scholarly journals Patterns of Immunodominance in HIV-1–specific Cytotoxic T Lymphocyte Responses in Two Human Histocompatibility Leukocyte Antigens (HLA)-identical Siblings with HLA-A*0201 Are Influenced by Epitope Mutation

1997 ◽  
Vol 185 (8) ◽  
pp. 1423-1433 ◽  
Author(s):  
P.J.R. Goulder ◽  
A.K. Sewell ◽  
D.G. Lalloo ◽  
D.A. Price ◽  
J.A. Whelan ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Low Frequency ◽  
State Level ◽  
Hla Class I ◽  
Leukocyte Antigens ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
Epitope Selection ◽  
Immunodominant Epitopes ◽  
Ctl Responses

Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201–restricted SLYNTVATL and HLA-A3–restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201–restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.

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 HLA-B57-Restricted Cytotoxic T-Lymphocyte Activity in a Single Infected Subject toward Two Optimal Epitopes, One of Which Is Entirely Contained within the Other

2000 ◽  
Vol 74 (11) ◽  
pp. 5291-5299 ◽  
Author(s):  
Philip J. R. Goulder ◽  
Yanhua Tang ◽  
Stephen I. Pelton ◽  
Bruce D. Walker
Keyword(s):  
Mhc Class I ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
Class I ◽  
Peptide Epitopes ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Lymphocyte Activity ◽  
Ctl Responses

ABSTRACT Viral peptides are recognized by cytotoxic T lymphocytes (CTL) as a complex with major histocompatibility complex (MHC) class I molecules, but the extent to which a single HLA allele can accommodate epitope peptides of different length and sequence is not well characterized. Here we report the identification of clonal CTL responses from the same donor that independently recognize one of two HLA-B57-restricted epitopes, KAFSPEVIPMF (KF11; p24Gag residues 30 to 40) and KAFSPEVI (KF8; p24Gag residues 30 to 37). Although lysis studies indicated that the KF11 peptide stabilized the HLA-B57-peptide complex more efficiently than the KI8 peptide, strong clonal responses were directed at each epitope. In samples from a second donor, the same phenomenon was observed, in which distinct CTL clones recognized peptide epitopes presented by the same HLA class I allele (in this case, HLA-A3) which were entirely overlapping. These data are relevant to the accurate characterization of CTL responses, which is fundamental to a detailed understanding of MHC class I-restricted immunity. In addition, these studies demonstrate marked differences in the length of peptides presented by HLA-B57, an allele which is associated with nonprogressive human immunodeficiency virus infection.

scholarly journals Evaluation of Cytotoxic T-Lymphocyte Responses in Human and Nonhuman Primate Subjects Infected with Human Immunodeficiency Virus Type 1 or Simian/Human Immunodeficiency Virus

2001 ◽  
Vol 75 (1) ◽  
pp. 73-82 ◽  
Author(s):  
Tong-Ming Fu ◽  
Daniel C. Freed ◽  
Wendy L. Trigona ◽  
Liming Guan ◽  
Lan Zhu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Nonhuman Primate ◽  
Cytotoxic T Lymphocyte ◽  
Human Subjects ◽  
Culture Conditions ◽  
Effector Cells ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses ◽  
Ctl Responses

ABSTRACT Cytotoxic T-lymphocyte (CTL) responses have been implicated as playing an important role in control of human immunodeficiency virus (HIV) infection. However, it is technically difficult to demonstrate CTL responses consistently in nonhuman primate and human subjects using traditional cytotoxicity assay methods. In this study, we systematically evaluated culture conditions that may affect the proliferation and expansion of CTL effector cells and presented a sensitive method for detection of cytotoxicity responses with bulk CTL cultures. We confirmed the sensitivity and specificity of this method by demonstration of vigorous CTL responses in a simian-HIV (SHIV)-infected rhesus macaque. The expansion of epitope-specific CTL effector cells was also measured quantitatively by CTL epitope-major histocompatibility complex tetramer complex staining. In addition, two new T-cell determinants in the SIV gag region are identified. Last, we showed the utility of this method for studying CTL responses in chimpanzee and human subjects.

scholarly journals Sendai virus-specific, H-2-restricted cytotoxic T lymphocyte responses of nude mice grafted with allogeneic or semi-allogeneic thymus glands.

1980 ◽  
Vol 152 (6) ◽  
pp. 1805-1810 ◽  
Author(s):  
J P Lake ◽  
M E Andrew ◽  
C W Pierce ◽  
T J Braciale
Keyword(s):  
T Lymphocyte ◽  
Nude Mice ◽  
Sendai Virus ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Self Recognition ◽  
Parental Haplotype ◽  
Lymphocyte Responses ◽  
Ctl Responses

The in vitro secondary cytotoxic T lymphocyte (CTL) response to Sendai virus-treated stimulator cells by primed spleen cells from thymus gland-grafted nude mice was examined. BALB/c (H-2d) nude mice grafted with allogeneic C57BL/10 (H-2b) thymus glands developed CTL responses directed exclusively to Sendai virus-infected H-2d target cells. (C57BL/6 X BALB/c)F1 nude mice grafted with thymus glands of either parent developed CTL responses preferentially against infected target cells expressing the MHC antigens present in the parental thymus graft, but also had detectable activity for infected target cells of the parental haplotype not expressed in the thymus. These results provide evidence against the concept that self recognition by MHC-restricted CTL is directed exclusively by the MCH type of the thymus.

scholarly journals Cytotoxic T Lymphocyte Responses to Human Immunodeficiency Virus: Control and Escape

Stem Cells ◽  
2000 ◽  
Vol 18 (4) ◽  
pp. 230-244 ◽  
Author(s):  
Andrew K. Sewell ◽  
David A. Price ◽  
Annette Oxenius ◽  
Anthony D. Kelleher ◽  
Rodney E. Phillips
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Virus Control ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Control ◽  
Lymphocyte Responses

scholarly journals Rapid Definition of Five Novel HLA-A∗3002-Restricted Human Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Epitopes by Elispot and Intracellular Cytokine Staining Assays

2001 ◽  
Vol 75 (3) ◽  
pp. 1339-1347 ◽  
Author(s):  
Philip J. R. Goulder ◽  
, Marylyn M. Addo ◽  
Marcus A. Altfeld ◽  
Eric S. Rosenberg ◽  
Yanhua Tang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Intracellular Cytokine Staining ◽  
Initial Step ◽  
Peripheral Blood Mononuclear ◽  
Hla Restriction ◽  
Immunodeficiency Virus ◽  
Definition Of ◽  
Ctl Responses

ABSTRACT Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) play a major role in control of viral replication. To understand the contribution of this antiviral response, an initial step is to fully define the specific epitopes targeted by CTL. These studies focused on CTL responses restricted by HLA-A∗3002, one of the HLA-A molecules most prominent in African populations. To avoid the time-consuming effort and expense involved in culturing CTL prior to defining epitopes and restricting alleles, we developed a method combining Elispot assays with intracellular gamma interferon staining of peripheral blood mononuclear cells to first map the optimal epitopes targeted and then define the HLA restriction of novel epitopes. In two A∗3002-positive subjects whose CTL responses were characterized in detail, the strongest response in both cases was to an epitope in p17 Gag, RSLYNTVATLY (residues 76 to 86). Using this method, CTL epitopes for which there were no motif predictions were optimized and the HLA restriction was established within 48 to 72 h of receipt of blood. This simple and convenient approach should prove useful especially in the characterization of CTL responses specific to HIV and other viruses, particularly in localities where performing cytotoxicity assays would be problematic.

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