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C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells.

Verani A, Scarlatti G, Comar M, Tresoldi E, Polo S, Giacca M, Lusso P, Siccardi AG, Vercelli D - J. Exp. Med. (1997)

Bottom Line: A combination of recombinant C-C chemokines blocked HIV-1 infection as effectively as LPS.Here, we report an inhibitory effect of C-C chemokines on HIV replication in primary macrophages.Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological and Technological Research, San Raffaele Scientific Institute, Milan, Italy.

ABSTRACT
Human immunodeficiency virus-1 (HIV-1) expression in monocyte-derived macrophages (MDM) infected in vitro is known to be inhibited by lipopolysaccharide (LPS). However, the mechanisms are incompletely understood. We show here that HIV-1 suppression is mediated by soluble factors released by MDM stimulated with physiologically significant concentrations of LPS. LPS-conditioned supernatants from MDM inhibited HIV-1 replication in both MDM and T cells. Depletion of C-C chemokines (RANTES, MIP-1 alpha, and MIP-1 beta) neutralized the ability of LPS-conditioned supernatants to inhibit HIV-1 replication in MDM. A combination of recombinant C-C chemokines blocked HIV-1 infection as effectively as LPS. Here, we report an inhibitory effect of C-C chemokines on HIV replication in primary macrophages. Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.

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Effects of LPS stimulation and/or HIV-1 infection  on IL-6 and TNF-α secretion by  MDM. Uninfected or HIV-1Ba-Linfected MDM were cultured in  the presence or absence of LPS  (1 μg/ml). LPS was added to the  cultures every 3 d. IL-6 and  TNF-α concentrations in the supernatants were measured by  ELISA. The data are representative of four separate experiments.
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Figure 4: Effects of LPS stimulation and/or HIV-1 infection on IL-6 and TNF-α secretion by MDM. Uninfected or HIV-1Ba-Linfected MDM were cultured in the presence or absence of LPS (1 μg/ml). LPS was added to the cultures every 3 d. IL-6 and TNF-α concentrations in the supernatants were measured by ELISA. The data are representative of four separate experiments.

Mentions: A number of cytokines have been described that regulate HIV-1 expression. In particular, TNF-α and IL-6 enhance HIV-1 replication in acutely infected MDM. The HIV-1–inducing effect of TNF-α is mainly, if not exclusively, mediated by the activation of NF-κB, which activates LTR-driven viral RNA transcription (26). IL-6 induces expression of viral proteins and RT activity to levels comparable to those induced by TNF-α, but unlike TNF-α, does not increase significantly the levels of steady-state viral mRNA (27). Therefore, we investigated whether a decrease in the production of these HIV-1 stimulatory cytokines may underlie LPS-dependent inhibition of HIV-1 replication in MDM. Fig. 4 shows that LPS-induced IL-6 secretion was vigorous and comparable in both uninfected and HIV-1–infected MDM cultures. In contrast, infected cultures treated with LPS showed an impairment in their ability to sustain TNF-α secretion over time. However, stimulation with LPS released high and comparable levels of TNF-α (>40 ng/ml) from uninfected and infected cells at the initiation of the culture, before removal of unbound virus. The decrease in TNF-α detected after ⩾2 d of culture did not result from masking by shed soluble TNF receptors, nor from a selective upregulation of membrane TNF-α (data not shown). Addition of rTNF-α (10 and 100 U/ml) did not restore HIV-1 expression, as detected by p24 Ag (data not shown). Thus, the decrease in TNF-α was not responsible for the inhibitory effect of LPS on HIV-1 replication. Loss of sensitivity of HIV-1-infected MDM to TNF-α–mediated upregulation of HIV expression, rather than decreased levels of TNF-α, may be involved in LPS-induced inhibition of HIV infection. The mechanisms involved in TNF-α suppression are currently under investigation.


C-C chemokines released by lipopolysaccharide (LPS)-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells.

Verani A, Scarlatti G, Comar M, Tresoldi E, Polo S, Giacca M, Lusso P, Siccardi AG, Vercelli D - J. Exp. Med. (1997)

Effects of LPS stimulation and/or HIV-1 infection  on IL-6 and TNF-α secretion by  MDM. Uninfected or HIV-1Ba-Linfected MDM were cultured in  the presence or absence of LPS  (1 μg/ml). LPS was added to the  cultures every 3 d. IL-6 and  TNF-α concentrations in the supernatants were measured by  ELISA. The data are representative of four separate experiments.
© Copyright Policy
Related In: Results  -  Collection

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Figure 4: Effects of LPS stimulation and/or HIV-1 infection on IL-6 and TNF-α secretion by MDM. Uninfected or HIV-1Ba-Linfected MDM were cultured in the presence or absence of LPS (1 μg/ml). LPS was added to the cultures every 3 d. IL-6 and TNF-α concentrations in the supernatants were measured by ELISA. The data are representative of four separate experiments.
Mentions: A number of cytokines have been described that regulate HIV-1 expression. In particular, TNF-α and IL-6 enhance HIV-1 replication in acutely infected MDM. The HIV-1–inducing effect of TNF-α is mainly, if not exclusively, mediated by the activation of NF-κB, which activates LTR-driven viral RNA transcription (26). IL-6 induces expression of viral proteins and RT activity to levels comparable to those induced by TNF-α, but unlike TNF-α, does not increase significantly the levels of steady-state viral mRNA (27). Therefore, we investigated whether a decrease in the production of these HIV-1 stimulatory cytokines may underlie LPS-dependent inhibition of HIV-1 replication in MDM. Fig. 4 shows that LPS-induced IL-6 secretion was vigorous and comparable in both uninfected and HIV-1–infected MDM cultures. In contrast, infected cultures treated with LPS showed an impairment in their ability to sustain TNF-α secretion over time. However, stimulation with LPS released high and comparable levels of TNF-α (>40 ng/ml) from uninfected and infected cells at the initiation of the culture, before removal of unbound virus. The decrease in TNF-α detected after ⩾2 d of culture did not result from masking by shed soluble TNF receptors, nor from a selective upregulation of membrane TNF-α (data not shown). Addition of rTNF-α (10 and 100 U/ml) did not restore HIV-1 expression, as detected by p24 Ag (data not shown). Thus, the decrease in TNF-α was not responsible for the inhibitory effect of LPS on HIV-1 replication. Loss of sensitivity of HIV-1-infected MDM to TNF-α–mediated upregulation of HIV expression, rather than decreased levels of TNF-α, may be involved in LPS-induced inhibition of HIV infection. The mechanisms involved in TNF-α suppression are currently under investigation.

Bottom Line: A combination of recombinant C-C chemokines blocked HIV-1 infection as effectively as LPS.Here, we report an inhibitory effect of C-C chemokines on HIV replication in primary macrophages.Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological and Technological Research, San Raffaele Scientific Institute, Milan, Italy.

ABSTRACT
Human immunodeficiency virus-1 (HIV-1) expression in monocyte-derived macrophages (MDM) infected in vitro is known to be inhibited by lipopolysaccharide (LPS). However, the mechanisms are incompletely understood. We show here that HIV-1 suppression is mediated by soluble factors released by MDM stimulated with physiologically significant concentrations of LPS. LPS-conditioned supernatants from MDM inhibited HIV-1 replication in both MDM and T cells. Depletion of C-C chemokines (RANTES, MIP-1 alpha, and MIP-1 beta) neutralized the ability of LPS-conditioned supernatants to inhibit HIV-1 replication in MDM. A combination of recombinant C-C chemokines blocked HIV-1 infection as effectively as LPS. Here, we report an inhibitory effect of C-C chemokines on HIV replication in primary macrophages. Our results raise the possibility that monocytes may play a dual role in HIV infection: while representing a reservoir for the virus, they may contribute to the containment of the infection by releasing factors that suppress HIV replication not only in monocytes but also in T lymphocytes.

Show MeSH
Related in: MedlinePlus