Citation: Oldstone MBA (2009) Anatomy of Viral Persistence. PLoS Pathog5(7): e1000523. https://doi.org/10.1371/journal.ppat.1000523
Editor: Hiten D. Madhani, University of California San Francisco, United States of America
Published: July 31, 2009
Copyright: © 2009 Michael B. A. Oldstone. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported over the years by NIH grants AI009484 and AI045927. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The author has declared that no competing interests exist.
Ingredients of a Chronic Viral Infection
The many millions of humans who have life-long virus infections represent a major health issue for the 21st century but also a unique opportunity for investigative virologists. For persistent virus infections to endure, two ingredients are essential. The first is a unique strategy of viral replication; that is, instead of killing its host cell, the pathogen causes little to no damage so it can continue to reside in those cells. The second requirement for persistent virus infection is an immune response that does not react to or remove virus-infected cells. Overall, our knowledge of how viral genes and cellular factors interact to allow persistence to occur is incomplete. Although our libraries contain volumes of facts on this subject, many physiologic functions and interrelationships of viral genes with host genes that establish persistence remain, in large part, unknown. We do know that acutely infected cells express viral peptides, which, when attached to host major histocompatibility complex (MHC) molecules on their surfaces, signal the immune system to kill such cells. However, viruses apply numerous avoidance strategies to persist. One is direct selective pressure to suppress the infected host's innate and/or adoptive immune system that would otherwise destroy them (reviewed ,) . For example, viruses can alter or interfere with the processing of viral peptides by professional antigen-presenting cells, thereby restricting expression of MHC/peptide complexes on cell surfaces, a requirement for activation and expansion of the T cells that normally remove infected cells. Additionally, viruses can downregulate co-stimulatory and/or MHC molecules also required for T cell signaling and expansion; they can inhibit the differentiation of antigen-presenting conventional dendritic cells (cDCs), and can infect effector T and B cells directly. Similarly, to persist in infected cells, viruses can disrupt the processing or migration of viral peptides or viral peptide/MHC complexes to the cells' surface, thereby removing the recognition signals for activated killer T cells. Finally, viruses that persist frequently infect neurons, which have defects in TAP, a molecule required for the translocation of viral peptides to endoplasmic reticulum (ER) ,. Perhaps neurons can also actively prevent cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells from degranulating and thereby limit the activity of such virus-removing effector cells. Since neurons are essential to health but rarely regenerate when destroyed, Darwinian selection likely caused them to evolve mechanisms to avoid immunologic assault. Such events would allow infected neurons to escape immune recognition and live, as well as allow viruses to persist in a neuronal safe house.
Immunological Tolerance as a Mechanism to Explain Viral Persistence
Viruses can cause persistent infection early in life directly from mother to child in utero or in newborns whose immune system is immature, and even later in adults after the immune system has matured. Infection in early life was initially attributed to immunologic tolerance, that is, deletion or removal of cell clones that generate an antiviral immune response . The model for this concept was congenital lymphocytic choriomeningitis virus (LCMV) infection of mice, a life-long symptomless viral carrier state induced by in utero or neonatal infection . Like early hepatitis B or C virus (HBV/HCV) infection of today, LCMV infection studied in the past (LCMV-carrier mouse) was characterized by persistent high titers of virus throughout life without detectable antiviral immune response. This pattern was duplicated in vertically transmitted murine retroviral infections. Thus immunologic tolerance was defined (originally in the LCMV-carrier model) as 1) resistance of normal newborn mice to a viral dose lethal for mature adults; 2) presence of high titers of virus in organs and blood of adults infected in utero or neonatally with resistance to an ordinarily lethal LCMV challenge; and 3) absence of complement-fixing or neutralizing antibodies and of LCMV-specific CTLs (later after the discovery of CTLs) in adults infected in utero or neonatally.
Problems with the Immunological Tolerance Model
However, results from our work , and that of Jamieson and Ahmed  indicated major problems with that theory. First, free antiviral antibodies are present not in the circulation but bound to viruses and viral antigens to form v-Ab complexes. These v-Ab complexes deposit primarily in the glomeruli of kidneys, blood vessels, and choroid plexus. Specific anti-LCMV antibodies are readily isolated from the complex by using a low ionic and low pH buffer and quantitatively comprise over 65% of the total immunoglobulin extracted from the glomeruli, a factor 50 to 100 times greater than the specific antiviral LCMV antibody found in the immunoglobulin fraction of adult mice immunized with LCMV . A similar scenario occurs with the in utero or neonatal murine retroviral infections . Further, circulating and glomerular-deposited v-Ab complexes are found in humans with persistent viral infections.
Specific antiviral CTLs are rarely found in adult mice or in humans persistently infected early in life. Reconstitution of virus-specific T cells first shown by adoptive transfer of anti-LCMV-specific CD4 and CD8 T cells readily purged viruses and cleared infection from blood and tissues of LCMV-carrier mice . After virus was cleared, these adult mice, when rechallenged with LCMV, generated a robust specific anti-LCMV CTL response with normal kinetics and intensity and developed immunologic memory, that is, protection against an ordinarily lethal intracerebral challenge with LCMV .
Therefore, we conclude that viral infection initiated in neonates or in utero does not lead to deletion of T or B cell clones specific for the virus –. Rather, antibodies are made but do not circulate freely in blood, because they quickly bind to the virus (viral antigen) that is in excess to form immune complexes. Indeed, deposition of such v-Ab complexes leads to tissue injury that accompanies persistent infections. Further, detection of immune complexes is often a reliable marker for persistent virus infection. T cell clones are not deleted, but they are not active or observed until the viral load is lowered or removed. For the treatment of HCV and HBV carriers infected in utero or neonatally, who also fail to show virus-specific T cells, these findings suggest that removal of virus and viral antigens followed by specific immunization may provide a cure.
Viruses Actively Suppress the Host's Immune Responses
Immune responses reflect the sum of positive versus negative regulators of that response. Negative regulators function to prevent an excessive immunologic response leading to immunopathologic disease. Of those so far identified –, IL-10 , and PD-1  have claimed the most interest. They evidently function via separate pathways ,, so combination therapy that neutralizes both has been more effective than removal of either one alone .
Viruses that initiate persistent infections in juveniles or adults take advantage of this negative regulatory system by actively causing hosts to make regulators that turn off or exhaust the expected antiviral immune response. The discovery that viruses can escape immunologic attack and persist by this means again came from the study of LCMV infection in its natural murine host – and has been extended to studies of humans persistently infected with HIV and HCV – and primates infected with simian immunodeficiency virus .
In the LCMV persistent infection induced in adults, IL-10 is produced primarily by virus-infected cDCs and perhaps by B cells . In vivo, neither CD4 nor CD8 T cells produce significant amounts of IL-10. Still not clear, though, is which cells IL-10 affects. What is known is that by 9 days after a persistent LCMV infection is initiated in adult mice, T cells become unresponsive; that is, they fail to or poorly lyse virus-infected targets and do not make the positive immune regulators IL-2, interferon-γ, or TNF-α. However, when IL-10 is blockaded with antibody to IL-10 receptors, T cell functions are restored, and their numbers increase sufficiently to clear virus from blood and tissues . Interestingly, although IL-10 plays a major role in T cell exhaustion of adult mice persistently infected with LCMV, as yet no similar role for IL-10 has been found in the persistent infection of adults infected in utero or neonatally (D. Brooks, D. McGavern, M. Oldstone, unpublished data).
PD-1 expression increases on T cells during persistent LCMV infection and, as stated above, these T cells become hyporesponsive or exhausted and cannot clear infection ,. Blockade of PD-L1 by specific antibody restores T cell function, which then allows these effector T cells to control the virus infection .
The exploration and understanding of negative immune regulators, including IL-10 and PD-1, are still at an early stage; nevertheless, the implications are important and profound. First, exhausted or hyporesponsive T cells found in persistent infections can be resurrected to functional capacity. This is true not only for the LCMV model in which the phenomenon was uncovered –, but also for HIV and HCV in vitro and simian immunodeficiency virus in vivo –. Second, the environment in which negative regulators are induced by the virus provides one of the major problems in treating persistent infections. Our prediction is that when vaccination strategies to treat persistent infection fail, the likely cause is not a faulty immunogen or adjuvant approach, but overwhelming control of the environment by negative regulators. Indeed, therapeutic vaccination against ongoing persistent LCMV infection was effective only when IL-10 or PD-L1 was first neutralized ,.
Clearance of a persistent LCMV infection requires virus-specific CD4 T cell help to assist virus-specific CD8 T cells –. Recently, IL-21 was identified as essential for CD4 T cell help and allowing CD8 T cells to control the persistent infection –.
The Future and Potential Applications for Treating Persistent Viral Infections
Currently our laboratory and others are engaged in the discovery of additional negative immune regulators and their signaling pathway(s) using gene chip and forward genetics technology. These projects have a multitude of applications. Some examples are the development of pharmacologic small molecules as effective antagonists of negative immune regulators, the use of transient negative regulator blockers as an adjuvant approach to enhance both prophylactic and therapeutic vaccination, and the determination of how long during the course of persistent virus infection exhausted T cells can be rescued to become antiviral effector T cells. As always, the goal is to understand basic principles in viral pathogenesis and to extend results in the murine model to resolve persistent infections of humans.
Dendritic cells (DC) present viral peptide/MHC complexes to activate T cells. There is an initial expansion phase following infections that lead to either clearance of the virus or virus persistence. For virus clearance, following the acute infection positive immune regulators (IL-2, IFN-γ, TNF, etc.) are generated that expand the effector virus-specific T cell pool, resulting in elimination of virally infected cells, termination of the infection, and resultant development of immune memory. By contrast, with viruses that persist there is a decreased expansion, and in some cases deletion, of virus-specific T cells. Remaining T cells become exhausted or hyporesponsive and are defective in the release of positive immune regulators and hence are unable to terminate the virus infection. The cause is the virus' induction of negative regulators of the immune response, i.e., IL-10 and PD-L1, and the cure is the blockade of such negative regulators with appropriate antibodies (see –).
The 10.7-kb genome of these viruses differs by only six nucleotides that code for three amino acids. One amino acid located in the viral spike protein GP-1 at aa 260 (Leu Cl 13/Phe ARM 53b) is responsible for high affinity binding (2.5 logs higher affinity for Cl 13 over ARM 53b) for the LCMV receptor alpha-dystroglycan, which is located in the immune system, preferentially on DCs (see ,). A second important mutation is in the viral polymerase at aa 1079 (Leu Cl 13/Gln ARM 53b) and is associated with enhanced transcription and replication of LCMV Cl 13. Recent studies have also implicated infection of the fibroblastic reticular cells in lymphoid organs as contributing to the persistent infection (see ). Figure 2 shows this using a whole body section of a mouse. The tissue section was placed on a membrane and stained with a riboprobe to LCMV at 30 days after initiation of LCMV infection with either LCMV Cl 13 or LCMV ARM 53b. The presence of viral nucleic acids in mice receiving Cl 13 correlates directly with high titers of virus carried in the sera (PFU/ml) at 30 days post-infection and the lack of a CTL response observed 7 days after initiation of infection. By comparison, mice receiving LCMV ARM 53b at 30 days post-infection fail to display viral nucleic acid sequences or virus in their sera, as virus has been successfully purged. Further, mice infected with LCMV ARM 53b generate a robust CTL response 7 days following virus infection.
This is Publication Number 20069 from The Scripps Research Institute. The author acknowledges the work of many past postdoctoral fellows and colleagues who contributed to this work, including Michael Buchmeier, Raymond Welsh, J. Lindsay Whitton, Rafi Ahmed, Yves Riviere, Etienne Joly, Lennart Mucke, Jean-Edouard Gairin, Peter Southern, Maria Salvato, Persephone Borrow, Claire Evans, Juan Carlos de la Torre, Glenn Rall, Noemi Sevilla, Dietmar Berger, Matthias von Herrath, Dirk Homann, Kevin Campbell, David Brooks, Dorian McGavern, and Elina Zuniga.
- 1. Biron C, Sen GC Innate response to viral infections. In: Knipe D, Howley P, editors. Fields virology. Fifth edition. Philadelphia: Lippincott Williams & Wilkins. pp. 249–278.C. BironGC SenInnate response to viral infections.D. KnipeP. HowleyFields virology. Fifth editionPhiladelphiaLippincott Williams & Wilkins249278
- 2. Braciale TJ, Hahn YS, Burton DR The adoptive immune response to viruses. In: Knipe D, Howley P, editors. Fields virology. Fifth edition. Philadelphia: Lippincott Williams & Wilkins. pp. 279–326.TJ BracialeYS HahnDR BurtonThe adoptive immune response to viruses.D. KnipeP. HowleyFields virology. Fifth editionPhiladelphiaLippincott Williams & Wilkins279326
- 3. Zuniga EI, Liou LY, Mack L, Mendoza M, Oldstone MBA (2008) Persistent virus infection inhibits type I interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections. Cell Host Microbe 4: 374–386.EI ZunigaLY LiouL. MackM. MendozaMBA Oldstone2008Persistent virus infection inhibits type I interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections.Cell Host Microbe4374386
- 4. Joly E, Mucke L, Oldstone MBA (1991) Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science 253: 1283–1285.E. JolyL. MuckeMBA Oldstone1991Viral persistence in neurons explained by lack of major histocompatibility class I expression.Science25312831285
- 5. Joly E, Oldstone MBA (1992) Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron 8: 1185–1190.E. JolyMBA Oldstone1992Neuronal cells are deficient in loading peptides onto MHC class I molecules.Neuron811851190
- 6. Burnet FM (1949) The production of antibodies. Melbourne: MacMillan Co. FM Burnet1949The production of antibodiesMelbourneMacMillan Co
- 7. Traub E (1936) Persistence of lymphocytic choriomeningitis virus in immune animals and its relation to immunity. J Exp Med 63: 847–861.E. Traub1936Persistence of lymphocytic choriomeningitis virus in immune animals and its relation to immunity.J Exp Med63847861
- 8. Oldstone MBA, Dixon FJ (1967) Lymphocytic choriomeningitis: production of antibody by “tolerant” infected mice. Science 158: 1193–1195.MBA OldstoneFJ Dixon1967Lymphocytic choriomeningitis: production of antibody by “tolerant” infected mice.Science15811931195
- 9. Oldstone MBA, Aoki T, Dixon FJ (1972) The antibody response of mice to murine leukemia virus in spontaneous infection: absence of classical immunologic tolerance (AKR mice-complement-fixing antibodies-lymphocytic choriomeningitis virus-immunofluorescence-glomerular deposits of antigen-antibody complexes). Proc Natl Acad Sci U S A 69: 134–138.MBA OldstoneT. AokiFJ Dixon1972The antibody response of mice to murine leukemia virus in spontaneous infection: absence of classical immunologic tolerance (AKR mice-complement-fixing antibodies-lymphocytic choriomeningitis virus-immunofluorescence-glomerular deposits of antigen-antibody complexes).Proc Natl Acad Sci U S A69134138
- 10. Jamieson BD, Ahmed R (1988) T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells. Proc Natl Acad Sci U S A 85: 2265–2268.BD JamiesonR. Ahmed1988T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells.Proc Natl Acad Sci U S A8522652268
- 11. Oldstone MBA, Blount P, Southern PJ, Lampert PW (1986) Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system. Nature 321: 239–243.MBA OldstoneP. BlountPJ SouthernPW Lampert1986Cytoimmunotherapy for persistent virus infection reveals a unique clearance pattern from the central nervous system.Nature321239243
- 12. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, et al. (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439: 682–687.DL BarberEJ WherryD. MasopustB. ZhuJP Allison2006Restoring function in exhausted CD8 T cells during chronic viral infection.Nature439682687
- 13. Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, et al. (2006) Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12: 1301–1309.DG BrooksMJ TrifiloKH EdelmannL. TeytonDB McGavern2006Interleukin-10 determines viral clearance or persistence in vivo.Nat Med1213011309
- 14. Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, et al. (2006) Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 203: 2461–2472.M. EjrnaesCM FilippiMM MartinicEM LingLM Togher2006Resolution of a chronic viral infection after interleukin-10 receptor blockade.J Exp Med20324612472
- 15. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, et al. (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10: 29–37.SD BlackburnH. ShinWN HainingT. ZouCJ Workman2009Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.Nat Immunol102937
- 16. Brooks DG, Ha SJ, Elsaesser H, Sharpe AH, Freeman GJ, et al. (2008) IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc Natl Acad Sci U S A 105: 20428–20433.DG BrooksSJ HaH. ElsaesserAH SharpeGJ Freeman2008IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection.Proc Natl Acad Sci U S A1052042820433
- 17. Landay AL, Clerici M, Hashemi F, Kessler H, Berzofsky JA, et al. (1996) In vitro restoration of T cell immune function in human immunodeficiency virus-positive persons: effects of interleukin (IL)-12 and anti-IL-10. J Infect Dis 173: 1085–1091.AL LandayM. ClericiF. HashemiH. KesslerJA Berzofsky1996In vitro restoration of T cell immune function in human immunodeficiency virus-positive persons: effects of interleukin (IL)-12 and anti-IL-10.J Infect Dis17310851091
- 18. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, et al. (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443: 350–354.CL DayDE KaufmannP. KiepielaJA BrownES Moodley2006PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.Nature443350354
- 19. Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med 203: 2223–2227.GJ FreemanEJ WherryR. AhmedAH Sharpe2006Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade.J Exp Med20322232227
- 20. Barrett L, Gallant M, Howley C, Bowmer MI, Hirsch G, et al. (2008) Enhanced IL-10 production in response to hepatitis C virus proteins by peripheral blood mononuclear cells from human immunodeficiency virus-monoinfected individuals. BMC Immunol 13: 28.L. BarrettM. GallantC. HowleyMI BowmerG. Hirsch2008Enhanced IL-10 production in response to hepatitis C virus proteins by peripheral blood mononuclear cells from human immunodeficiency virus-monoinfected individuals.BMC Immunol1328
- 21. Brockman MA, Kwon DS, Tighe DP, Pavlik DF, Rosato PC, et al. (2009) IL-10 is upregulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood. Epub ahead of print. MA BrockmanDS KwonDP TigheDF PavlikPC Rosato2009IL-10 is upregulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells.Blood. Epub ahead of print
- 22. Velu V, Titanji K, Zhu B, Husain S, Pladevega A, et al. (2009) Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458: 206–210.V. VeluK. TitanjiB. ZhuS. HusainA. Pladevega2009Enhancing SIV-specific immunity in vivo by PD-1 blockade.Nature458206210
- 23. Brooks DG, Lee AM, Elsaesser H, McGavern DB, Oldstone MBA (2008) IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J Exp Med 205: 533–541.DG BrooksAM LeeH. ElsaesserDB McGavernMBA Oldstone2008IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection.J Exp Med205533541
- 24. Ha SJ, Mueller SN, Wherry EJ, Barber DL, Aubert RD, et al. (2008) Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J Exp Med 205: 543–555.SJ HaSN MuellerEJ WherryDL BarberRD Aubert2008Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection.J Exp Med205543555
- 25. Battegay M, Moskophidis D, Rahemtulla A, Hengartner H, Mak TW, et al. (1994) Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice. J Virol 68: 4700–4704.M. BattegayD. MoskophidisA. RahemtullaH. HengartnerTW Mak1994Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice.J Virol6847004704
- 26. Matloubian M, Concepcion RJ, Ahmed R (1994) CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68: 8056–8063.M. MatloubianRJ ConcepcionR. Ahmed1994CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection.J Virol6880568063
- 27. Tishon A, Lewicki H, Rall G, von Herrath M, Oldstone MBA (1995) An essential role for type 1 interferon-gamma in terminating persistent viral infection. Virology 212: 244–250.A. TishonH. LewickiG. RallM. von HerrathMBA Oldstone1995An essential role for type 1 interferon-gamma in terminating persistent viral infection.Virology212244250
- 28. Berger DP, Homann D, Oldstone MBA (2000) Defining parameters for successful immunocytotherapy of persistent viral infection. Virology 266: 257–263.DP BergerD. HomannMBA Oldstone2000Defining parameters for successful immunocytotherapy of persistent viral infection.Virology266257263
- 29. Elsaesser H, Sauer K, Brooks DG (2009) IL-21 is required to control chronic viral infection. Science 324: 1569–1572.H. ElsaesserK. SauerDG Brooks2009IL-21 is required to control chronic viral infection.Science32415691572
- 30. Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, et al. (2009) IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324: 1576–1580.A. FrohlichJ. KisielowI. SchmitzS. FreigangAT Shamshiev2009IL-21R on T cells is critical for sustained functionality and control of chronic viral infection.Science32415761580
- 31. Yi JS, Du M, Zajac AJ (2009) A vital role for interleukin-21 in the control of a chronic viral infection. Science 324: 1572–1576.JS YiM. DuAJ Zajac2009A vital role for interleukin-21 in the control of a chronic viral infection.Science32415721576
- 32. Sevilla N, Kunz S, Holz A, Lewicki H, Homann D, et al. (2000) Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells. J Exp Med 192: 1249–1260.N. SevillaS. KunzA. HolzH. LewickiD. Homann2000Immunosuppression and resultant viral persistence by specific viral targeting of dendritic cells.J Exp Med19212491260
- 33. Kunz S, Sevilla N, McGavern DB, Campbell KP, Oldstone MBA (2001) Molecular analysis of the interaction of LCMV with its cellular receptor [alpha]-dystroglycan. J Cell Biol 155: 301–310.S. KunzN. SevillaDB McGavernKP CampbellMBA Oldstone2001Molecular analysis of the interaction of LCMV with its cellular receptor [alpha]-dystroglycan.J Cell Biol155301310
- 34. Mueller SN, Matloubian M, Clemens DM, Sharpe AH, Freeman GJ, et al. (2007) Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc Natl Acad Sci USA 104: 15430–15435.SN MuellerM. MatloubianDM ClemensAH SharpeGJ Freeman2007Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection.Proc Natl Acad Sci USA1041543015435