Impaired induction of IL-15 in response to herpes simplex virus type 1 infection in peripheral blood mononuclear cells of HIV-infected patients
Ahmad, Aliacd; Ahmad, Rasheedac; Toma, Emilbc; Morisset, Richardbc; Menezes, Joséac
aSte-Justine Hospital, bHôtel-Dieu Hospital and cDepartment of Microbiology and Immunology, University of Montreal, 3175 Côte Ste-Catherine, Montreal, Quebec, Canada H3T 1C5. dCorresponding author
Sponsorship: This work was supported by a research grant from the Medical Research Council of Canada.
Received: 23 December 1999; accepted: 7 January 2000.
IL-15 is a relatively novel cytokine that shares many biological activities with IL-2 [1,2]. The two cytokines have similar tertiary structure, and use β and γ chains of the IL-2 receptor complex for binding and signal transduction. However, unlike IL-2, which is produced by activated T cells, IL-15 is produced from a wide variety of cells and tissues in the body. Furthermore, it has a unique receptor component (α-chain), which also has much wider cell and tissue distribution compared with its corresponding α-chain for IL-2. In blood, monocyte-macrophages represent the main cell type that produces IL-15. This cytokine markedly increases the cytolytic potential of natural killer (NK) and cytotoxic T cells, and induces proliferation and antibody secretion in antigen-activated B cells. In vivo, it has been shown to be essential for the development and maturation of NK cells [1,2]. IL-15 is induced in the host as a defence to viral and non-viral intracellular pathogens. Human herpesviruses have been demonstrated to enhance NK activity of human peripheral blood mononuclear cells (PBMC) via IL-15 induction [3,4]. The enhanced NK activity is well known to play a role in the control of these infections .
AIDS, which results from infection with HIV-1, is accompanied by decreased resistance of the infected individuals to opportunistic infections including herpesviruses. Decreased NK activities and defective antimicrobicidal potential of the macrophages have been well documented in HIV-infected individuals [6,7]. The decreased NK activities occur even in the early stages of the infection . The reasons for this decrease are not fully understood. Reduced production of the NK activity-enhancing cytokines, e.g. IL-2 and IL-12 has been reported in HIV-infected individuals [8,9]. However, few studies have been conducted to investigate the role of IL-15 in these infections.
In order to investigate the capacity of HIV-infected individuals to induce IL-15 in response to a herpesviral infection, we obtained PBMC from 12 of these individuals as well as from age-matched HIV-seronegative control subjects after their informed consent. The HIV-infected individuals represented all stages of the infection, were not on highly active antiretroviral therapy and had one or more AIDS-defining conditions. Four million PBMC from each donor were infected in vitro with 50 μl of a herpes simplex virus type 1 (HSV-1) viral preparation that was produced in VERO cells and contained 1 × 108 plaque-forming units per millilitre. After infection at 37°C for 1 h, the cells were washed and incubated in one millilitre of the culture medium (RPMI-1640 with 10% heat-inactivated fetal bovine serum and antibodies). Twenty four hours later, the culture supernatants were collected and passed through 0.2 μ filters. These supernatants were concentrated 10-fold for proteins by using filters (Microconcentrator 10; Amicon, Beverly, MA, USA), and their IL-15 content was determined using a commercial enzyme-linked immunosorbent assay kit (Immunocorp, Montreal, Canada). The results obtained from these determinations are shown in Fig. 1. On average, the PBMC from HIV-infected/AIDS patients secreted less IL-15 than their HIV-seronegative counterparts in response to HSV-1 infection. IL-15 was not detectable in similarly prepared supernatants from mock-infected PBMC (except for three HIV-infected donors); the average optical density values of enzyme-linked immunosorbent assay between the two groups of donors did not differ significantly (P > 0.05; data not shown).
These results suggest that there is compromised induction of the IL-15 gene in the PBMC of HIV-infected individuals in response to HSV-1 infection. This virus is known to enhance the NK activity of human PBMC in vitro; however, this enhancement is much less in HIV-infected individuals compared with the HIV-seronegative controls . Our results suggest that impaired IL-15 production in the PBMC of the infected individuals may be one of the reasons for their less than normal increase in NK activity in response to HSV-1 infection. Our results are corroborated by those of Chehimi et al. , who also reported decreased production of IL-15 in response to a bacterial infection in the PBMC of HIV-infected individuals compared with HIV-seronegative control subjects. In addition to IL-2 and IL-12, HIV-infected individuals thus also seem to produce less IL-15 upon stimulation. Although IL-15 enhances immune function and the expansion of virus-specific cytotoxic T lymphocytes in HIV infections [11,12], it has also been incriminated in the polyclonal B cell activation and T cell-induced alveolitis in AIDS patients [13,14]. Clearly, further studies are needed to investigate how this important cytokine is modulated in the course of HIV infections.
1. Tagaya Y, Bamford RN, deFilipis AP, Waldmann TA. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 1996, 4: 329–336.
2. Waldmann TA, Tagaya Y. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in the NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol 1999, 17: 19–49.
3. Flamand L, Stefanescu I, Menezes J. Human herpes virus-6 enhances natural killer cytotoxicity via IL-15. J Clin Invest 1996, 97: 1373–1381.
4. Atedzoé BN, Ahmad A, Menezes J. Enhancement of natural killer cell cytotoxicity by the human herpesvirus-7 via IL-15 induction. J Immunol 1997, 159: 4966–4972.
5. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 1999, 17: 189–220.
6. Ullum H, Gotzsche PC, Victor J, Dickmeiss E, Skinhoj P, Pederson BK. Defective natural immunity: an early manifestation of human immunodeficiency virus infection. J Exp Med 1995, 182: 789–799.
7. Ahmad A, Menezes J. Antibody-dependent cellular cytotoxicity in HIV-infections. FASEB J 1996, 10: 258–266.
8. Chemimi J, Starr SE, Frank I. et al
. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med 1994, 179: 1361–1366.
9. Fan J, Bass HZ, Fahey JL. Elevated INF-γ and decreased IL-2 gene expression are associated with HIV-infection. J Immunol 1993, 151: 5031–5040.
10. Hersh EM, Gutterman JU, Spector S. et al
. Impaired in vitro interferon, blastogenic and natural killer cell responses to viral stimulation in acquired immune deficiency syndrome. Cancer Res 1985, 45: 406–410.
11. Chehimi J, Marshall JD, Salvucci O. et al
. IL-15 enhances immune functions during HIV infection. J Immunol 1997, 158: 5978–5987.
12. Kanai T, Thomas EK, Tasutomi Y, Letvin NL. IL-15 stimulates the expansion of AIDS virus-specific CTL. J Immunol 1996, 157: 3681–3687.
13. Kacani L, Stoiber H, Dierich MP. Role of IL-15 in HIV-1-associated hypergammaglobulinemia. Clin Exp Immunol 1997, 108: 14-18.
14. Agnosti C, Trentin L, Sancetta R. et al
. Interleukin-15 triggers activation and growth of the CD8 T-cell pool in extravascular tissues of patients with acquired immunodeficiency syndrome. Blood 1997, 90: 1115–1123.
© 2000 Lippincott Williams & Wilkins, Inc.