NK cells improve control of friend virus infection in mice persistently infected with murine cytomegalovirus
© Francois et al.; licensee BioMed Central Ltd. 2013
Received: 2 January 2013
Accepted: 19 May 2013
Published: 5 June 2013
Co-infection of HIV patients with cytomegalovirus (CMV) is associated with enhanced AIDS progression and CMV end-organ diseases. On the other hand, persistent CMV infection has recently been shown to decrease tumor relapse and protect against lethal bacterial infection. The influence of persistent CMV on the outcome of an acute retroviral superinfection is still unknown.
Here we show that a persistent murine CMV (mCMV) infection surprisingly confers higher resistance to a primary Friend retrovirus infection (FV) of mice. Decreased FV titers and augmented FV-specific CD8 T-cell responses were found in mCMV infected mice during primary FV superinfection. NK cells produced higher amounts of IFNgamma after FV infection of persistently mCMV infected mice suggesting that these cells were involved in the ‘protective’ effect. Depletion of NK1.1+ cells or neutralization of IFNgamma during FV superinfection abrogated the mCMV-mediated effect.
Our data demonstrate for the first time that a persistent CMV infection induces long-lasting NK cell responses that can enhance immunity to primary retroviral infections. To our knowledge, studies investigating primary HIV infection have not analyzed the role of the CMV seropositivity in these patients. Our observations suggest that NK cells in CMV seropositive individuals might contribute to the control of primary HIV infection.
Approximately 34 million people worldwide are currently infected with HIV and approximately 2.5 million new infections occur per year. Co-infections of HIV infected individuals with unrelated viruses like human cytomegalovirus (CMV) are associated with AIDS progression and CMV end-organ diseases (CMV-EOD) . In a natural course of CMV/HIV co-infection, CMV-EOD occurs predominantly in HIV patients with low CD4 T cell counts [2–5]. CMV is a very common viral infection and approximately 40-80% of the human population worldwide is CMV seropositive. In an immunocompetent individual a primary CMV infection is mostly asymptomatic and during latency CMV is well controlled by the immune system. CMV seropositivity in HIV infected patients or transplant recipients, as well as presence of CMV-infected cells in transplant organs, has been associated with poor prognosis, i.e. AIDS progression and transplant rejection [6–8]. However, these studies are mainly describing patients in the late phase of HIV infection when immunodeficiency starts to develop, but very little is known about acute HIV infection of CMV seropositive individuals. Recent publications have shown that persistent CMV infection can be beneficial for the host [9, 10]; the group of Elmaagacli et al. showed that an early ‘controlled’ CMV replication reduced leukemia relapse in acute myeloid leukemia patients who underwent allogeneic stem cell transplantation . Along with this finding, Barton et al. described that during persistent infection with murine cytomegalovirus (mCMV) or murine gammaherpesvirus 68 (γHV68) mice are protected against lethal bacterial infections by prolonged macrophage activation and IFNγ secretion . To our knowledge nothing is known about the influence of a persistent CMV infection on a primary HIV infection. Based on the findings that CMV can be helpful for the host to control tumor relapse and bacterial superinfections it would be important to investigate the influence of a persistent CMV infection on the outcome of a primary retroviral infection.
Therefore, we established a mouse model to mimic a retroviral superinfection in a persistently CMV infected host. We used the well-established Friend virus (FV) as a model for retroviral infection and mCMV which has been used as a model to study CMV immunobiology and pathogenesis [11, 12]. Similar to CMV, infectious mCMV can be isolated from infected mice over several months indicating a persistent infection. Additionally, strong NK cell and T cell responses are detectable in these mice . Recently, it has been shown that NK cells are modulated during mCMV infection and memory-like NK cell population developed . During acute mCMV infection the mCMV-specific protein m157 binds to the Ly49H receptor of NK cells and induces a proliferation of this subpopulation [15, 16]. Friend virus (FV) is a retroviral complex comprised of two components, the replication-competent non-pathogenic helper virus called Friend murine leukemia virus and the replication-defective pathogenic spleen focus-forming virus . In adult C57BL/6 mice a primary FV infection induces a transient splenomegaly . During the acute phase of infection, virus-specific CD8 T cells are important for controlling viral replication, but NK and CD4 T cells are not significantly contributing to keep the infection in check [19, 20].
Here we show for the first time that a persistent mCMV infection significantly reduced viral load during acute retroviral infection and demonstrate that mCMV induced NK cell and IFNγ responses augmented anti-viral T cell responses in vivo.
Viral loads during primary FV infection were reduced in mice persistently infected with mCMV
During the acute phase of FV infection, there is an increase in the number of erythrocyte precursor cells (Ter119+), which represent the most important target cells of FV . We therefore investigated if persistent mCMV infection interfered with the FV-induced expansion of Ter119+ target cells. However, we found no difference in number of Ter119+ cells in FV infected naïve and persistently mCMV infected mice (Figure 1b). Moreover, the numbers of CD19+ B cells, which also get infected by FV , were not different (Figure 1c). These data suggest that the reduced FV titers found in persistently mCMV infected mice were not a result of an impaired expansion of FV target cells.
mCMV persistence augmented the FV-specific CD8 T cell response
NK cells and IFNγ in persistently mCMV infected mice contributed to enhanced FV-specific T cell responses
Our data demonstrate for the first time that a persistent mCMV infection can be beneficial during a primary retroviral infection by augmenting anti-retroviral CD8 T cell immunity that resulted in decreasing FV loads in superinfected mice.
Previous reports demonstrated that mice persistently infected with γHV68 or mCMV were protected against superinfections with lethal doses of either Listeria monocytogenes or Yersinia pestis . These effects were mediated by systemic activation of macrophages and prolonged IFNγ production in γHV68-infected mice. We were unable to detect prolonged macrophage activation (F4/80+, MHC classII+) in the spleen or sustained IFNγ secretion in the sera of mice persistently infected with mCMV (data not shown). A possible explanation is that a persistent γHV68 infection triggers a higher expression of IFNγ than the persistent mCMV infection. However, we were able to detect significant differences in the expression of IFNγ in NK cells between naïve and persistently mCMV infected mice early after FV infection. Moreover, blocking IFNγ during FV superinfection of mCMV infected mice resulted in enhanced FV titers and reduced FV-specific CD8 T cell responses, indicating that IFNγ was important in the mCMV-mediated effects. Depletion of NK1.1+ cells resulted in the same effect as IFNγ blockage. Our NK1.1+ depletion protocol depleted NK cells as well as NKT cells, but no effect on γδ+ and αβ+ CD8 T cells was found (data not shown). Therefore the loss of NKT cells might also contribute to the effect described after NK1.1+ depletion. However, our data suggest that persistent mCMV infection mainly modulated the NK cell response that resulted in significantly enhanced numbers of IFNγ+ NK cells at day 4.5 post FV infection, which might positively influenced the FV-specific CD8 T cell response.
The influence of cytokines on CD8 T cell priming differs depending on the time-point and amount of cytokine secretion during T cell priming. For example IL-2 or type I IFN can enhance or inhibit T cell responses depending on the time-point after virus infection [25–28]. Virus-specific CD8 T cell numbers are markedly reduced in IFNγ−/− and IFNγR−/− mice after LCMV infection  suggesting that IFNγ can be necessary for an effective primary anti-viral CD8 T cell response. However, it has also been shown that IFNγ can have a negative impact on virus-specific CD8 T cells . In this study, a co-infection of FV together with the lactate dehydrogenase-elevating virus (LDV) resulted in a reduced FV-specific CD8 T cell response mediated by the strong LDV-dependent IFNγ production. Duley et al. reported that high concentrations of serum IFNγ were detected only immediately after infection (1 day post infection), which inhibited CD8 T cell priming. In contrast, high IFNγ serum concentrations were not found in our study, but intracellular IFNγ expression by splenic NK cells was detected starting at day 4.5 post FV infection of persistently mCMV infected mice. These results suggest that the timing and the strength of the IFNγ response may be critical for its effect on CD8 T cell priming in FV infection. Our data is supported by a previous study showing that secretion of IFNγ by activated NK cells can facilitate the priming of tumor-specific CD8 T cells .
Recent studies demonstrated that superinfections of β-herpesvirus infected mice with West Nile virus (WNV) or LCMV did not influence the outcome of the second infection [10, 32, 33]. There were no differences in the survival of naïve and γHV68-infected mice after WNV superinfection . Our current results may be different from these studies for a number of possible reasons: 1) NK cell activation likely differs during mCMV and γHV68 infection 2) these activities of NK cells may be modulated by the virus dose or strain and 3) control of WNV might be mediated differently compared to FV since WNV replicates in neurons  whereas FV replicates in erythrocyte precursor cells and B cells. To our knowledge NK cell responses have not been characterized in persistently γHV68 infected mice so far.
Recently Mekker et al. published that LCMV clearance in mice was not influenced by persistent mCMV infection . In their mCMV infection model the virus was cleared at 6–8 weeks post infection whereas we could detect replicating mCMV in salivary glands at least up to 12 weeks post mCMV infection (Additional file 1: Figure S1) suggesting that replicating mCMV might be necessary to influence anti-viral immune responses against a secondary infection. Additionally Mekker et al. used the mCMV Δm157 virus, which does not induce a strong NK cell response in C57BL/6 mice. Instead, we used the mCMV Smith strain in C57BL/6 mice, which was shown to induce strong NK cell response that is responsible for the early control of the mCMV infection . The mCMV specific m157 protein binds to the NK cell receptor Ly49H and induces strong NK cell activation and proliferation. This interaction combined with long-term virus replication might be necessary to generate effector and/or memory NK cell responses, which can improve anti-viral immune responses .
Our data suggests that mCMV-primed NK cells increased the magnitude of the FV-specific CD8 T cell response. At first glance our findings seem to be contradictory to recently published studies showing a negative effect of NK cells on the priming of virus-specific CD8 T cell responses [36–38]. However, in these studies the impact of NK cells on the outcome of a primary virus infection was examined in previously naïve mice. In our study, we demonstrated the positive impact of previously activated, memory-type NK cells in mice persistently infected with mCMV on the priming of retrovirus-specific CD8 T cells. In high-risk HIV-exposed seronegative individuals, an increased NK cell activity has been found, indicating that NK cells might also be involved in the resistance against primary HIV-1 infection [39, 40].
Our current data also seem to contradict previous studies on the interaction of CMV and retroviruses in HIV infected patients. These studies demonstrate reactivation of CMV in the late stage of HIV infection, when patients have low CD4 T cell counts [2–5] and a drop in CMV-specific CD4 T cell numbers . Under these circumstances CMV seropositivity can clearly be harmful for a retrovirus infected host. However, here we studied a primary retrovirus infection in a CMV seropositive host, a scenario that has not been studied so far in HIV infected patients. These contradictory findings indicate that on one hand CMV seropositivity might be beneficial during a primary retrovirus infection on the other hand it becomes detrimental during a chronic retrovirus infection.
Taken together, mCMV primed NK cells that produce IFNγ were able to promote the FV-specific CD8 T cell response after FV superinfection. Our results suggest that activated NK cells in CMV seropositive individuals might also contribute to the control of primary HIV infection. There are several studies on primary HIV infection but none of them analyzes the CMV status of these patients.
Six to eight weeks old C57BL/6 (H-2b) male mice were obtained from Harlan (Horst, Netherlands). The mice were infected i.p. with 1 × 105 PFU mCMV (Smith strain) or were inoculated with PBS as control. The mCMV stock was prepared from salivary glands of Balb/c mice 15 days post infection . During the persistent phase (5–10 weeks post infection), persistently mCMV and naive mice (controls) were infected i.v. with 20,000 spleen focus-forming units (SFFU) of Friend virus (FV). The FV stock was obtained from 15% spleen cell homogenates from BALB/c mice infected 14 days previously with 3,000 SFFU. The FV stock was not contaminated by lactate dehydrogenase-elevating virus (LDV) . All virus stocks were diluted with PBS. Mice were maintained under pathogen-free conditions and treated in according with the regulations and guidelines of institutional animal care of the University Duisburg-Essen, Germany.
Virus titer detection
Titrations of single-cell suspensions of FV infected splenocytes were performed on susceptible Mus dunni cells, co-cultivated for 3 days and stained with F-MuLV envelope-specific monoclonal antibody 720 as previously described . Results were detected as log10 infectious centers (IC) per spleen.
The number of mCMV PFU was determined by plaque assay using a 10% homogenate of tissue taken from individual mice and tenfold dilutions of this homogenate on mouse embryonic fibroblasts (GTKO) cells were used to quantify mCMV titers . Titers reported are numbers of log10 PFU per whole liver and salivary gland.
Cell-surface and intracellular staining by flow cytometry
Cell-surface staining was performed with the following antibodies: anti-CD3 (17A2), anti-CD49b (DX5), anti-CD69 (H1.2 F3), anti-NK1.1 (PK136), anti-CD43 (1B11), anti-CD4 (RM4-5), anti-CD8 (53–6.7), anti-CD107a (1D4B), anti-Ter119 (TER-119), anti-KLRG-1 (2 F1), anti-CD44 (IM7), anti-CD19 (MB19-1), anti-B220 (RA3-6B2) and anti-CD62L (MEL-14).
Dead cells (positive for fixable viable dye; eBioscience) were excluded from analysis. Data were acquired on a LSR II flow cytometer (BD Biosciences) and analyses were performed using FACSDiva (BD Biosciences) and Flow Jo (Tree Star) software.
For intracellular staining of IFNγ in NK cells, up to 4 × 106 splenocytes were stimulated with PMA (400 ng/ml) and ionomycin (500 ng/ml) in the presence of brefeldin A for 3 h at 37°C. Stimulated cells were pre-incubated with an Fc Block (2.4G2) in FACS buffer (HBBS, 2% FCS, 0.1% NaN3) and stained for 20 min at 4°C with various combinations of fluorescently tagged monoclonal antibodies. After washing, cells were permeabilized using BD Cytofix/Cytoperm solution and then stained in BD Permwash using monoclonal antibodies specific for various cytokines. Intracellular staining of granzmye B (clone GB12) and Foxp3 was performed without in vitro stimulation. Foxp3 expression was detected using the Foxp3 antibody (clone FJK-16 s) and the Foxp3 staining kit (eBioscience).
Tetramers and tetramer staining
For quantification of virus-specific CD8 T cells, spleen cells were stained with anti-CD8, anti-CD43 and MHC class I H2-Db tetramers specific for the FV GagL epitope [45, 46] for 30 min at room temperature as described .
In vivocytotoxicity assay
The in vivo CTL assay was performed as described previously . Briefly, splenocytes from naïve CD45.1+ C57BL/6 mice were loaded with 1 μM DbGagL peptide [45, 46]. These loaded splenocytes were stained with 200 nM 5-(and 6-) carboxyfluorescein diacetate succinimidyl ester (CFSE; Molecular Probes). As control, spleen cells without peptide and no CSFE labeling were used. Peptide loaded and non-loaded splenocytes were mixed 1:1 and transferred i.v. (107 cells of each population) into FV-infected CD45.2+ C56BL/6 mice at day 8 post FV infection. Two hours after the transfer of cells, splenocytes were harvested, and cell suspensions were prepared. Target cells were distinguished from recipient cells by the surface molecules CD45.1 and CD45.1 and peptide loaded and non-loaded cells by CFSE staining. The percentage of killing was calculated as follows: 100 − ([(% peptide pulsed in infected/% unpulsed in infected)/(% peptide pulsed in uninfected/% unpulsed in uninfected)] × 100).
NK1.1+ cell depletion was performed using 0.5 ml of supernatant fluid containing NK1.1-specific monoclonal antibody PK136 . Four days after the last NK1.1 injection over 90% off all NK cells (DX5+, NK1.1+, NKp46+, CD3-) were depleted in naïve and persistently mCMV infected mice. Additionally we detected an up to 89% depletion of NKT cells (NK1.1+, NKp46+, CD3-) in naïve and persistently mCMV infected mice at this time-point. No depletion of γδT and CD8 T cells was detected after NK1.1 antibody injection. Neutralization of IFNγ was done by injection of 150 to 250 μg XMG1.2 antibody in 0.2 ml PBS (Bio-X-Cell). Antibodies were injected i.p. into mice at day −1, 2 and 4 post FV infection.
Mouse IFNγ levels were detected using the Femto-HS Elisa kit (eBioscience) according to the manufacturers’ instructions.
Animal experiments were performed in strict accordance with the German regulations of the Society for Laboratory Animal Science (GV-SOLAS) and the European Health Law of the Federation of Laboratory Animal Science Associations (FELASA). The protocol was approved by the North Rhine-Westphalia State Agency for Nature, Environment and Consumer Protection (LANUF). All efforts were made to minimize suffering.
We thank Stephen Waggoner (University of Massachusetts Medical School) for advise and critical reading the manuscript. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (TRR60) and from the University Hospital Essen (IFORES).
- Mori Y, Yamanishi K: HHV-6A, 6B, and 7: pathogenesis, host response, and clinical disease. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Edited by: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K. 2007, Cambridge: Cambridge University Press, Chapter 46Google Scholar
- Bronke C, Palmer NM, Jansen CA, Westerlaken GH, Polstra AM, Reiss P, Bakker M, Miedema F, Tesselaar K, van Baarle D: Dynamics of cytomegalovirus (CMV)-specific T cells in HIV-1-infected individuals progressing to AIDS with CMV end-organ disease. J Infect Dis. 2005, 191: 873-880. 10.1086/427828.View ArticlePubMedGoogle Scholar
- Bronke C, Westerlaken GH, Miedema F, Tesselaar K, van Baarle D: Progression to CMV end-organ disease in HIV-1-infected individuals despite abundance of highly differentiated CMV-specific CD8+ T-cells. Immunol Lett. 2005, 97: 215-224. 10.1016/j.imlet.2004.11.004.View ArticlePubMedGoogle Scholar
- Sison RF, Holland GN, MacArthur LJ, Wheeler NC, Gottlieb MS: Cytomegalovirus retinopathy as the initial manifestation of the acquired immunodeficiency syndrome. Am J Ophthalmol. 1991, 112: 243-249.View ArticlePubMedGoogle Scholar
- Erice A, Tierney C, Hirsch M, Caliendo AM, Weinberg A, Kendall MA, Polsky B: Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) burden, CMV end-organ disease, and survival in subjects with advanced HIV infection (AIDS clinical trials group protocol 360). Clin Infect Dis. 2003, 37: 567-578. 10.1086/375843.View ArticlePubMedGoogle Scholar
- Guardia-Silva AC, Stucchi RS, Sampaio AM, Milan A, Costa SC, Boin IF: Detection of cytomegalovirus and human herpesvirus-6 DNA in liver biopsy specimens and their correlation with rejection after liver transplantation. Transplant Proc. 2012, 44: 2441-2444. 10.1016/j.transproceed.2012.07.027.View ArticlePubMedGoogle Scholar
- van der Bij W, Speich R: Management of cytomegalovirus infection and disease after solid-organ transplantation. Clin Infect Dis. 2001, 33 (Suppl 1): S32-S37.View ArticlePubMedGoogle Scholar
- Lerner CW, Tapper ML: Opportunistic infection complicating acquired immune deficiency syndrome. Clinical features of 25 cases. Medicine (Baltimore). 1984, 63: 155-164.View ArticleGoogle Scholar
- Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, Christoph S, Gromke T, Kordelas L, Ottinger HD, et al: Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood. 2011, 118: 1402-1412. 10.1182/blood-2010-08-304121.View ArticlePubMedGoogle Scholar
- Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M, Diamond MS, Miller VL, Virgin HWT: Herpesvirus latency confers symbiotic protection from bacterial infection. Nature. 2007, 447: 326-329. 10.1038/nature05762.View ArticlePubMedGoogle Scholar
- Krmpotic A, Bubic I, Polic B, Lucin P, Jonjic S: Pathogenesis of murine cytomegalovirus infection. Microbes Infect. 2003, 5: 1263-1277. 10.1016/j.micinf.2003.09.007.View ArticlePubMedGoogle Scholar
- Reddehase MJ, Simon CO, Seckert CK, Lemmermann N, Grzimek NK: Murine model of cytomegalovirus latency and reactivation. Curr Top Microbiol Immunol. 2008, 325: 315-331. 10.1007/978-3-540-77349-8_18.PubMedGoogle Scholar
- Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang SM, Norris PJ, et al: Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A. 2011, 108: 14725-14732. 10.1073/pnas.1110900108.PubMed CentralView ArticlePubMedGoogle Scholar
- Sun JC, Lopez-Verges S, Kim CC, DeRisi JL, Lanier LL: NK cells and immune “memory”. J Immunol. 2011, 186: 1891-1897. 10.4049/jimmunol.1003035.PubMed CentralView ArticlePubMedGoogle Scholar
- Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL: Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science. 2002, 296: 1323-1326. 10.1126/science.1070884.View ArticlePubMedGoogle Scholar
- Smith HR, Heusel JW, Mehta IK, Kim S, Dorner BG, Naidenko OV, Iizuka K, Furukawa H, Beckman DL, Pingel JT, et al: Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci USA. 2002, 99: 8826-8831.PubMed CentralView ArticlePubMedGoogle Scholar
- Kabat D: Molecular biology of friend viral erythroleukemia. Curr Top Microbiol Immunol. 1989, 148: 1-42. 10.1007/978-3-642-74700-7_1.PubMedGoogle Scholar
- Chesebro B, Wehrly K, Stimpfling J: Host genetic control of recovery from friend leukemia virus-induced splenomegaly: mapping of a gene within the major histocompatability complex. J Exp Med. 1974, 140: 1457-1467. 10.1084/jem.140.6.1457.PubMed CentralView ArticlePubMedGoogle Scholar
- Zelinskyy G, Balkow S, Schimmer S, Werner T, Simon MM, Dittmer U: The level of friend retrovirus replication determines the cytolytic pathway of CD8+ T-cell-mediated pathogen control. J Virol. 2007, 81: 11881-11890. 10.1128/JVI.01554-07.PubMed CentralView ArticlePubMedGoogle Scholar
- Gerlach N, Schimmer S, Weiss S, Kalinke U, Dittmer U: Effects of type I interferons on friend retrovirus infection. J Virol. 2006, 80: 3438-3444. 10.1128/JVI.80.7.3438-3444.2006.PubMed CentralView ArticlePubMedGoogle Scholar
- Hasenkrug KJ, Brooks DM, Dittmer U: Critical role for CD4(+) T cells in controlling retrovirus replication and spread in persistently infected mice. J Virol. 1998, 72: 6559-6564.PubMed CentralPubMedGoogle Scholar
- Sun JC, Lanier LL: NK cell development, homeostasis and function: parallels with CD8(+) T cells. Nat Rev Immunol. 2011, 11: 645-657. 10.1038/nri3044.PubMed CentralView ArticlePubMedGoogle Scholar
- Dokun AO, Kim S, Smith HR, Kang HS, Chu DT, Yokoyama WM: Specific and nonspecific NK cell activation during virus infection. Nat Immunol. 2001, 2: 951-956. 10.1038/ni714.View ArticlePubMedGoogle Scholar
- Stromnes IM, Dittmer U, Schumacher TN, Schepers K, Messer RJ, Evans LH, Peterson KE, Race B, Hasenkrug KJ: Temporal effects of gamma interferon deficiency on the course of friend retrovirus infection in mice. J Virol. 2002, 76: 2225-2232. 10.1128/jvi.76.5.2225-2232.2002.PubMed CentralView ArticlePubMedGoogle Scholar
- Blattman JN, Grayson JM, Wherry EJ, Kaech SM, Smith KA, Ahmed R: Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat Med. 2003, 9: 540-547. 10.1038/nm866.View ArticlePubMedGoogle Scholar
- Van Parijs L, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D: Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death. Immunity. 1999, 11: 281-288. 10.1016/S1074-7613(00)80103-X.View ArticlePubMedGoogle Scholar
- Tough DF, Borrow P, Sprent J: Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science. 1996, 272: 1947-1950. 10.1126/science.272.5270.1947.View ArticlePubMedGoogle Scholar
- McNally JM, Zarozinski CC, Lin MY, Brehm MA, Chen HD, Welsh RM: Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses. J Virol. 2001, 75: 5965-5976. 10.1128/JVI.75.13.5965-5976.2001.PubMed CentralView ArticlePubMedGoogle Scholar
- Whitmire JK, Tan JT, Whitton JL: Interferon-gamma acts directly on CD8+ T cells to increase their abundance during virus infection. J Exp Med. 2005, 201: 1053-1059. 10.1084/jem.20041463.PubMed CentralView ArticlePubMedGoogle Scholar
- Duley AK, Ploquin MJ, Eksmond U, Ammann CG, Messer RJ, Myers L, Hasenkrug KJ, Kassiotis G: Negative impact of IFN-gamma on early host immune responses to retroviral infection. J Immunol. 2012, 189: 2521-2529. 10.4049/jimmunol.1201125.PubMed CentralView ArticlePubMedGoogle Scholar
- Fan Z, Yu P, Wang Y, Fu ML, Liu W, Sun Y, Fu YX: NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to reject established tumors. Blood. 2006, 107: 1342-1351. 10.1182/blood-2005-08-3485.PubMed CentralView ArticlePubMedGoogle Scholar
- Mekker A, Tchang VS, Haeberli L, Oxenius A, Trkola A, Karrer U: Immune senescence: relative contributions of age and cytomegalovirus infection. PLoS Pathog. 2012, 8: e1002850-10.1371/journal.ppat.1002850.PubMed CentralView ArticlePubMedGoogle Scholar
- Cicin-Sain L, Brien JD, Uhrlaub JL, Drabig A, Marandu TF, Nikolich-Zugich J: Cytomegalovirus infection impairs immune responses and accentuates T-cell pool changes observed in mice with aging. PLoS Pathog. 2012, 8: e1002849-10.1371/journal.ppat.1002849.PubMed CentralView ArticlePubMedGoogle Scholar
- Shrestha B, Gottlieb D, Diamond MS: Infection and injury of neurons by west nile encephalitis virus. J Virol. 2003, 77: 13203-13213. 10.1128/JVI.77.24.13203-13213.2003.PubMed CentralView ArticlePubMedGoogle Scholar
- Babic M, Krmpotic A, Jonjic S: All is fair in virus-host interactions: NK cells and cytomegalovirus. Trends Mol Med. 2011, 17: 677-685. 10.1016/j.molmed.2011.07.003.PubMed CentralView ArticlePubMedGoogle Scholar
- Mitrovic M, Arapovic J, Jordan S, Fodil-Cornu N, Ebert S, Vidal SM, Krmpotic A, Reddehase MJ, Jonjic S: The NK cell response to mouse cytomegalovirus infection affects the level and kinetics of the early CD8(+) T-cell response. J Virol. 2012, 86: 2165-2175. 10.1128/JVI.06042-11.PubMed CentralView ArticlePubMedGoogle Scholar
- Waggoner SN, Cornberg M, Selin LK, Welsh RM: Natural killer cells act as rheostats modulating antiviral T cells. Nature. 2011, 481: 394-398.PubMed CentralPubMedGoogle Scholar
- Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, Elford AR, Dhanji S, Shaabani N, Tran CW, et al: Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci U S A. 2012, 109: 1210-1215. 10.1073/pnas.1118834109.PubMed CentralView ArticlePubMedGoogle Scholar
- Ravet S, Scott-Algara D, Bonnet E, Tran HK, Tran T, Nguyen N, Truong LX, Theodorou I, Barre-Sinoussi F, Pancino G, Paul P: Distinctive NK-cell receptor repertoires sustain high-level constitutive NK-cell activation in HIV-exposed uninfected individuals. Blood. 2007, 109: 4296-4305. 10.1182/blood-2006-08-040238.View ArticlePubMedGoogle Scholar
- Scott-Algara D, Truong LX, Versmisse P, David A, Luong TT, Nguyen NV, Theodorou I, Barre-Sinoussi F, Pancino G: Cutting edge: increased NK cell activity in HIV-1-exposed but uninfected Vietnamese intravascular drug users. J Immunol. 2003, 171: 5663-5667.View ArticlePubMedGoogle Scholar
- Bukowski JF, Woda BA, Habu S, Okumura K, Welsh RM: Natural killer cell depletion enhances virus synthesis and virus-induced hepatitis in vivo. J Immunol. 1983, 131: 1531-1538.PubMedGoogle Scholar
- Robertson SJ, Ammann CG, Messer RJ, Carmody AB, Myers L, Dittmer U, Nair S, Gerlach N, Evans LH, Cafruny WA, Hasenkrug KJ: Suppression of acute anti-friend virus CD8+ T-cell responses by coinfection with lactate dehydrogenase-elevating virus. J Virol. 2008, 82: 408-418. 10.1128/JVI.01413-07.PubMed CentralView ArticlePubMedGoogle Scholar
- Dittmer U, Brooks DM, Hasenkrug KJ: Characterization of a live-attenuated retroviral vaccine demonstrates protection via immune mechanisms. J Virol. 1998, 72: 6554-6558.PubMed CentralPubMedGoogle Scholar
- Chen HD, Fraire AE, Joris I, Welsh RM, Selin LK: Specific history of heterologous virus infections determines anti-viral immunity and immunopathology in the lung. Am J Pathol. 2003, 163: 1341-1355. 10.1016/S0002-9440(10)63493-1.PubMed CentralView ArticlePubMedGoogle Scholar
- Chen W, Qin H, Chesebro B, Cheever MA: Identification of a gag-encoded cytotoxic T-lymphocyte epitope from FBL-3 leukemia shared by friend, moloney, and rauscher murine leukemia virus-induced tumors. J Virol. 1996, 70: 7773-7782.PubMed CentralPubMedGoogle Scholar
- Schepers K, Toebes M, Sotthewes G, Vyth-Dreese FA, Dellemijn TA, Melief CJ, Ossendorp F, Schumacher TN: Differential kinetics of antigen-specific CD4+ and CD8+ T cell responses in the regression of retrovirus-induced sarcomas. J Immunol. 2002, 169: 3191-3199.View ArticlePubMedGoogle Scholar
- Zelinskyy G, Dietze KK, Husecken YP, Schimmer S, Nair S, Werner T, Gibbert K, Kershaw O, Gruber AD, Sparwasser T, Dittmer U: The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response. Blood. 2009, 114: 3199-3207. 10.1182/blood-2009-03-208736.View ArticlePubMedGoogle Scholar
- Gibbert K, Joedicke JJ, Meryk A, Trilling M, Francois S, Duppach J, Kraft A, Lang KS, Dittmer U: Interferon-alpha subtype 11 activates NK cells and enables control of retroviral infection. PLoS Pathog. 2012, 8: e1002868-10.1371/journal.ppat.1002868.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.