scholarly journals Use of Major Histocompatibility Complex Class I/Peptide/β2M Tetramers To Quantitate CD8+ Cytotoxic T Lymphocytes Specific for Dominant and Nondominant Viral Epitopes in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys

1999 ◽  
Vol 73 (7) ◽  
pp. 5466-5472 ◽  
Author(s):  
Michael A. Egan ◽  
Marcelo J. Kuroda ◽  
Gerald Voss ◽  
Jörn E. Schmitz ◽  
William A. Charini ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Rhesus Monkeys ◽  
Cytotoxic T Lymphocyte ◽  
Low Frequencies ◽  
Ctl Epitopes ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT To evaluate the impact of the diversity of antigen recognition by T lymphocytes on disease pathogenesis, we must be able to identify and analyze simultaneously cytotoxic T-lymphocyte (CTL) responses specific for multiple viral epitopes. Many of the studies of the role of CD8+ CTLs in AIDS pathogenesis have been done with simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys. These studies have frequently made use of the well-defined SIV Gag CTL epitope p11C,C-M presented to CTL by the HLA-A homologue molecule Mamu-A*01. In the present study we identified and fine mapped two novel Mamu-A*01-restricted CTL epitopes: the SIVmac Pol-derived epitope p68A (STPPLVRLV) and the human immunodeficiency virus type 1 (HIV-1) Env-derived p41A epitope (YAPPISGQI). The frequency of CD8+ CTLs specific for the p11C,C-M, p68A, and p41A epitopes was quantitated in the same animals with a panel of tetrameric Mamu-A*01/peptide/β2m complexes. All SHIV-infected Mamu-A*01+ rhesus monkeys tested had a high frequency of SIVmac Gag-specific CTLs to the p11C,C-M epitope. In contrast, only a fraction of the monkeys tested had detectable CTLs specific for the SIVmac Pol p68A and HIV-1 Env p41A epitopes, and these responses were detected at very low frequencies. Thus, the p11C,C-M-specific CD8+ CTL response is dominant and the p41A- and p68A-specific CD8+ CTL responses are nondominant. These results indicate that CD8+CTL responses to dominant CTL epitopes can be readily quantitated with the tetramer technology; however, CD8+ CTL responses to nondominant epitopes, due to the low frequency of these epitope-specific cells, may be difficult to detect and quantitate by this approach.

scholarly journals Elicitation of High-Frequency Cytotoxic T-Lymphocyte Responses against both Dominant and Subdominant Simian-Human Immunodeficiency Virus Epitopes by DNA Vaccination of Rhesus Monkeys

2001 ◽  
Vol 75 (5) ◽  
pp. 2462-2467 ◽  
Author(s):  
Dan H. Barouch ◽  
Abie Craiu ◽  
Sampa Santra ◽  
Michael A. Egan ◽  
Jörn E. Schmitz ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Plasmid Dna ◽  
High Frequency ◽  
Rhesus Monkeys ◽  
Cytotoxic T Lymphocyte ◽  
Ctl Response ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT Increasing evidence suggests that the generation of cytotoxic T-lymphocyte (CTL) responses specific for a diversity of viral epitopes will be needed for an effective human immunodeficiency virus type 1 (HIV-1) vaccine. Here, we determine the frequencies of CTL responses specific for the simian immunodeficiency virus Gag p11C and HIV-1 Env p41A epitopes in simian-human immunodeficiency virus (SHIV)-infected and vaccinated rhesus monkeys. The p11C-specific CTL response was high frequency and dominant and the p41A-specific CTL response was low frequency and subdominant in both SHIV-infected monkeys and in monkeys vaccinated with recombinant modified vaccinia virus Ankara vectors expressing these viral antigens. Interestingly, we found that plasmid DNA vaccination led to high-frequency CTL responses specific for both of these epitopes. These data demonstrate that plasmid DNA may be useful in eliciting a broad CTL response against multiple epitopes.

scholarly journals Reduction of Simian-Human Immunodeficiency Virus 89.6P Viremia in Rhesus Monkeys by Recombinant Modified Vaccinia Virus Ankara Vaccination

2001 ◽  
Vol 75 (11) ◽  
pp. 5151-5158 ◽  
Author(s):  
Dan H. Barouch ◽  
Sampa Santra ◽  
Marcelo J. Kuroda ◽  
Jörn E. Schmitz ◽  
Ronald Plishka ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Disease Progression ◽  
Rhesus Monkeys ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT Since cytotoxic T lymphocytes (CTLs) are critical for controlling human immunodeficiency virus type 1 (HIV-1) replication in infected individuals, candidate HIV-1 vaccines should elicit virus-specific CTL responses. In this report, we study the immune responses elicited in rhesus monkeys by a recombinant poxvirus vaccine and the degree of protection afforded against a pathogenic simian-human immunodeficiency virus SHIV-89.6P challenge. Immunization with recombinant modified vaccinia virus Ankara (MVA) vectors expressing SIVmac239gag-pol and HIV-1 89.6 env elicited potent Gag-specific CTL responses but no detectable SHIV-specific neutralizing antibody (NAb) responses. Following intravenous SHIV-89.6P challenge, sham-vaccinated monkeys developed low-frequency CTL responses, low-titer NAb responses, rapid loss of CD4+ T lymphocytes, high-setpoint viral RNA levels, and significant clinical disease progression and death in half of the animals by day 168 postchallenge. In contrast, the recombinant MVA-vaccinated monkeys demonstrated high-frequency secondary CTL responses, high-titer secondary SHIV-89.6-specific NAb responses, rapid emergence of SHIV-89.6P-specific NAb responses, partial preservation of CD4+ T lymphocytes, reduced setpoint viral RNA levels, and no evidence of clinical disease or mortality by day 168 postchallenge. There was a statistically significant correlation between levels of vaccine-elicited CTL responses prior to challenge and the control of viremia following challenge. These results demonstrate that immune responses elicited by live recombinant vectors, although unable to provide sterilizing immunity, can control viremia and prevent disease progression following a highly pathogenic AIDS virus challenge.

scholarly journals Vaccine-Elicited Memory Cytotoxic T Lymphocytes Contribute to Mamu-A*01-Associated Control of Simian/Human Immunodeficiency Virus 89.6P Replication in Rhesus Monkeys

2005 ◽  
Vol 79 (8) ◽  
pp. 4580-4588 ◽  
Author(s):  
Michael S. Seaman ◽  
Sampa Santra ◽  
Michael H. Newberg ◽  
Valerie Philippon ◽  
Kelledy Manson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Rhesus Monkeys ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Immunodeficiency Virus ◽  
Memory Cytotoxic T Lymphocytes ◽  
The Impact ◽  
Ctl Responses

ABSTRACT The expression of particular major histocompatibility complex (MHC) class I alleles can influence the rate of disease progression following lentiviral infections. This effect is a presumed consequence of potent cytotoxic T-lymphocyte (CTL) responses that are restricted by these MHC class I molecules. The present studies have examined the impact of the MHC class I allele Mamu-A*01 on simian/human immunodeficiency virus 89.6P (SHIV-89.6P) infection in unvaccinated and vaccinated rhesus monkeys by exploring the contribution of dominant-epitope specific CTL in this setting. Expression of Mamu-A*01 in immunologically naive monkeys was not associated with improved control of viral replication, CD4+ T-lymphocyte loss, or survival. In contrast, Mamu-A*01 + monkeys that had received heterologous prime/boost immunizations prior to challenge maintained higher CD4+ T-lymphocyte levels and better control of SHIV-89.6P replication than Mamu-A*01 − monkeys. This protection was associated with the evolution of high-frequency anamnestic CTL responses specific for a dominant Mamu-A*01-restricted Gag epitope following infection. These data indicate that specific MHC class I alleles can confer protection in the setting of a pathogenic SHIV infection by their ability to elicit memory CTL following vaccination.

scholarly journals Cross-Reactions between the Cytotoxic T-Lymphocyte Responses of Human Immunodeficiency Virus-Infected African and European Patients

1998 ◽  
Vol 72 (5) ◽  
pp. 3547-3553 ◽  
Author(s):  
Deniz Durali ◽  
Jacques Morvan ◽  
Franck Letourneur ◽  
Doris Schmitt ◽  
Nelly Guegan ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Recombinant Virus ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Cross Reactions ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

ABSTRACT The great variability of protein sequences from human immunodeficiency virus (HIV) type 1 (HIV-1) isolates represents a major obstacle to the development of an effective vaccine against this virus. The surface protein (Env), which is the predominant target of neutralizing antibodies, is particularly variable. Here we examine the impact of variability among different HIV-1 subtypes (clades) on cytotoxic T-lymphocyte (CTL) activities, the other major component of the antiviral immune response. CTLs are produced not only against Env but also against other structural proteins, as well as some regulatory proteins. The genetic subtypes of HIV-1 were determined for Env and Gag from several patients infected either in France or in Africa. The cross-reactivities of the CTLs were tested with target cells expressing selected proteins from HIV-1 isolates of clade A or B or from HIV type 2 isolates. All African patients were infected with viruses belonging to clade A for Env and for Gag, except for one patient who was infected with a clade A Env-clade G Gag recombinant virus. All patients infected in France were infected with clade B viruses. The CTL responses obtained from all the African and all the French individuals tested showed frequent cross-reactions with proteins of the heterologous clade. Epitopes conserved between the viruses of clades A and B appeared especially frequent in Gag p24, Gag p18, integrase, and the central region of Nef. Cross-reactivity also existed among Gag epitopes of clades A, B, and G, as shown by the results for the patient infected with the clade A Env-clade G Gag recombinant virus. These results show that CTLs raised against viral antigens from different clades are able to cross-react, emphasizing the possibility of obtaining cross-immunizations for this part of the immune response in vaccinated individuals.

scholarly journals Prior Vaccination Increases the Epitopic Breadth of the Cytotoxic T-Lymphocyte Response That Evolves in Rhesus Monkeys following a Simian-Human Immunodeficiency Virus Infection

2002 ◽  
Vol 76 (12) ◽  
pp. 6376-6381 ◽  
Author(s):  
Sampa Santra ◽  
Dan H. Barouch ◽  
Marcelo J. Kuroda ◽  
Jörn E. Schmitz ◽  
Georgia R. Krivulka ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Infection ◽  
T Lymphocyte ◽  
Rhesus Monkeys ◽  
Cytotoxic T Lymphocyte ◽  
Virus Challenge ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT Although recent evidence has confirmed the importance of cytotoxic T-lymphocyte (CTL) responses in controlling human immunodeficiency virus type 1 and simian immunodeficiency virus replication, the relevance of the epitopic breadth of those CTL responses remains unexplored. In the present study, we sought to determine whether vaccination can expand CTL populations which recognize a repertoire of viral epitopes that is greater than is typically generated in the course of a viral infection. We demonstrate that potent secondary CTL responses to subdominant epitopes are rapidly generated following a pathogenic simian-human immunodeficiency virus challenge of rhesus monkeys vaccinated with plasmid DNA or recombinant modified vaccinia virus Ankara vaccines. These data indicate that prior vaccination can increase the breadth of the CTL response that evolves after an AIDS virus infection.

scholarly journals Effects of Cytotoxic T Lymphocytes (CTL) Directed against a Single Simian Immunodeficiency Virus (SIV) Gag CTL Epitope on the Course of SIVmac239 Infection

2002 ◽  
Vol 76 (20) ◽  
pp. 10507-10511 ◽  
Author(s):  
Todd M. Allen ◽  
Peicheng Jing ◽  
Briana Calore ◽  
Helen Horton ◽  
David H. O'Connor ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Cytotoxic T Lymphocytes ◽  
Ctl Epitope ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Sivmac239 Infection ◽  
Ctl Responses

ABSTRACT Vaccine-induced cytotoxic T lymphocytes (CTL) have been implicated in the control of virus replication in simian immunodeficiency virus (SIV)-challenged and simian-human immunodeficiency virus-challenged macaques. Therefore, we wanted to test the impact that vaccine-induced CTL responses against an immunodominant Gag epitope might have in the absence of other immune responses. By themselves, these strong CTL responses failed to control SIVmac239 replication.

scholarly journals Clustering Patterns of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1 (HIV-1) Proteins Reveal Imprints of Immune Evasion on HIV-1 Global Variation

2002 ◽  
Vol 76 (17) ◽  
pp. 8757-8768 ◽  
Author(s):  
Karina Yusim ◽  
Can Kesmir ◽  
Brian Gaschen ◽  
Marylyn M. Addo ◽  
Marcus Altfeld ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Amino Acid Sequences ◽  
Ctl Epitopes ◽  
Ctl Epitope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human cytotoxic T-lymphocyte (CTL) response to human immunodeficiency virus type 1 (HIV-1) has been intensely studied, and hundreds of CTL epitopes have been experimentally defined, published, and compiled in the HIV Molecular Immunology Database. Maps of CTL epitopes on HIV-1 protein sequences reveal that defined epitopes tend to cluster. Here we integrate the global sequence and immunology databases to systematically explore the relationship between HIV-1 amino acid sequences and CTL epitope distributions. CTL responses to five HIV-1 proteins, Gag p17, Gag p24, reverse transcriptase (RT), Env, and Nef, have been particularly well characterized in the literature to date. Through comparing CTL epitope distributions in these five proteins to global protein sequence alignments, we identified distinct characteristics of HIV amino acid sequences that correlate with CTL epitope localization. First, experimentally defined HIV CTL epitopes are concentrated in relatively conserved regions. Second, the highly variable regions that lack epitopes bear cumulative evidence of past immune escape that may make them relatively refractive to CTLs: a paucity of predicted proteasome processing sites and an enrichment for amino acids that do not serve as C-terminal anchor residues. Finally, CTL epitopes are more highly concentrated in alpha-helical regions of proteins. Based on amino acid sequence characteristics, in a blinded fashion, we predicted regions in HIV regulatory and accessory proteins that would be likely to contain CTL epitopes; these predictions were then validated by comparison to new sets of experimentally defined epitopes in HIV-1 Rev, Tat, Vif, and Vpr.

scholarly journals Persistence of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Clones in a Subject with Rapid Disease Progression

2001 ◽  
Vol 75 (10) ◽  
pp. 4907-4911 ◽  
Author(s):  
Sabina A. Islam ◽  
Christine M. Hay ◽  
Kelly E. Hartman ◽  
Suqin He ◽  
Amy K. Shea ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytotoxic T Lymphocyte ◽  
Cell Receptor ◽  
Clonal Deletion ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT We longitudinally measured T-cell receptor transcript frequencies of human immunodeficiency virus type 1 (HIV-1) specific cytotoxic T lymphocytes (CTL) in an individual with rapidly progressive disease and high levels of viremia. CTL clones elicited during acute HIV-1 infection were present at the time of death, despite absent functional CTL responses, arguing against clonal deletion as a mechanism for the decline of CTL responses observed during HIV-1 infection.

scholarly journals Differential Impairment of Lytic and Cytokine Functions in Senescent Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes

2003 ◽  
Vol 77 (5) ◽  
pp. 3077-3083 ◽  
Author(s):  
Mirabelle Dagarag ◽  
Hwee Ng ◽  
Rachel Lubong ◽  
Rita B. Effros ◽  
Otto O. Yang
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antigenic Specificity ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

ABSTRACT Telomere length is abnormally short in the CD8+ T-cell compartment of human immunodeficiency virus type 1 (HIV-1)-infected persons, likely because of chronic cell turnover. Although clonal exhaustion of CD8+ cytotoxic T lymphocytes (CTL) has been proposed as a mechanism for loss of antigen-specific responses, the functional consequences of exhaustion are poorly understood. Here we used telomerase transduction to evaluate the impact of senescence on CTL effector functions. Constitutive expression of telomerase in an HIV-1-specific CTL clone results in enhanced proliferative capacity, in agreement with prior studies of other human cell types. Whereas the CTL remain phenotypically normal in terms of antigenic specificity and requirements for proliferation, their cytolytic and antiviral capabilities are superior to those of control CTL. In contrast, their ability to produce gamma interferon and RANTES is essentially unchanged. The selective enhancement of cytolytic function in memory CTL by ectopic telomerase expression implies that loss of this function (but not cytokine production) is a specific consequence of replicative senescence. These data suggest a unifying mechanism for the in vivo observations that telomere lengths are shortened in the CD8+ cells of HIV-1-infected persons and that HIV-1-specific CTL are deficient in perforin. Telomerase transduction could therefore be a tool with which to explore a potential therapeutic approach to an important pathophysiologic process of immune dysfunction in chronic viral infection.

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