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Originally published online as doi:10.1189/jlb.0305167 on July 6, 2005

Published online before print July 6, 2005
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(Journal of Leukocyte Biology. 2005;78:772-776.)
© 2005 by Society for Leukocyte Biology

Morphine inhibits CD8+ T cell-mediated, noncytolytic, anti-HIV activity in latently infected immune cells

Xu Wang*, Ning Tan{dagger}, Steven D. Douglas*, Ting Zhang*, Yan-Jian Wang* and Wen-Zhe Ho*,1

* Division of Allergy and Immunology, Joseph Stokes, Jr., Research Institute at The Children’s Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine; and
{dagger} Department of Medicine, The People’s Hospital of Guangdong Province, Guangzhou, People’s Republic of China

1Correspondence: Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, 34th Street & Civic Center Boulevard, Philadelphia, PA 19104. E-mail: ho{at}email.chop.edu


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ABSTRACT
 
Opiates have profound effects on the function of human immune cells and are a possible cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) disease. We investigated the impact of morphine on CD8+ T cell-mediated, noncytotoxic, anti-HIV activity in latently infected human immune cells. Morphine inhibited the noncytotoxic, anti-HIV activity of CD8+ T cells in HIV latently infected cells (U1 and J1.1). Naltrexone abrogated the morphine-mediated, inhibitory effect on the noncytotoxic, anti-HIV activity of CD8+ T cells. Interferon-{gamma} (IFN-{gamma}), a potent antiviral cytokine produced by CD8+ T cells, was partially responsible for CD8+ T cell-mediated, noncytotoxic, anti-HIV activity. The anti-HIV activity of IFN-{gamma} was also compromised by morphine treatment. Further, morphine attenuated CD8+ T cell-mediated suppression of the HIV long-terminal repeat promoter activation. Morphine also inhibited CD8+ T cell-induced expression of the signal transducer and activator of transcription-1, an important transcriptional factor in the IFN signaling pathway. These data provide additional evidence to support the notion that opioids play a role in impairing the anti-HIV function of the immune system.

Key Words: IFN-{gamma} • PBMC • U1 cells • J1.1 cells


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INTRODUCTION
 
Injection drug use (IDU) is a significant risk for acquiring human immunodeficiency virus (HIV) infection [1 ] and contributes to the spread of the virus [2 ]. Approximately 30% of patients with HIV infection and AIDS have a history of IDU, which frequently involves opiate abuse. Opioids have profound effects on the functions of human immune cells [3 4 5 ] and are implicated as a cofactor in the immunopathogenesis of HIV disease [1 , 2 , 5 , 6 ]. In the present study, we examined the impact of opioids on the anti-HIV function of CD8+ T cells, which have important direct and indirect antiviral effects on the control of HIV replication. CD8+ T cells suppress HIV replication in latently infected, immune cells [7 ]. Although the direct killing of virus-infected cells by antigen-specific cytotoxic T lymphocytes is the dominant mechanism of virus suppression, a noncytotoxic, soluble factor(s) released by the CD8+ T cell also plays a critical role in inhibiting HIV replication [8 9 10 11 ]. As opioid abuse has the ability to impair the host defense mechanisms against HIV infection, we speculated that morphine, the active metabolite of heroin, compromises CD8+ T cell-mediated suppression of HIV replication in latently infected human immune cells.


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MATERIALS AND METHODS
 
Cell lines
The promonocytic (U1) and T (J1.1 and 1G5) cell lines were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institutes of Health (NIH; Bethesda, MD). U1 is a cloned cell line derived from U937 cells surviving acute HIV infection [12 ]. J1.1 is a subclone of the Jurkat E6.1 (J/W) T cell line, which is latently infected with HIV [13 ]. 1G5 is a Juckat T cell line that harbors two copies of a stable transfected plasmid, containing the luciferase reporter gene downstream of the HIV long-terminal repeat (LTR) [14 ]. J1.1, U1, and 1G5 cells were cultured as described [12 13 14 ].

Reagents
Morphine sulfate was obtained from Elkins-Sinn, Inc. (Cherry Hill, NJ). Tumor necrosis factor-{alpha} (TNF-{alpha}), mouse monoclonal antibody against CD3 receptor, mouse monoclonal anti-human interferon-{gamma} (IFN-{gamma}) antibody, and recombinant IFN-{gamma} were purchased from R&D Systems (Minneapolis, MN). Naltrexone and rabbit polyclonal antibody against actin were obtained from Sigma Chemical Co. (St. Louis, MO). Rabbit polyclonal antibody against signal transducer and activator of transcription-1 (STAT-1) was obtained from Santa Cruz Biotechnology (CA). Horseradish peroxidase-conjugated goat anti-rabbit immunoglobulin G was purchased from Jackson ImmunoResearch Labs (West Grove, PA).

Preparation of CD8+ T cell culture supernatants (SN)
Peripheral blood samples were obtained from five asymptomatic, HIV-infected, adult subjects with CD4+ T cell counts ranging from 400 to 1200/mm3. The Institutional Review Board of the Children{0305-167.772.cjs1227}s Hospital of Philadelphia (PA) approved this investigation. Informed consent was obtained from the subjects. Peripheral blood mononuclear cells (PBMC) were processed as described previously [15 ] using lymphocyte separation medium (Amersham Pharmacia Biotech, Uppsala, Sweden). PBMC were subjected to CD8+ T lymphocyte purification using magnetic cell sorter CD8 microbeads, according to the manufacturer’s instructions (Miltenyi Biotec, Auburn, CA). CD8+ T cell culture SN were prepared as follows: Purified CD8+ T lymphocytes were cultivated in a 48-well plate precoated with the anti-CD3 antibody (3 µg/ml) in RPMI-1640 media containing interleukin-2 (50 U/ml) for 72 h. SN were collected from the cell cultures and stored at –70°C.

Treatment with morphine, naltrexone, and/or CD8+ SN
U1 and J1.1 cells plated in triplicate (2x104 cells/well) in a 96-well culture plate were incubated with or without morphine (10–10–10–6M) for 2 h before the addition of CD8+ SN (25%, v/v) for 2 h. For the experiments using naltrexone, the cells were treated with naltrexone (10–8M), first for 30 min prior to the addition of morphine and/or CD8+ SN as stated above. Naltrexone was not washed out before the addition of morphine. The latent HIV in these cells was activated by treatment with TNF-{alpha} (2 ng/ml). HIV reverse transcriptase (RT) activity was measured in culture SN collected 48 h post-TNF-{alpha} treatment. 1G5 cells in 48-well culture plates (2x105 cells/well) were treated for 2 h with or without morphine (10–8 M) before the addition of CD8+ SN (25% v/v) for 16 h. The lysed cells were subjected to luciferase assay 8 h after TNF-{alpha} (10 ng/ml) stimulation. CD8+ T cell-depleted PBMC were stimulated with phytohemagglutinin (PHA) for 72 h and then seeded into 48-well plates (106 cells/well), precoated anti-CD3 antibody (1 µg/ml). The cells were incubated at 37°C with or without morphine for 2 h before the addition of CD8+ SN (25%, v/v). HIV RT activity was measured in culture SN collected at Day 9 post-treatment.

HIV RT assay and luciferase assay
HIV RT activity was determined based on the technique of Willey et al. [16 ] with modification [17 ]. The luciferase activity was determined using a luciferase assay kit (Promega Biotec, Madsion, WI), according to the manufacturer’s instruction.

Western blot analysis
U1 and J1.1 cells were washed with phosphate-buffered saline and lysed by lysis buffer (Promega Biotec). The cell lysates were collected, and protein concentration was determined using the Bio-Rad dendritic cell protein assay kit (Bio-Rad Laboratories, Hercules, CA). Approximately, 10 ug protein was resuspended in NuPAGE® lithium dodecyl sulfate sample buffer (Invitrogen, Carlsbad, CA) and heated for 3 min at 100°C, and the equal amounts of protein for each sample were analyzed by Western blot as described previously [18 ].

Statistical analysis
All variables were tested in triplicate, and all experiments were repeated at least three times. Triplicate wells had variability of less than 15%. One-way ANOVA was used to test for difference in means, and the post-hoc t-test was used for comparisons. Differences were considered significant if P < 0.05.


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RESULTS
 
To determine whether morphine has the ability to inhibit the anti-HIV activity of CD8+ SN, PBMC from HIV-infected subjects, U1 and J1.1 cells, were treated with CD8+ SN in the presence or absence of morphine. The anti-HIV activity of CD8+SN was impaired in morphine-treated U1 and J1.1 cells and PBMC (Fig. 1 ). As U1 and J1.1 cells express µ-opioid receptors (data not shown), we speculated that the morphine action on the anti-HIV activity of CD8+ SN is mediated through the µ-opioid receptor. Thus, we determined whether naltrexone, a pan-opioid receptor antagonist, has the ability to block the morphine action. Naltrexone abrogated the inhibitory effect of morphine on the anti-HIV activity of CD8+ SN in U1, J1.1, and PBMC (Fig. 1B and 1C) , and the addition of naltrexone alone to the cell cultures had no impact on HIV replication (Fig. 1B and 1C) .



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  		Figure 1. Effect of morphine on the anti-HIV activity of CD8+ SN in U1 and J1.1 cells and latently infected PBMC. (A) A dose-dependent effect of morphine on CD8+ SN-mediated, anti-HIV activity. U1 and J1 cells were incubated with or without morphine at indicated concentrations for 2 h before the treatment with CD8+ SN (25%, v/v) for an additional 2 h. TNF-{alpha} (2 ng/ml) was then added to the cultures to induce HIV replication. SN were collected for measurement of RT activity 48 h post-TNF-{alpha} induction. The data are expressed as HIV RT activity relative (percent) to untreated control, which is defined as 100%. (B) Effect of morphine and/or naltrexone on CD8+ SN-mediated, anti-HIV activity in U1 and J1.1 cells, which were incubated with or without naltrexone (10–8M) for 30 min and then morphine (10–8M) for 2 h before the addition of CD8+ SN (25%, v/v) to the cultures. TNF-{alpha} (2 ng/ml) was added to the cultures to induce HIV replication 2 h after treatment with CD8+ SN, and SN were collected for measurement of HIV RT activity 48 h after TNF-{alpha} stimulation. The data are expressed as HIV RT activity relative (percent) to untreated control, which is defined as 100%. (C) Effect of morphine and/or naltrexone on CD8+ SN-mediated anti-HIV activity in PBMC from HIV-infected patients. CD8+ T cell-depleted PBMC were stimulated with 1% PHA (v/v) for 72 h. Cells then were incubated with or without CD8+ SN, morphine (10–8 M), and/or naltrexone (10–8 M) as indicated. Cultures were refed with fresh medium containing the indicated reagent every 3 days. Day 9 culture SN were collected for measurement of RT activity. The data are expressed as HIV RT activity relative (percent) to untreated control, which is defined as 100%. The results (A and B) shown are the mean ± SD of HIV RT activity in triplicate cultures, representative of five independent experiments. The result (C) shown is the mean ± SD of HIV RT activity in triplicate cultures, representative of three independent experiments using PBMC from three different HIV-infected subjects. +, In the presence; –, in the absence.

As CD8+ T cells are the primary source of IFN-{gamma}, a potent, antiviral cytokine [19 ], we determined whether IFN-{gamma} contributes, at least in part, to the anti-HIV activity of CD8+ SN. Antibody to IFN-{gamma} partially reversed the anti-HIV activity of CD8+ SN (Fig. 2A ). To further confirm that IFN-{gamma} plays a role in CD8+ SN-mediated inhibition of HIV replication, we used exogenous IFN-{gamma} to treat U1 and J1.1 cells. IFN-{gamma} significantly inhibited (up to 80%) TNF-{alpha}-induced HIV replication (Fig. 2A) . The activation of HIV promoter LTR is responsible for the virus replication in the latently infected cells. We speculated that morphine-mediated inhibition of the anti-HIV activity of CD8+ T cells is associated with its ability to activate HIV promoter LTR. We used 1G5 cells [14 ], which contain a stably integrated HIV LTR linked to a luciferase gene, to examine this speculation. Although morphine had no direct effect on TNF-{alpha}-induced HIV LTR activation (Fig. 2B) , morphine treatment inhibited CD8+ SN-mediated suppression of HIV LTR activation (Fig. 2B) . Morphine also reduced exogenous IFN-{gamma}-mediated suppression of HIV LTR activation (Fig. 2B) . The antibody to IFN-{gamma} partially neutralized the inhibitory effect of CD8+ SN-mediated suppression of HIV LTR activation (Fig. 2B) .



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  		Figure 2. Effect of morphine on CD8+ SN- or IFN-{gamma}-mediated inhibition of anti-HIV activity and HIV LTR activation. (A) Effect of morphine on CD8+ SN- or exogenous IFN-{gamma}-mediated inhibition of anti-HIV activity in U1 and J1.1 cells, which were incubated with or without morphine (10–8M) for 2 h prior to the addition of CD8+ SN (25%, v/v) or IFN-{gamma} (500 U/ml). TNF-{alpha} (2 ng/ml) was then added to the cultures to induce HIV replication. For an anti-IFN-{gamma} antibody neutralization experiment, CD8+ SN, preincubated with or without anti-IFN-{gamma} antibody (1:100) for 30 min, was added to U1 or J1.1 cells. SN were collected for measurement of HIV RT activity 48 h after the addition of TNF-{alpha}. The data are expressed as HIV RT activity relative (percent) to untreated control, which is defined as 0%. The results shown are the mean ± SD of HIV RT activity in triplicate cultures, representative of five independent experiments. (B) Effect of morphine on CD8+ SN- or IFN-{gamma}-mediated inhibition of HIV LTR activation. 1G5 cells were incubated with or without morphine for 2 h prior to the addition of CD8+ SN or IFN-{gamma}. LTR-directed luciferase expression was induced by treatment of 1G5 cells with TNF-{alpha} (10 ng/ml) 16 h after treatment with CD8+ SN or IFN-{gamma}. Cell lysates were collected for measurement of luciferase activity 8 h after TNF-{alpha} treatment. For an anti-IFN-{gamma} antibody neutralization experiment, CD8+ SN, preincubated with or without anti-IFN-{gamma} antibody (1:100) for 30 min, was added to 1G5 cell cultures. LTR-directed luciferase expression was induced by treatment of 1G5 cells with TNF-{alpha} 16 h after treatment with the neutralized CD8+ SN. Cell lysates were collected for measurement of luciferase activity 8 h after TNF-{alpha} treatment. The data are expressed as luciferase activity normalized with total protein content relative (percent) to untreated control, which is defined as 100%. The results shown are the mean ± SD of triplicate cultures, representative of five independent experiments using CD8+ SN from five different donors. +, In the presence; –, in the absence; Ab, antibody.

As soluble factor(s) secreted from CD8+ T lymphocytes inhibit HIV replication through activation of STAT-1, a critical transcriptional factor in IFN signaling pathways [20 ], we investigated whether morphine has the ability to reduced CD8+ SN-mediated activation of STAT-1. CD8+ SN activated STAT-1 expression in U1 and J1.1 cells (Fig. 3 ). This CD8+ SN-mediated activation of STAT-1, however, was inhibited by morphine (Fig. 3) .



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  		Figure 3. Effect of morphine on CD8+ SN-activated STAT-1 protein expression in U1 (A) and J1.1 (B) cells, which were incubated with or without morphine (10–8 M) for 2 h before the treatment with CD8+ SN (25%, v/v) for an additional 2 h. TNF-{alpha} (2 ng/ml) was then added to the cell cultures. Cellular proteins were extracted from the cells 48 h post-TNF-{alpha} treatment and then subjected to immunobloting assay using the antibodies to STAT-1 and actin. The arrows indicate the position of STAT-1 (91 kD) or actin (42 kD). The insets below the panels show the signal intensities [density scan unit (DSU)] of protein bands of the representative blot, expressed as densitometry scanning units. The results shown are representative of three independent experiments. CD8 SN, CD8+ SN.


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DISCUSSION
 
Opioids have a cofactor role in the immunopathogenesis of HIV disease, as demonstrated by in vitro [15 , 21 22 23 ] and in vivo [2 , 24 , 25 ] studies. In the present study, we focused on the impact of morphine on the noncytotoxic, anti-HIV function of CD8+ T cells, as CD8+ T cells have a critical role in suppressing HIV replication in latently infected, immune cells [7 ]. The noncytotoxic, anti-HIV activity is demonstrated using activated CD8+ T cell culture SN [26 ]. We demonstrated that morphine reduced the anti-HIV activity of CD8+ SN in the latently infected immune cells. This action of morphine is specific, as naltrexone abrogated the morphine-mediated, inhibitory effect on the noncytotoxic, anti-HIV activity of CD8+SN.

IFN-{gamma} has pleiotropic effects on HIV replication in macrophage and T cell lines [27 28 29 ]. The loss of CD4+ T cells is associated with a deficiency of IFN-{gamma} production by CD8+ T cells in HIV-infected subjects with advanced disease [30 ]. These findings prompted us to investigate whether morphine has the ability to suppress the anti-HIV activity of CD8 T cell-produced IFN-{gamma} in latently infected immune cells. We showed that the antibody to IFN-{gamma} partially neutralized CD8+ SN anti-HIV ability (Fig. 2) . We also observed that the antibody to IFN-{gamma} partially reversed the inhibitory effect of CD8+ SN on HIV LTR activation (Fig. 2) . This finding is in agreement with the study by Chang et al. [20 ] showing that the antibodies to IFN-ß and IFN-{gamma}, but not the antibody to IFN-{alpha}, modestly reversed the CD8 T cell-mediated inhibition of HIV LTR activation in Hela cells. The role of CD8+ T cell-released IFN-{gamma} in suppressing HIV and its promoter activation was further supported by our data, showing that exogenous IFN-{gamma} inhibited TNF-mediated HIV and HIV LTR activation in U1, J1.1, and 1G5 cells. Collectively, these observations support the studies showing that CD8+ T cell-released, soluble factors inhibit HIV RNA transcription, particularly at the step of HIV LTR-driven gene expression [31 32 33 ]. The antagonizing effect of morphine on CD8+ SN-mediated inhibition of HIV and LTR is not a result of its direct effect on the activation of the HIV LTR promoter, as morphine alone had little impact on the promoter (Fig. 2) . The lack of a direct effect of morphine on HIV and its promoter LTR in our cell system provided us with the opportunity to examine whether morphine has a negative impact on CD8+ T cell-mediated, noncytotoxic, anti-HIV activity on HIV replication. Our findings, however, are contradictory to the report showing that morphine directly transactivated the HIV LTR promoter in human neuroblastoma cells [34 ]. The discrepancies between the observations of Squinto et al [34 ] and our study may be attributable to different target cells used in the studies. Morphine also inhibits CD8+ T cell-induced expression of the STAT-1, which constitutes a mechanism responsible for morphine’s inhibitory action on the noncytotoxic, anti-HIV activity of CD8+ T cells (Fig. 3) .

Taken together, our study provides compelling evidence that morphine has the ability to impair the noncytotoxic, anti-HIV activity of CD8+ T cells. These findings, in conjunction with our earlier reports [15 , 23 ] showing that morphine enhances HIV infection of human immune cells, support the notion that opiates indeed have a cofactor role in promoting HIV disease. It is most important that understanding the impact of opiates on the host immune system against HIV infection is of great interest for developing future strategies of controlling the virus and reconstituting the immune system in HIV-infected opiate abusers.


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ACKNOWLEDGEMENTS
 
This work was supported by NIH Grants DA 12815, DA16022 (to W-Z. H.), and MH 49981, AA13547 (to S. D. D). X. W. and N. T. contributed equally to this study.

Received March 28, 2005; revised May 26, 2005; accepted May 27, 2005.


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