scholarly journals Correlates of cytotoxic T–lymphocyte–mediated virus control: implications for immuno–suppressive infections and their treatment

2000 ◽  
Vol 355 (1400) ◽  
pp. 1059-1070 ◽  
Author(s):  
Dominik Wodarz ◽  
Martin A. Nowak
Keyword(s):  
Viral Replication ◽  
Mathematical Models ◽  
Cytotoxic T Lymphocyte ◽  
Hiv Persistence ◽  
Ctl Response ◽  
Virus Load ◽  
Memory Response ◽  
Immunodeficiency Virus ◽  
The Relationship

A very important question in immunology is to determine which factors decide whether an immune response can efficiently clear or control a viral infection, and under what circumstances we observe persistent viral replication and pathology. This paper summarizes how mathematical models help us gain new insights into these questions, and explores the relationship between antiviral therapy and long–term immunological control in human immunodeficiency virus (HIV) infection. We find that cytotoxic Tlymphocyte (CTL) memory, defined as antigen–independent persistence of CTL precursors, is necessary for the CTL response to clear an infection. The presence of such a memory response is associated with the coexistence of many CTL clones directed against multiple epitopes. If CTL memory is inefficient, then persistent replication can be established. This outcome is associated with a narrow CTL response directed against only one or a few viral epitopes. If the virus replicates persistently, occurrence of pathology depends on the level of virus load at equilibrium, and this can be determined by the overall efficacy of the CTL response. Mathematical models suggest that controlled replication is reflected by a positive correlation between CTLs and virus load. On the other hand, uncontrolled viral replication results in higher loads and the absence of a correlation between CTLs and virus load. A negative correlation between CTLs and virus load indicates that the virus actively impairs immunity, as observed with HIV. Mathematical models and experimental data suggest that HIV persistence and pathology are caused by the absence of sufficient CTL memory. We show how mathematical models can help us devise therapy regimens that can restore CTL memory in HIV patients and result in long–term immunological control of the virus in the absence of life–long treatment.

scholarly journals Lentivirus-Specific Cytotoxic T-Lymphocyte Responses Are Rapidly Lost in Thymectomized Cats Infected with Feline Immunodeficiency Virus

2005 ◽  
Vol 79 (13) ◽  
pp. 8237-8242 ◽  
Author(s):  
Kathleen A. Hayes ◽  
Sadi Köksoy ◽  
Andrew J. Phipps ◽  
Wayne R. Buck ◽  
Gary J. Kociba ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Feline Immunodeficiency Virus ◽  
Cytotoxic T Lymphocyte ◽  
Significant Loss ◽  
Ctl Response ◽  
Virus Load ◽  
Immunodeficiency Virus ◽  
Plasma Virus Load ◽  
Lymphocyte Responses ◽  
Ctl Responses

ABSTRACT To what extent the thymus is needed to preserve the virus-specific cytotoxic T-lymphocyte (CTL) response of lentivirus-infected adults is unclear. Presented here is the first definitive study using thymectomized (ThX) animals to directly evaluate the contribution of thymic function to lentivirus-specific CTL response and the control of lentivirus infections. ThX and mock-ThX cats were inoculated with feline immunodeficiency virus (FIV) and monitored for their FIV-specific CTL responses. Early in infection, both FIV-ThX and FIV-mock-ThX cats produced similar CTL responses, but surprisingly, after 20 weeks, the FIV-ThX cats showed a statistically significant loss of FIV-specific CTL activity, while FIV-infected cats with intact thymuses continued to maintain FIV-specific CTL. The loss of CTL did not affect plasma virus load, which remained elevated for both groups. These results emphasize the importance of thymic integrity in maintaining immunity to lentiviruses, but also bring into question the notion that virus load is regulated predominantly by the virus-specific CTL response.

scholarly journals Simian Immunodeficiency Virus (SIV) gag DNA-Vaccinated Rhesus Monkeys Develop Secondary Cytotoxic T-Lymphocyte Responses and Control Viral Replication after Pathogenic SIV Infection

2000 ◽  
Vol 74 (16) ◽  
pp. 7485-7495 ◽  
Author(s):  
Michael A. Egan ◽  
William A. Charini ◽  
Marcelo J. Kuroda ◽  
Jörn E. Schmitz ◽  
Paul Racz ◽  
...  
Keyword(s):  
Viral Replication ◽  
Dna Vaccine ◽  
T Lymphocyte ◽  
Plasmid Dna ◽  
Rhesus Monkeys ◽  
Cytotoxic T Lymphocyte ◽  
Ctl Response ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
And Control

ABSTRACT The potential contribution of a plasmid DNA construct to vaccine-elicited protective immunity was explored in the simian immunodeficiency virus (SIV)/macaque model of AIDS. Making use of soluble major histocompatibility class I/peptide tetramers and peptide-specific killing assays to monitor CD8+T-lymphocyte responses to a dominant SIV Gag epitope in genetically selected rhesus monkeys, a codon-optimized SIV gag DNA vaccine construct was shown to elicit a high-frequency SIV-specific cytotoxic T-lymphocyte (CTL) response. This CTL response was demonstrable in both peripheral blood and lymph node lymphocytes. Following an intravenous challenge with the highly pathogenic viral isolate SIVsm E660, these vaccinated monkeys developed a secondary CTL response that arose with more rapid kinetics and reached a higher frequency than did the postchallenge CTL response in control plasmid-vaccinated monkeys. While peak plasma SIV RNA levels were comparable in the experimentally and control-vaccinated monkeys during the period of primary infection, the gag plasmid DNA-vaccinated monkeys demonstrated better containment of viral replication by 50 days following SIV challenge. These findings indicate that a plasmid DNA vaccine can elicit SIV-specific CTL responses in rhesus monkeys, and this vaccine-elicited immunity can facilitate the generation of secondary CTL responses and control of viral replication following a pathogenic SIV challenge. These observations suggest that plasmid DNA may prove a useful component of a human immunodeficiency virus type 1 vaccine.

scholarly journals Characterization of an Effective CTL Response against HIV and SIV Infections

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Meritxell Genescà
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Viral Replication ◽  
T Cell Response ◽  
Ctl Response ◽  
Mucosal Tissues ◽  
Immunodeficiency Virus ◽  
The Face ◽  
Portal Of Entry

A vaccine inducing protective immunity in mucosal tissues and secretions may stop or limit HIV infection. Although cytotoxic T lymphocytes (CTLs) are clearly associated with control of viral replication in HIV and simian immunodeficiency virus (SIV) infections, there are examples of uncontrolled viral replication in the face of strong CD8+T-cell responses. The number of functions, breadth, avidity, and magnitude of CTL response are likely to be important factors in the effectiveness of anti-HIV T-cell response, but the location and persistence of effector CD8+T cells are also critical factors. Although the only HIV vaccine clinical trial targeting cellular immunity to prevent HIV infection failed, vaccine strategies using persistent agents against pathogenic mucosal challenge in macaque models are showing unique success. Thus, the key to control the initial focus of viral replication at the portal of entry may rely on the continuous generation of effector CTL responses at mucosal level.

scholarly journals Modifications of the Human Immunodeficiency Virus Envelope Glycoprotein Enhance Immunogenicity for Genetic Immunization

2002 ◽  
Vol 76 (11) ◽  
pp. 5357-5368 ◽  
Author(s):  
Bimal K. Chakrabarti ◽  
Wing-pui Kong ◽  
Bei-yue Wu ◽  
Zhi-Yong Yang ◽  
Jacques Friborg ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cytotoxic T Lymphocyte ◽  
Expression Vectors ◽  
Response Elimination ◽  
Virus Envelope ◽  
Ctl Response ◽  
Humoral Immune ◽  
Immunodeficiency Virus ◽  
Heptad Repeats

ABSTRACT In this study, we have investigated the effect of specific mutations in human immunodeficiency virus type 1 (HIV-1) envelope (Env) on antibody production in an effort to improve humoral immune responses to this glycoprotein by DNA vaccination. Mice were injected with plasmid expression vectors encoding HIV Env with modifications in regions that might affect this response. Elimination of conserved glycosylation sites did not substantially enhance humoral or cytotoxic-T-lymphocyte (CTL) immunity. In contrast, a modified gp140 with different COOH-terminal mutations intended to mimic a fusion intermediate and stabilize trimer formation enhanced humoral immunity without reducing the efficacy of the CTL response. This mutant, with deletions in the cleavage site, fusogenic domain, and spacing of heptad repeats 1 and 2, retained native antigenic conformational determinants as defined by binding to known monoclonal antibodies or CD4, oligomer formation, and virus neutralization in vitro. Importantly, this modified Env, gp140ΔCFI, stimulated the antibody response to native gp160 while it retained its ability to induce a CTL response, a desirable feature for an AIDS vaccine.

Nonlinear Models Used to Analyze the Relation between Inflation and Unemployment

2020 ◽  
Vol 11 (2) ◽  
pp. 667
Author(s):  
Laura UNGUREANU ◽  
Madalina CONSTANTINESCU ◽  
Cristina POPÎRLAN
Keyword(s):  
Neural Networks ◽  
Mathematical Models ◽  
Nonlinear Models ◽  
Numerical Data ◽  
Optimization Models ◽  
Numerical Application ◽  
Forecasting Methods ◽  
Nonlinear Forecasting ◽  
The Relationship

Many mathematical models have been developed in the last years in order to analyze economic phenomena and processes. Some of these models are optimization models, static or dynamic, while others are developed specially to study the evolution of economic phenomena. The topic of this paper is forecasting with nonlinear models. A few well-known nonlinear models are introduced, and their properties are discussed. The variety of nonlinear relationships is important both from the perspective of estimation and from the precision of forecasts in the medium and especially long term. Most nonlinear forecasting methods and all methods based on neural networks lead to predictions that have a better quality than the forecasts obtained by linear methods. The last section of this paper contains a detailed study of the relationship between inflation and unemployment and a numerical application with numerical data from Romania.

scholarly journals T cell receptor usage and fine specificity of human immunodeficiency virus 1-specific cytotoxic T lymphocyte clones: analysis of quasispecies recognition reveals a dominant response directed against a minor in vivo variant.

1996 ◽  
Vol 183 (4) ◽  
pp. 1669-1679 ◽  
Author(s):  
S A Kalams ◽  
R P Johnson ◽  
M J Dynan ◽  
K E Hartman ◽  
T Harrer ◽  
...  
Keyword(s):  
T Cell Receptor ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Ctl Response ◽  
Immunodeficiency Virus ◽  
Hla Type ◽  
A Minor ◽  
Hiv 1

Numerous virus-specific, class I-restricted cytotoxic T lymphocyte (CTL) epitopes have been identified, yet little information is available regarding the specificity of the CTL response in persons of the same human histocompatibility leukocyte antigen (HLA) type. In this study, the human immunodeficiency virus (HIV) 1 envelope-specific CTL response was evaluated in five HLA-B14-positive persons. CTL responses specific for a previously described nine-amino acid epitope in gp41 (aa 584-592, ERYLKDQQL) could be identified in all subjects, and CTL clones specific for this epitope could be isolated from four persons. Despite heterogeneous T cell receptor usage, the fine specificity of the clones was similar, as defined by recognition of alanine-substituted peptides as well as peptides representing natural HIV-1 sequence variants. Correlation with in vivo virus sequences revealed that the dominant species in two of the subjects represented poorly recognized variants, with a K-->Q substitution at amino acid 588, whereas no variants were observed in the other two subjects. Although clonal type-specific responses to these dominant variants could be identified, the magnitude of these responses remained small, and the dominant CTL response was directed at the minor in vivo variant. These studies indicate that despite similar epitope-specific immunologic pressure in persons of the same HLA type, the in vivo quasispecies may differ, and that the major in vivo immune response to a given CTL epitope can be directed at a minor variant.

scholarly journals Persistent Antibody Responses but Declining Cytotoxic T-Lymphocyte Responses to Multiple Human Immunodeficiency Virus Type 1 Antigens in a Long-Term Nonprogressing Individual with a Defective p17 Proviral Sequence and No Detectable Viral RNA Expression

1998 ◽  
Vol 72 (4) ◽  
pp. 3472-3474 ◽  
Author(s):  
James M. Binley ◽  
Xia Jin ◽  
Yaoxing Huang ◽  
Linqi Zhang ◽  
Yunzhen Cao ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Antibody Responses ◽  
The Past ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
Hiv 1

ABSTRACT Long-term nonprogressor AD-18 has been infected with human immunodeficiency virus type 1 (HIV-1) for at least 16 years. During the past 5 years, he has had undetectable levels of plasma viremia, and HIV-1 cannot be isolated from him. Sequencing of proviral DNA indicates that the only HIV-1 sequences that can be identified in AD-18 have gross defects in the p17-encoding regions of the gag gene (Y. Huang, L. Zhang, and D. D. Ho, Virology 240:36–49, 1998). However, AD-18 has strong, sustained antibody responses to several HIV-1 antigens, including p17. Cytotoxic T-lymphocyte responses to Env and Gag antigens have gradually diminished over the past 4 years, at a time when the titers of antibodies to the same proteins have remained stable. We discuss what these observations might mean for the generation and maintenance of immunological memory.

scholarly journals Between-Host Evolution of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1: an Approach Based on Phylogenetically Independent Comparisons

2004 ◽  
Vol 78 (21) ◽  
pp. 11758-11765 ◽  
Author(s):  
Helen Piontkivska ◽  
Austin L. Hughes
Keyword(s):  
Natural Selection ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Ctl Epitopes ◽  
Term Evolution ◽  
Immunodeficiency Virus ◽  
Host Evolution ◽  
Hiv 1

ABSTRACT In human immunodeficiency virus type 1 (HIV-1), mutations that escape from cytotoxic T-lymphocyte (CTL) recognition have been documented, and sequence analyses have provided indirect support for the hypothesis that natural selection has favored CTL escape mutants within an infected host. In spite of such evidence for within-host selection by CTL, it has been more difficult to determine how natural selection by host CTL has influenced long-term evolution of HIV-1. We used statistical analysis of published HIV-1 genomic sequences to examine the role of natural selection in between-host evolution of CTL epitopes. Based on a phylogenetic analysis, we identified 21 pairs of closely related genomes isolated from different hosts and examined the pattern of nucleotide substitution in genomic regions encoding well-characterized CTL epitopes. The results revealed that certain CTL epitopes have been subject to repeated positive selection across the population, while others are generally conserved. Furthermore, evidence of positive selection was associated with divergence from the canonical epitope sequence and with an enhanced frequency of convergent amino acid sequence changes in CTL epitopes. The results support the hypothesis that CTL-driven selection has been a major factor in the long-term evolution of HIV-1.

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