Organ-specific selection of viral variants during chronic infection.

This study demonstrates organ specific selection of viral variants during chronic lymphocytic choriomeningitis virus (LCMV) infection in its natural host. Isolates with different biological properties were present in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the wt Armstrong strain of LCMV. Viral isolates from the CNS were similar to the wt Armstrong strain and induced potent virus-specific cytotoxic T lymphocyte (CTL) responses in adult mice and the infection was cleared within 2 wk. In contrast, LCMV isolates derived from the lymphoid tissues caused a chronic infection in adult mice associated with suppressed CTL responses. Revertants with wt Armstrong phenotype were present in the CNS of mice infected with a spleen isolate showing unequivocally the importance of host tissues in the selection of viral variants. These results provide a possible mechanism by which viral variants emerge in nature and suggest that tissue- and cell-specific selection is an important aspect of virus evolution.

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Papillomavirus Pseudovirus: a Novel Vaccine To Induce Mucosal and Systemic Cytotoxic T-Lymphocyte Responses

Journal of Virology ◽

10.1128/jvi.75.21.10139-10148.2001 ◽

2001 ◽

Vol 75 (21) ◽

pp. 10139-10148 ◽

Cited By ~ 45

Author(s):

Wei Shi ◽

Jianzhong Liu ◽

Yujun Huang ◽

Liang Qiao

Keyword(s):

Dna Vaccine ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Oral Immunization ◽

Lymphocytic Choriomeningitis ◽

Lymphoid Tissues ◽

Adjuvant Effect ◽

Ctl Response ◽

Lymphocyte Responses ◽

Ctl Responses

ABSTRACT Intestinal mucosa is a portal for many infectious pathogens. Systemic immunization, in general, does not induce a cytotoxic T-lymphocyte (CTL) response at the mucosal surface. Because papillomavirus (PV) naturally infects mucosa and skin, we determined whether PV pseudovirus, i.e., PV-like particles in which unrelated DNA plasmids are packaged, could generate specific mucosal immunity. We found that the pseudovirus that encoded the lymphocytic choriomeningitis virus gp33 epitope induced a stronger CTL response than a DNA vaccine (plasmid) encoding the same epitope given systemically. The virus-like particles that were used to make the pseudoviruses provided an adjuvant effect for induction of CTLs by the DNA vaccine. The PV pseudovirus pseudoinfected mucosal and systemic lymphoid tissues when administered orally. Oral immunization with the pseudovirus encoding human PV type 16 mutant E7 induced mucosal and systemic CTL responses. In comparison, a DNA vaccine encoding E7, when given orally, did not induce a CTL response in intestinal mucosal lymphoid tissue. Further, oral immunization with the human PV pseudovirus encoding E7 protected mice against mucosal challenge with an E7-expressing bovine PV pseudovirus. Thus, PV pseudovirus can be used as a novel vaccine to induce mucosal and systemic CTL responses.

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Underwhelming the Immune Response: Effect of Slow Virus Growth on CD8+-T-Lymphocyte Responses

Journal of Virology ◽

10.1128/jvi.78.5.2247-2254.2004 ◽

2004 ◽

Vol 78 (5) ◽

pp. 2247-2254 ◽

Cited By ~ 68

Author(s):

Gennady Bocharov ◽

Burkhard Ludewig ◽

Antonio Bertoletti ◽

Paul Klenerman ◽

Tobias Junt ◽

...

Keyword(s):

Growth Rate ◽

Viral Replication ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Immune Surveillance ◽

Lymphocytic Choriomeningitis ◽

Virus Infections ◽

Lower Growth ◽

Virus Growth ◽

Ctl Responses

ABSTRACT The speed of virus replication has typically been seen as an advantage for a virus in overcoming the ability of the immune system to control its population growth. Under some circumstances, the converse may also be true: more slowly replicating viruses may evoke weaker cellular immune responses and therefore enhance their likelihood of persistence. Using the model of lymphocytic choriomeningitis virus (LCMV) infection in mice, we provide evidence that slowly replicating strains induce weaker cytotoxic-T-lymphocyte (CTL) responses than a more rapidly replicating strain. Conceptually, we show a “bell-shaped” relationship between the LCMV growth rate and the peak CTL response. Quantitative analysis of human hepatitis C virus infections suggests that a reduction in virus growth rate between patients during the incubation period is associated with a spectrum of disease outcomes, from fulminant hepatitis at the highest rate of viral replication through acute resolving to chronic persistence at the lowest rate. A mathematical model for virus-CTL population dynamics (analogous to predator [CTL]-prey [virus] interactions) is applied in the clinical data-driven analysis of acute hepatitis B virus infection. The speed of viral replication, through its stimulus of host CTL responses, represents an important factor influencing the pathogenesis and duration of virus persistence within the human host. Viruses with lower growth rates may persist in the host because they “sneak through” immune surveillance.

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Infection of lymphocytes by a virus that aborts cytotoxic T lymphocyte activity and establishes persistent infection.

Journal of Experimental Medicine ◽

10.1084/jem.174.1.203 ◽

1991 ◽

Vol 174 (1) ◽

pp. 203-212 ◽

Cited By ~ 35

Author(s):

P Borrow ◽

A Tishon ◽

M B Oldstone

Keyword(s):

Immune System ◽

T Lymphocytes ◽

T Lymphocyte ◽

Persistent Infection ◽

Infectious Virus ◽

Cytotoxic T Lymphocyte ◽

Lymphoid Tissues ◽

Wild Type ◽

Ctl Response ◽

Adult Mice

For viruses to establish persistent infections in their hosts, they must possess some mechanism for evading clearance by the immune system. When inoculated into adult immunocompetent mice, wild-type lymphocytic choriomeningitis virus (LCMV ARM) induces a CD8(+)-mediated cytotoxic T lymphocyte (CTL) response that clears the infection within 7-14 d (CTL+ [P-]). By contrast, variant viruses isolated from lymphoid tissues of persistently infected mice fail to induce a CTL response and are thus able to establish a persistent infection in adult mice (CTL- [P+]). This report compares the interaction of CTL+ (P-) and CTL- (P+) viruses with cells of the immune system. Both types of virus initially bind to 2-4% of CD4+ and CD8+ T lymphocytes and replicate within cells of both subsets. The replication of CTL- (P+) and CTL+ (P-) viruses in lymphocytes in vivo is similar for the first 5 d after initiating infection. Thereafter, in mice infected with CTL- (P+) variants, lymphocytes retain viral genetic information, and infectious virus can be recovered throughout the animals' lives. In contrast, when adult mice are infected with wild-type CTL+ (P-) LCMV ARM, virus is not recovered from lymphocytes for greater than 7 d after infection. A CD8(+)-mediated anti-LCMV CTL response is induced in such mice. Clearance of infected lymphocytes is produced by these LCMV-specific CTLs, as shown by their ability to lyse lymphocytes expressing LCMV determinants in vitro and the fact that depletion of CD8+ lymphocytes before infection with CTL+ (P-) viruses results in levels of infected lymphocytes similar to those found in undepleted CTL- (P+)-infected mice. Hence, CTL-mediated lysis of T lymphocytes carrying infectious virus is a critical factor determining whether virus persists or the infection is terminated.

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Bone Marrow–Derived Antigen-Presenting Cells Are Required for the Generation of Cytotoxic T Lymphocyte Responses to Viruses and Use Transporter Associated with Antigen Presentation (Tap)-Dependent and -Independent Pathways of Antigen Presentation

Journal of Experimental Medicine ◽

10.1084/jem.192.8.1143 ◽

2000 ◽

Vol 192 (8) ◽

pp. 1143-1150 ◽

Cited By ~ 108

Author(s):

Luis J. Sigal ◽

Kenneth L. Rock

Keyword(s):

Bone Marrow ◽

Antigen Presentation ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Antigen Presenting Cells ◽

Lymphocytic Choriomeningitis ◽

Ctl Response ◽

Lymphocyte Responses ◽

Antigen Presenting ◽

Ctl Responses

Bone marrow (BM)-derived professional antigen-presenting cells (pAPCs) are required for the generation of cytotoxic T lymphocyte (CTL) responses to vaccinia virus and poliovirus. Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP). In this report we analyze the requirements for BM-derived pAPCs and TAP in the initiation of CTL responses to lymphocytic choriomeningitis virus (LCMV) and influenza virus (Flu). Our results indicate a requirement for BM-derived pAPCs for the CTL responses to these viruses. However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396–404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent. The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is ∼10–300-fold less efficient than the TAP-dependent pathway.

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Selection of Virus Variants and Emergence of Virus Escape Mutants after Immunization with an Epitope Vaccine

Journal of Virology ◽

10.1128/jvi.72.2.1403-1410.1998 ◽

1998 ◽

Vol 72 (2) ◽

pp. 1403-1410 ◽

Cited By ~ 68

Author(s):

Lorenzo Mortara ◽

Franck Letourneur ◽

Helene Gras-masse ◽

Alain Venet ◽

Jean-Gerard Guillet ◽

...

Keyword(s):

Amino Acids ◽

Mononuclear Cells ◽

Cytotoxic T Lymphocyte ◽

Target Cells ◽

Epitope Vaccine ◽

Peripheral Blood Mononuclear ◽

Gag Proteins ◽

Escape Mutants ◽

Selection Of ◽

Ctl Responses

ABSTRACT In this report, we assessed the evolution of the cytotoxic T-lymphocyte (CTL) response induced by an epitope vaccine. In two macaques immunized with a mixture of lipopeptides derived from simian immunodeficiency virus (SIV) Nef and Gag proteins, CTL responses were directed against the same, single epitope of the Nef protein (amino acids 128 to 137) presenting an alanine at position 136 (Nef 128-137/136A). However, after 5 months of SIV infection, peripheral blood mononuclear cells from both macaques lost their ability to be stimulated by autologous SIV-infected cells while still retaining their capacity to generate cytotoxic responses after specific Nef 128-137/136A peptide stimulation. The sequences of the pathogenic viral isolate used for the challenge showed a mixture of several variants. Within the Nef epitopic sequence from amino acids 128 to 137, 82% of viral variants expressed the epitopic peptide Nef 128-137/136A; the remaining variants presented a threonine at position 136 (Nef 128-137/136T). In contrast, sequence analysis of cloned proviral DNA obtained from both macaques 5 months after SIV challenge showed a different pattern of quasi-species variants; 100% of clones presented a threonine at position 136 (Nef 128-137/136T), suggesting the disappearance of viral variants with an alanine at this position under antiviral pressure exerted by Nef 128-137/136A-specific CTLs. In addition, 12 months after SIV challenge, six of eight clones from one macaque presented a glutamic acid at position 131 (Nef 128-137/131E+136T), which was not found in the infecting isolate. Furthermore, CTLs generated very early after SIV challenge were able to lyse cells sensitized with the Nef 128-137/136A epitope. In contrast, lysis was significantly less effective or even did not occur when either the selected peptide Nef 128-137/136T or the escape variant peptide Nef 128-137/131E+136T was used in a target cell sensitization assay. Dose analysis of peptides used to sensitize target cells as well as a major histocompatibility complex (MHC)-peptide stability assay suggested that the selected peptide Nef 128-137/136T has an altered capacity to bind to the MHC. These data suggest that CTL pressure leads to the selection of viral variants and to the emergence of escape mutants and supports the fact that immunization should elicit broad CTL responses.

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PrP-associated resistance to scrapie in five highly infected goat herds

Journal of General Virology ◽

10.1099/vir.0.047225-0 ◽

2013 ◽

Vol 94 (1) ◽

pp. 241-245 ◽

Cited By ~ 43

Author(s):

Fabien Corbière ◽

Cécile Perrin-Chauvineau ◽

Caroline Lacroux ◽

Pierrette Costes ◽

Myriam Thomas ◽

...

Keyword(s):

Infection Risk ◽

Classical Scrapie ◽

Lymphoid Tissues ◽

Goat Population ◽

Infected Goat ◽

The Central Nervous System ◽

Scrapie Infection ◽

Prp Gene ◽

Selection Of ◽

Control And Eradication

The PrP gene polymorphisms at codons 142 (I/M), 154 (R/H), 211 (R/Q), 222 (Q/K) and 240 (S/P) and their association with susceptibility to classical scrapie infection were investigated in five French goat herds displaying a high disease prevalence (>10 %). On the basis of PrPSc detection in the central nervous system and in various lymphoid tissues, 301 of 1343 goats were found to be scrapie infected. The statistical analyses indicated that while P240 mutation had no direct impact on scrapie infection risk, the H154, Q211 and K222 mutations were associated with high resistance to scrapie. The M142 mutated allele was associated with a limited protection level against the disease. These results further reinforce the view that, like in sheep, the control and eradication of classical scrapie through the selection of certain PrP alleles could be envisaged in commercial goat population.

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PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1917298117 ◽

2020 ◽

Vol 117 (8) ◽

pp. 4292-4299 ◽

Cited By ~ 2

Author(s):

Se Jin Im ◽

Bogumila T Konieczny ◽

William H. Hudson ◽

David Masopust ◽

Rafi Ahmed

Keyword(s):

T Cells ◽

Viral Infection ◽

Cd8 T Cells ◽

Chronic Infection ◽

Lymphocytic Choriomeningitis ◽

T Cell Response ◽

Chronic Viral Infection ◽

Lymphoid Tissues ◽

Migratory Patterns ◽

Lcmv Infection

The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice. This was in contrast to parabionts between mice that had undergone an acute LCMV infection where virus-specific CD8 T cells established equilibrium demonstrating circulation of memory T cells generated after viral clearance. We have identified a population of PD-1+ TCF1+CXCR5+Tim-3- stemlike virus-specific CD8 T cells that reside in lymphoid tissues and act as resource cells for maintaining the T cell response during chronic infection. These are the cells that proliferate and give rise to the more terminally differentiated PD-1+ CXCR5-Tim-3+ CD8 T cells. Both the stemlike CD8 T cells and their terminally differentiated progeny showed minimal migration during chronic infection and the few LCMV-specific CD8 T cells that were present in circulation were the recently emerging progeny from the stemlike CD8 T cells. The PD-1+ TCF1+CXCR5+ stemlike CD8 T cells were truly resident in lymphoid tissues and did not circulate in the blood. We propose that this residency in specialized niches within lymphoid tissues is a key aspect of their biology and is essential for maintaining their quiescence and stemlike program under conditions of a chronic viral infection.

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Resistance of Neonatal Mice to Scrapie Is Associated with Inefficient Infection of the Immature Spleen

Journal of Virology ◽

10.1128/jvi.80.1.474-482.2006 ◽

2006 ◽

Vol 80 (1) ◽

pp. 474-482 ◽

Cited By ~ 17

Author(s):

Michelle Ierna ◽

Christine F. Farquhar ◽

George W. Outram ◽

Moira E. Bruce

Keyword(s):

Prion Protein ◽

Early Stage ◽

Follicular Dendritic Cell ◽

Lymphoid Tissues ◽

Neonatal Mice ◽

Adult Mice ◽

Replication Sites ◽

The Central Nervous System ◽

Almost All ◽

Cell Networks

ABSTRACT Previous studies demonstrated that neonatal mice up to about a week old are less susceptible than adult mice to infection by intraperitoneal inoculation with mouse-passaged scrapie. In peripherally inoculated adult mice, scrapie replicates in lymphoid tissues such as the spleen before invading the central nervous system. Here, we investigated scrapie susceptibility in neonatal mice in more detail, concentrating on spleen involvement. First, we demonstrated that neonatal mice are about 10 times less susceptible than adults to intraperitoneal scrapie inoculation. Then we injected mice intraperitoneally with a scrapie dose that produced disease in all mice inoculated at 10 days or older but in only about a third of neonatally inoculated mice. In this experiment, spleens collected 70 days after scrapie injection of mice 10 days old or older almost all contained pathological prion protein, PrPSc, and those that were bioassayed all contained high infectivity levels. In contrast, at this early stage, only two of six spleens from neonatally inoculated mice had detectable, low infectivity levels; no PrPSc was detected, even in the two spleens. Therefore, neonatal mice have an impaired ability to replicate scrapie in their spleens, suggesting that replication sites are absent or sparse at birth but mature within 10 days. The increase in susceptibility with age correlated with the first immunocytochemical detection of the normal cellular form of prion protein, PrPc, on maturing follicular dendritic cell networks. As lymphoid tissues are more mature at birth in sheep, cattle, and humans than in mice, our results suggest that in utero infection with scrapie-like agents is theoretically possible in these species.

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Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1603892113 ◽

2016 ◽

Vol 113 (17) ◽

pp. E2383-E2392 ◽

Cited By ~ 80

Author(s):

Katrin Klocke ◽

Shimon Sakaguchi ◽

Rikard Holmdahl ◽

Kajsa Wing

Keyword(s):

De Novo ◽

Cytotoxic T Lymphocyte ◽

Treg Cells ◽

Peripheral Tolerance ◽

Autoimmune Encephalomyelitis ◽

Congenital Deficiency ◽

Adult Mice ◽

Conditional Deletion ◽

Organ Specific ◽

Deficient Mice

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies. However, in contrast to congenital deficiency, this was not fatal. CTLA-4 deletion induced preferential expansion of CD4+Foxp3+ Treg cells. However, T cells from CTLA-4–deficient inducible KO mice were able to adoptively transfer the diseases into T cell-deficient mice. Notably, cell transfer of thymocytes de novo produced myocarditis, otherwise not observed in donor mice depleted in adulthood. Moreover, CTLA-4 deletion in adult mice had opposing impacts on induced autoimmune models. Thus, although CTLA-4–deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of protein-induced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression.

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