scholarly journals Macaques infected long-term with attenuated simian immunodeficiency virus (SIVmac) remain resistant to wild-type challenge, despite declining cytotoxic T lymphocyte responses to an immunodominant epitope

2004 ◽  
Vol 85 (9) ◽  
pp. 2591-2602 ◽  
Author(s):  
Sally A. Sharpe ◽  
Alethea Cope ◽  
Stuart Dowall ◽  
Neil Berry ◽  
Claire Ham ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
Wild Type ◽  
Immunodominant Epitope ◽  
Cell Responses ◽  
Tetramer Staining ◽  
Immunodeficiency Virus

To further investigate mechanisms of protective immunity that are induced by live, attenuated simian immunodeficiency virus (SIV), three macaques were infected with SIVmacGX2, a nef-disrupted molecular clone. In two of these animals, which expressed the MamuA*01 major histocompatibility complex class I allele, loss of functional activity against an SIV-Gag-encoded immunodominant cytotoxic T lymphocyte (CTL) epitope was observed following prolonged infection. Nonetheless, all three animals were resistant to challenge with an uncloned pool of wild-type SIVmac, whereas four naïve controls became infected. Tetramer staining revealed the rapid generation of CD8+ T-cell responses against gag- and tat-encoded immunodominant epitopes in MamuA*01+ challenge controls. The dynamics of these T-cell responses to the wild-type virus were similar to those observed following primary infection of the vaccine group with attenuated virus. In contrast, neither tetramer staining nor gamma interferon ELISpot assay revealed an immediate, systemic, anamnestic response in the wild-type-challenged, attenuated SIV-infected animals. Functional CTL capacity had not been lost in this group, as lytic activity was still evident 17 weeks after challenge. Both attenuated and wild-type viruses induced a disseminated CD8+ T-cell response, which was of a higher magnitude in lymphoid tissues than in the periphery. These results suggest that, at least as measured in the periphery, protection against wild-type infection that is induced by live, attenuated SIV is not dependent on a rechallenge-driven expansion of immunodominant epitope-specific CD8+ T cells and, therefore, pre-existing activity may be sufficient to prevent superinfection.

scholarly journals Consistent Cytotoxic-T-Lymphocyte Targeting of Immunodominant Regions in Human Immunodeficiency Virus across Multiple Ethnicities

2004 ◽  
Vol 78 (5) ◽  
pp. 2187-2200 ◽  
Author(s):  
Nicole Frahm ◽  
B. T. Korber ◽  
C. M. Adams ◽  
J. J. Szinger ◽  
R. Draenert ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
Peptide Sequence ◽  
Immune Recognition ◽  
Cell Responses ◽  
Clade B ◽  
Immunodeficiency Virus

ABSTRACT Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8+-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8+-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8+-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

scholarly journals De Novo Generation of Escape Variant-Specific CD8+ T-Cell Responses following Cytotoxic T-Lymphocyte Escape in Chronic Human Immunodeficiency Virus Type 1 Infection

2005 ◽  
Vol 79 (20) ◽  
pp. 12952-12960 ◽  
Author(s):  
Todd M. Allen ◽  
Xu G. Yu ◽  
Elizabeth T. Kalife ◽  
Laura L. Reyor ◽  
Mathias Lichterfeld ◽  
...  
Keyword(s):  
T Cell ◽  
De Novo ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Wild Type ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) evades CD8+ T-cell responses through mutations within targeted epitopes, but little is known regarding its ability to generate de novo CD8+ T-cell responses to such mutants. Here we examined gamma interferon-positive, HIV-1-specific CD8+ T-cell responses and autologous viral sequences in an HIV-1-infected individual for more than 6 years following acute infection. Fourteen optimal HIV-1 T-cell epitopes were targeted by CD8+ T cells, four of which underwent mutation associated with dramatic loss of the original CD8+ response. However, following the G357S escape in the HLA-A11-restricted Gag349-359 epitope and the decline of wild-type-specific CD8+ T-cell responses, a novel CD8+ T-cell response equal in magnitude to the original response was generated against the variant epitope. CD8+ T cells targeting the variant epitope did not exhibit cross-reactivity against the wild-type epitope but rather utilized a distinct T-cell receptor Vβ repertoire. Additional studies of chronically HIV-1-infected individuals expressing HLA-A11 demonstrated that the majority of the subjects targeted the G357S escape variant of the Gag349-359 epitope, while the wild-type consensus sequence was significantly less frequently recognized. These data demonstrate that de novo responses against escape variants of CD8+ T-cell epitopes can be generated in chronic HIV-1 infection and provide the rationale for developing vaccines to induce CD8+ T-cell responses directed against both the wild-type and variant forms of CD8 epitopes to prevent the emergence of cytotoxic T-lymphocyte escape variants.

scholarly journals Infection with “Escaped” Virus Variants Impairs Control of Simian Immunodeficiency Virus SIVmac239 Replication in Mamu-B*08-Positive Macaques

2009 ◽  
Vol 83 (22) ◽  
pp. 11514-11527 ◽  
Author(s):  
Laura E. Valentine ◽  
John T. Loffredo ◽  
Alex T. Bean ◽  
Enrique J. León ◽  
Caitlin E. MacNair ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Mhc Class I ◽  
T Cell Responses ◽  
Class I ◽  
Wild Type ◽  
Viral Loads ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT An understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+ ) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+ T-cell epitopes to investigate the contribution of epitope-specific CD8+ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08 + macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08 + macaques. The five most immunodominant Mamu-B*08-restricted CD8+ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08+ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08+ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8+ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08 + macaques.

scholarly journals Increased Loss of CCR5+ CD45RA− CD4+ T Cells in CD8+ Lymphocyte-Depleted Simian Immunodeficiency Virus-Infected Rhesus Monkeys

2008 ◽  
Vol 82 (11) ◽  
pp. 5618-5630 ◽  
Author(s):  
Ronald S. Veazey ◽  
Paula M. Acierno ◽  
Kimberly J. McEvers ◽  
Susanne H. C. Baumeister ◽  
Gabriel J. Foster ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Simian Immunodeficiency Virus ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Lymphocyte Depletion ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Previously we have shown that CD8+ T cells are critical for containment of simian immunodeficiency virus (SIV) viremia and that rapid and profound depletion of CD4+ T cells occurs in the intestinal tract of acutely infected macaques. To determine the impact of SIV-specific CD8+ T-cell responses on the magnitude of the CD4+ T-cell depletion, we investigated the effect of CD8+ lymphocyte depletion during primary SIV infection on CD4+ T-cell subsets and function in peripheral blood, lymph nodes, and intestinal tissues. In peripheral blood, CD8+ lymphocyte-depletion changed the dynamics of CD4+ T-cell loss, resulting in a more pronounced loss 2 weeks after infection, followed by a temporal rebound approximately 2 months after infection, when absolute numbers of CD4+ T cells were restored to baseline levels. These CD4+ T cells showed a markedly skewed phenotype, however, as there were decreased levels of memory cells in CD8+ lymphocyte-depleted macaques compared to controls. In intestinal tissues and lymph nodes, we observed a significantly higher loss of CCR5+ CD45RA− CD4+ T cells in CD8+ lymphocyte-depleted macaques than in controls, suggesting that these SIV-targeted CD4+ T cells were eliminated more efficiently in CD8+ lymphocyte-depleted animals. Also, CD8+ lymphocyte depletion significantly affected the ability to generate SIV Gag-specific CD4+ T-cell responses and neutralizing antibodies. These results reemphasize that SIV-specific CD8+ T-cell responses are absolutely critical to initiate at least partial control of SIV infection.

scholarly journals Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4)- and Programmed Death 1 (PD-1)-Mediated Regulation of Monofunctional and Dual Functional CD4+ and CD8+ T-Cell Responses in a Chronic Helminth Infection

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Anuradha Rajamanickam ◽  
Saravanan Munisankar ◽  
Chandrakumar Dolla ◽  
Thomas B. Nutman ◽  
Subash Babu
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Helminth Infection ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
Content Type ◽  
Cell Responses ◽  
Dual Functional ◽  
Programmed Death ◽  
Programmed Death 1

ABSTRACT Chronic helminth infections are known to be associated with the modulation of antigen-specific T-cell responses. Strongyloides stercoralis infection is characterized by the downmodulation of antigen-specific Th1 and Th17 responses and the upregulation of Th2 and Th9 responses. Immune homeostasis is partially maintained by negative regulators of T-cell activation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), which dampen effector responses during chronic infections. However, their roles in S. stercoralis infection are yet to be defined. Therefore, we sought to determine the role of CTLA-4 and PD-1 in regulating CD4+ and CD8+ T-cell responses and examined the frequencies of monofunctional and dual functional Th1/T cytotoxic type 1 (Tc1), Th17/Tc17, Th2/Tc2, and Th9/Tc9 cells in S. stercoralis infection in 15 infected individuals stimulated with parasite antigen following CTLA-4 or PD-1 blockade. Our data reveal that CTLA-4 or PD-1 blockade results in significantly enhanced frequencies of monofunctional and dual functional Th1/Tc1 and Th17/Tc17 cells and, in contrast, diminishes the frequencies of monofunctional and dual functional Th2/Tc2 and Th9/Tc9 cells with parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that CTLA-4 and PD-1 limit the induction of particular T-cell subsets in S. stercoralis infection, which suggests the importance of CTLA-4 and PD-1 in immune modulation in a chronic helminth infection.

scholarly journals Reduced Protection from Simian Immunodeficiency Virus SIVmac251 Infection Afforded by Memory CD8+ T Cells Induced by Vaccination during CD4+ T-Cell Deficiency

2008 ◽  
Vol 82 (19) ◽  
pp. 9629-9638 ◽  
Author(s):  
Monica Vaccari ◽  
Joseph Mattapallil ◽  
Kaimei Song ◽  
Wen-Po Tsai ◽  
Anna Hryniewicz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Memory Cd8 T Cells ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus

ABSTRACT Adaptive CD4+ and CD8+ T-cell responses have been associated with control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication. Here, we have designed a study with Indian rhesus macaques to more directly assess the role of CD8 SIV-specific responses in control of viral replication. Macaques were immunized with a DNA prime-modified vaccinia virus Ankara (MVA)-SIV boost regimen under normal conditions or under conditions of antibody-induced CD4+ T-cell deficiency. Depletion of CD4+ cells was performed in the immunized macaques at the peak of SIV-specific CD4+ T-cell responses following the DNA prime dose. A group of naïve macaques was also treated with the anti-CD4 depleting antibody as a control, and an additional group of macaques immunized under normal conditions was depleted of CD8+ T cells prior to challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine-induced CD8+ T cells demonstrated that SIV-specific CD8+ T cells generated under conditions of CD4+ T-cell deficiency expressed low levels of Bcl-2 and interleukin-2 (IL-2), and plasma virus levels increased over time. Depletion of CD8+ T cells prior to challenge exposure abrogated vaccine-induced protection as previously shown. These data support the notion that adaptive CD4+ T cells are critical for the generation of effective CD8+ T-cell responses to SIV that, in turn, contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will be afforded only by T-cell vaccines for HIV that provide a balanced induction of CD4+ and CD8+ T-cell responses and protect against early depletion of CD4+ T cells postinfection.

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