Nerve growth factor is an autocrine factor essential for the survival of macrophages infected with HIV - PubMed (original) (raw)

Nerve growth factor is an autocrine factor essential for the survival of macrophages infected with HIV

E Garaci et al. Proc Natl Acad Sci U S A. 1999.

Abstract

Nerve growth factor (NGF) is a neurotrophin with the ability to exert specific effects on cells of the immune system. Human monocytes/macrophages (M/M) infected in vitro with HIV type 1 (HIV-1) are able to produce substantial levels of NGF that are associated with enhanced expression of the high-affinity NGF receptor (p140 trkA) on the M/M surface. Treatment of HIV-infected human M/M with anti-NGF Ab blocking the biological activity of NGF leads to a marked decrease of the expression of p140 trkA high-affinity receptor, a concomitant increased expression of p75(NTR) low-affinity receptor for NGF, and the occurrence of apoptotic death of M/M. Taken together, these findings suggest a role for NGF as an autocrine survival factor that rescues human M/M from the cytopathic effect caused by HIV infection.

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Figures

Figure 1

Figure 1

NGF production by macrophages infected with HIV. NGF production was assessed in the supernatants of M/M immediately before virus challenge (A, small dots) and 5 days after mock infection (big dots) or HIV infection (hatched bar). Immunocytochemical analysis was performed on M/M (B) at the same time points, that is, immediately before virus challenge (A) and 5 days after mock infection (B) or HIV infection (C). NGF production in the supernatants of HIV-infected M/M is statistically greater than that found in the supernatants of mock-infected M/M (either before or after mock infection) [ANOVA:F(2, 6) = 96.448; P = 0.001]. Values represent mean ± SE of an experiment representative of three.

Figure 2

Figure 2

Expression of high-affinity receptors on macrophages infected by HIV. Treatment of HIV-infected M/M with anti-NGF Ab (M/M + HIV + anti-NGF), but not with an IgG isotypic Ab (M/M + HIV + IgG), modifies the cellular expression of p140 trkA high-affinity receptor. Quantitative analysis of p140 trkA-immunoreactive cells carried out with a computerized image-analysis system (Zeiss Axiophot 2 microscope equipped with a Vidas Kontron system) shows that the increase of p140 trkA immunopositive cells in HIV-infected human M/M (M/M + HIV) was statistically significant (ANOVA: F(4, 85) = 116.017;P < 0.01) compared with mock-infected human M/M (M/M). Treatment of HIV-infected M/M with anti-NGF Ab (M/M + HIV + anti-NGF) yielded a statistically significant decrease (P < 0.01) of p140 trkA immunoreactivity in comparison to HIV-infected M/M (M/M + HIV), mock-infected human M/M (M/M + anti-NGF), or HIV-infected M/M with an irrelevant IgG Ab (M/M + HIV + IgG).

Figure 3

Figure 3

Expression of low-affinity receptors in macrophages infected with HIV. A dramatic increase of p75NTR receptor expression was consistently obtained by treating HIV-infected M/M with anti-NGF Ab. An IgG isotypic Ab was totally ineffective. A quantitative analysis of p75NTR immunoreactive cells (carried out with a computerized image-analysis system) shows a statistically significant increase of p75NTR immunopositive cells in HIV-infected human M/M treated with anti-NGF Ab compared with all other samples, either infected or not (ANOVA: F(4, 85) = 289.354;P = 0.001).

Figure 4

Figure 4

Programmed cell death in HIV-infected macrophages exposed to anti-NGF Ab. (Left) FACS analysis. Apoptosis was detected by DNA labeling with propidium iodide, a fluorescent intercalating dye that allows DNA quantification. Apoptotic nuclei appeared as a broad hypodiploid DNA peak (black arrow in each panel) easily discriminable from the narrow peak of nuclei with normal diploid DNA counted in the red fluorescence channel. DNA fragmentation has been detected in 5% of mock-infected human M/M (A). Results in the same range were observed in HIV-infected M/M (9.1% of propidium-positive cells; B), in mock-infected M/M exposed to anti-NGF Ab (6.9%; C), or in HIV-infected M/M treated with the IgG isotypic Ab (8.7%; E). By contrast, exposure of HIV-infected cells to anti-NGF Ab (D) induces DNA fragmentation in 40.3% of M/M in this experiment representative of five different tests. (Right) TUNEL. Immunocytochemical studies performed by TUNEL show nuclei with round condensed chromatin in HIV-infected M/M exposed to anti-NGF Ab (D) far more than in any of the other M/M samples tested (A, B,C, and E). The figure presents data from a typical experiment of three.

Figure 5

Figure 5

Effect of NGF starvation upon HIV production in macrophages. A dramatic difference of virus production was detected between HIV-infected M/M exposed to anti-NGF Ab (■), HIV-infected M/M (●), or HIV-infected M/M exposed to an IgG-isotypic irrelevant Ab (▴). HIV p24 gag antigen production was evaluated by commercially available ELISA at days 2, 5, 8, 11, and 14 after virus infection. The figure represents a typical experiment of three.

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