0.96 for CBMC, and 0.21 for DC in trans.) Any higher ICs for immature DC may reflect the 10-fold greater virus doses used to detect production infection in these assays.
FIG. 1.
FIG. 1.
Cell-type-specific variations in inhibitor activity. IC50s and IC90s were observed for CD4-IgG2 (A), PRO 140 (B), T-20 (C), and RANTES (D) against HIV-1JR-FL (open circles), HIV-1SF162 (filled squares), and HIV-1Case C 1/85 (filled triangles) on the indicated cell types. Overall mean log IC50s and IC90s for all assays are indicated with horizontal bars. Mean log ICs that differed significantly (P < 0.013) from the corresponding value for PBMC are indicated with an asterisk. (A) CD4-IgG2. The mean log IC90s and IC50s obtained for macrophages were significantly lower than those obtained for PBMC (P = 7.9 × 10−7 for both IC90 and IC50). Mean log ICs for CBMC were also lower than those for PBMC (P = 0.0039 and 0.0045 for IC90 and IC50, respectively). None of the other values were significantly different from those for PBMC. (For IC90s, P = 0.96 for immature DC and 0.78 for DC in trans. For IC50s, P = 0.91 for immature DC and 0.82 for DC in trans.) (B) PRO 140. The mean log IC90 for immature DC was significantly higher than that for PBMC (P = 5.7 × 10−4). None of the other mean log IC90s were different from those for PBMC (P = 0.63 for macrophages, 0.19 for CBMC, and 0.38 for DC in trans). None of the IC50s differed from that for PBMC (P = 0.33 for immature DC, 0.23 for macrophages, 0.94 for CBMC, and 0.89 for DC in trans). (C) T-20. Immature DC had an IC90 higher than that for PBMC (P = 8.8 × 10−4). No other cell types had IC90s different from those for PBMC (P = 0.47 for macrophages, 0.62 for CBMC, and 0.19 for DC in trans). No IC50s were different compared to those for PBMC (P = 0.17 for immature DC, 0.34 for macrophages, 0.32 for CBMC, and 0.76 for DC in trans). (D) RANTES. Macrophages had higher mean log ICs than did PBMC (P = 4.8 × 10−7 for IC90 and 2.9 × 10−4 for IC50). The IC90s for immature DC bordered on being significantly higher than those for PBMC (P = 0.013). No other cell types had ICs different from those for PBMC. (For IC90s, P = 0.43 for CBMC and 0.63 for DC in trans. For IC50s, P = 0.31 for immature DC, 0.96 for CBMC, and 0.21 for DC in trans.) Any higher ICs for immature DC may reflect the 10-fold greater virus doses used to detect production infection in these assays.
FIG. 1.
FIG. 1.
Cell-type-specific variations in inhibitor activity. IC50s and IC90s were observed for CD4-IgG2 (A), PRO 140 (B), T-20 (C), and RANTES (D) against HIV-1JR-FL (open circles), HIV-1SF162 (filled squares), and HIV-1Case C 1/85 (filled triangles) on the indicated cell types. Overall mean log IC50s and IC90s for all assays are indicated with horizontal bars. Mean log ICs that differed significantly (P < 0.013) from the corresponding value for PBMC are indicated with an asterisk. (A) CD4-IgG2. The mean log IC90s and IC50s obtained for macrophages were significantly lower than those obtained for PBMC (P = 7.9 × 10−7 for both IC90 and IC50). Mean log ICs for CBMC were also lower than those for PBMC (P = 0.0039 and 0.0045 for IC90 and IC50, respectively). None of the other values were significantly different from those for PBMC. (For IC90s, P = 0.96 for immature DC and 0.78 for DC in trans. For IC50s, P = 0.91 for immature DC and 0.82 for DC in trans.) (B) PRO 140. The mean log IC90 for immature DC was significantly higher than that for PBMC (P = 5.7 × 10−4). None of the other mean log IC90s were different from those for PBMC (P = 0.63 for macrophages, 0.19 for CBMC, and 0.38 for DC in trans). None of the IC50s differed from that for PBMC (P = 0.33 for immature DC, 0.23 for macrophages, 0.94 for CBMC, and 0.89 for DC in trans). (C) T-20. Immature DC had an IC90 higher than that for PBMC (P = 8.8 × 10−4). No other cell types had IC90s different from those for PBMC (P = 0.47 for macrophages, 0.62 for CBMC, and 0.19 for DC in trans). No IC50s were different compared to those for PBMC (P = 0.17 for immature DC, 0.34 for macrophages, 0.32 for CBMC, and 0.76 for DC in trans). (D) RANTES. Macrophages had higher mean log ICs than did PBMC (P = 4.8 × 10−7 for IC90 and 2.9 × 10−4 for IC50). The IC90s for immature DC bordered on being significantly higher than those for PBMC (P = 0.013). No other cell types had ICs different from those for PBMC. (For IC90s, P = 0.43 for CBMC and 0.63 for DC in trans. For IC50s, P = 0.31 for immature DC, 0.96 for CBMC, and 0.21 for DC in trans.) Any higher ICs for immature DC may reflect the 10-fold greater virus doses used to detect production infection in these assays.
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