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 Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response

2004 ◽  
Vol 200 (10) ◽  
pp. 1243-1256 ◽  
Author(s):  
Nicola A. Jones ◽  
Xiping Wei ◽  
Darren R. Flower ◽  
MaiLee Wong ◽  
Franziska Michor ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Hiv Infection ◽  
Viral Replication ◽  
Antigen Processing ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Viral Fitness ◽  
Viral Escape ◽  
Immunodeficiency Virus

CD8+ cytotoxic T lymphocytes (CTLs) play an important role in containment of virus replication in primary human immunodeficiency virus (HIV) infection. HIV's ability to mutate to escape from CTL pressure is increasingly recognized; but comprehensive studies of escape from the CD8 T cell response in primary HIV infection are currently lacking. Here, we have fully characterized the primary CTL response to autologous virus Env, Gag, and Tat proteins in three patients, and investigated the extent, kinetics, and mechanisms of viral escape from epitope-specific components of the response. In all three individuals, we observed variation beginning within weeks of infection at epitope-containing sites in the viral quasispecies, which conferred escape by mechanisms including altered peptide presentation/recognition and altered antigen processing. The number of epitope-containing regions exhibiting evidence of early CTL escape ranged from 1 out of 21 in a subject who controlled viral replication effectively to 5 out of 7 in a subject who did not. Evaluation of the extent and kinetics of HIV-1 escape from >40 different epitope-specific CD8 T cell responses enabled analysis of factors determining escape and suggested that escape is restricted by costs to intrinsic viral fitness and by broad, codominant distribution of CTL-mediated pressure on viral replication.

scholarly journals Stable expression of transdominant Rev protein in human T cells inhibits human immunodeficiency virus replication.

1992 ◽  
Vol 176 (4) ◽  
pp. 1197-1201 ◽  
Author(s):  
M H Malim ◽  
W W Freimuth ◽  
J Liu ◽  
T J Boyle ◽  
H K Lyerly ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Hiv Infection ◽  
Viral Replication ◽  
Cell Lines ◽  
Cell Function ◽  
T Cell Function ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Rev Protein

The human immunodeficiency virus (HIV) Rev protein is essential for viral structural protein expression (Gag, Pol, and Env) and, hence, for viral replication. In transient transfection assays, mutant forms of Rev have been identified that inhibit wild-type Rev activity and therefore suppress viral replication. To determine whether such transdominant Rev proteins could provide long-term protection against HIV infection without affecting T cell function, T leukemia cell lines were stably transduced with a retroviral vector encoding a transdominant mutant of the Rev protein, M10. While all the M10-expressing cell lines remained infectable by HIV-1, these same cells failed to support a productive replication cycle when infected with a cloned isolate of HIV-1. In addition, two out of three M10-expressing CEM clones were also resistant to highly productive infection by a heterogeneous HIV-1 pool. Expression of M10 did not affect induction of HIV transcription mediated by the kappa B regulatory element or Tat. Importantly, constitutive expression of Rev M10 did not alter the secretion of interleukin 2 in response to mitogen stimulation of EL-4 and Jurkat cells. The inhibition of HIV infection in cells stably expressing a transdominant Rev protein, in the absence of any deleterious effect on T cell function, suggests that such a strategy could provide a therapeutic effect in the T lymphocytes of acquired immunodeficiency syndrome patients.

scholarly journals Analysis of Total Human Immunodeficiency Virus (HIV)-Specific CD4+ and CD8+ T-Cell Responses: Relationship to Viral Load in Untreated HIV Infection

2001 ◽  
Vol 75 (24) ◽  
pp. 11983-11991 ◽  
Author(s):  
Michael R. Betts ◽  
David R. Ambrozak ◽  
Daniel C. Douek ◽  
Sebastian Bonhoeffer ◽  
Jason M. Brenchley ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Hiv Infection ◽  
Highly Active Antiretroviral Therapy ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV)-specific T-cell responses are thought to play a key role in viral load decline during primary infection and in determining the subsequent viral load set point. The requirements for this effect are unknown, partly because comprehensive analysis of total HIV-specific CD4+ and CD8+T-cell responses to all HIV-encoded epitopes has not been accomplished. To assess these responses, we used cytokine flow cytometry and overlapping peptide pools encompassing all products of the HIV-1 genome to study total HIV-specific T-cell responses in 23 highly active antiretroviral therapy naı̈ve HIV-infected patients. HIV-specific CD8+ T-cell responses were detectable in all patients, ranging between 1.6 and 18.4% of total CD8+ T cells. HIV-specific CD4+ T-cell responses were present in 21 of 23 patients, although the responses were lower (0.2 to 2.94%). Contrary to previous reports, a positive correlation was identified between the plasma viral load and the total HIV-, Env-, and Nef-specific CD8+ T-cell frequency. No correlation was found either between viral load and total or Gag-specific CD4+ T-cell response or between the frequency of HIV-specific CD4+ and CD8+ T cells. These results suggest that overall frequencies of HIV-specific T cells are not the sole determinant of immune-mediated protection in HIV-infection.

scholarly journals Rapid Onset of Intestinal Epithelial Barrier Dysfunction in Primary Human Immunodeficiency Virus Infection Is Driven by an Imbalance between Immune Response and Mucosal Repair and Regeneration

2007 ◽  
Vol 82 (1) ◽  
pp. 538-545 ◽  
Author(s):  
Sumathi Sankaran ◽  
Michael D. George ◽  
Elizabeth Reay ◽  
Moraima Guadalupe ◽  
Jason Flamm ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Hiv Infection ◽  
Viral Replication ◽  
Cell Depletion ◽  
Epithelial Barrier ◽  
T Cell Depletion ◽  
Primary Hiv Infection ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is a site for severe CD4+ T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4+ T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4+ T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability to control viral replication and repair and regenerate intestinal mucosal tissues.

scholarly journals Effective Simian Immunodeficiency Virus-Specific CD8+ T Cells Lack an Easily Detectable, Shared Characteristic

2009 ◽  
Vol 84 (2) ◽  
pp. 753-764 ◽  
Author(s):  
Lara Vojnov ◽  
Jason S. Reed ◽  
Kim L. Weisgrau ◽  
Eva G. Rakasz ◽  
John T. Loffredo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
T Cell Response ◽  
Cytokine Secretion ◽  
Effector Memory ◽  
Viral Control ◽  
Antiviral Efficacy ◽  
Immunodeficiency Virus

ABSTRACT The immune correlates of human/simian immunodeficiency virus control remain elusive. While CD8+ T lymphocytes likely play a major role in reducing peak viremia and maintaining viral control in the chronic phase, the relative antiviral efficacy of individual virus-specific effector populations is unknown. Conventional assays measure cytokine secretion of virus-specific CD8+ T cells after cognate peptide recognition. Cytokine secretion, however, does not always directly translate into antiviral efficacy. Recently developed suppression assays assess the efficiency of virus-specific CD8+ T cells to control viral replication, but these assays often use cell lines or clones. We therefore designed a novel virus production assay to test the ability of freshly ex vivo-sorted simian immunodeficiency virus (SIV)-specific CD8+ T cells to suppress viral replication from SIVmac239-infected CD4+ T cells. Using this assay, we established an antiviral hierarchy when we compared CD8+ T cells specific for 12 different epitopes. Antiviral efficacy was unrelated to the disease status of each animal, the protein from which the tested epitopes were derived, or the major histocompatibility complex (MHC) class I restriction of the tested epitopes. Additionally, there was no correlation with the ability to suppress viral replication and epitope avidity, epitope affinity, CD8+ T-cell cytokine multifunctionality, the percentage of central and effector memory cell populations, or the expression of PD-1. The ability of virus-specific CD8+ T cells to suppress viral replication therefore cannot be determined using conventional assays. Our results suggest that a single definitive correlate of immune control may not exist; rather, a successful CD8+ T-cell response may be comprised of several factors.

Characterization of the T cell response in allergic contact dermatitis caused by corticosteroids

2013 ◽  
Vol 68 (6) ◽  
pp. 357-368 ◽  
Author(s):  
Marie Baeck ◽  
Angèle Soria ◽  
Liliane Marot ◽  
Ivan Theate ◽  
Emilie Hendrickx ◽  
...  
Keyword(s):  
T Cell ◽  
Contact Dermatitis ◽  
Allergic Contact Dermatitis ◽  
Cell Response ◽  
T Cell Response ◽  
Allergic Contact

scholarly journals A Truncated Form of Nef Selected during Pathogenic Reversion of Simian Immunodeficiency Virus SIVmac239Δnef Increases Viral Replication

2003 ◽  
Vol 77 (2) ◽  
pp. 1245-1256 ◽  
Author(s):  
Lisa A. Chakrabarti ◽  
Karin J. Metzner ◽  
Tijana Ivanovic ◽  
Hua Cheng ◽  
Jean Louis-Virelizier ◽  
...  
Keyword(s):  
T Cell ◽  
Viral Replication ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Premature Stop Codon ◽  
Cell Depletion ◽  
Partial Recovery ◽  
Wild Type ◽  
T Cell Depletion ◽  
Immunodeficiency Virus

ABSTRACT The live, attenuated vaccine simian immunodeficiency virus SIVmac239Δnef efficiently protects rhesus macaques against infection with wild-type SIVmac but occasionally causes CD4+ T-cell depletion and progression to simian AIDS (SAIDS). Virus recovered from a vaccinated macaque (Rh1490) that progressed to SAIDS had acquired an additional deletion in the nef gene, resulting in a frameshift that restored the original nef open reading frame (R. I. Connor, D. C. Montefiori, J. M. Binley, J. P. Moore, S. Bonhoeffer, A. Gettie, E. A. Fenamore, K. E. Sheridan, D. D. Ho, P. J. Dailey, and P. A. Marx, J. Virol. 72:7501-7509, 1998). Intravenous inoculation of the Rh1490 viral isolate into four naive rhesus macaques induced CD4+ T-cell depletion and disease in three out of four animals within 2 years, indicating a restoration of virulence. A DNA fragment encompassing the truncated nef gene amplified from the Rh1490 isolate was inserted into the genetic backbone of SIVmac239. The resulting clone, SIVmac239-Δ2nef, expressed a Nef protein of approximately 23 kDa, while the original SIVmac239Δnef clone expressed a shorter protein of 8 kDa. The revertant form of Nef did not cause downregulation of CD4, CD3, or major histocompatibility complex class I. The infectivity of SIVmac239-Δ2nef was similar to that of SIVmac239Δnef in single-cycle assays using indicator cell lines. In contrast, SIVmac239-Δ2nef replicated more efficiently than SIVmac239Δnef in peripheral blood mononuclear cell (PBMC) cultures infected under unstimulated conditions. The p27 Gag antigen levels in SIVmac239-Δ2nef-infected cultures were still lower than those obtained with wild-type SIVmac239, consistent with a partial recovery of Nef function. The transcriptional activity of long terminal repeat (LTR)-luciferase constructs containing the nef deletions did not differ markedly from that of wild-type LTR. Introduction of a premature stop codon within Nef-Δ2 abolished the replicative advantage in PBMCs, demonstrating that the Nef-Δ2 protein, rather than the structure of the U3 region of the LTR, was responsible for the increase in viral replication. Taken together, these results show that SIV with a deletion in the nef gene can revert to virulence and that expression of a form of nef with multiple deletions may contribute to this process by increasing viral replication.

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