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 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 A High Viral Burden Predicts the Loss of CD8 T-Cell Responses Specific for Subdominant Gag Epitopes during Chronic Human Immunodeficiency Virus Infection

2007 ◽  
Vol 81 (24) ◽  
pp. 13809-13815 ◽  
Author(s):  
Christof Geldmacher ◽  
Clive Gray ◽  
Martha Nason ◽  
Jeffrey R. Currier ◽  
Antelmo Haule ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Baseline Viral Load ◽  
Viral Control ◽  
Cell Responses ◽  
Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV)-specific CD8 T-cell responses targeting products encoded within the Gag open reading frame have frequently been associated with better viral control and disease outcome during the chronic phase of HIV infection. To further clarify this relationship, we have studied the dynamics of Gag-specific CD8 T-cell responses in relation to plasma viral load and time since infection in 33 chronically infected subjects over a 9-month period. High baseline viral loads were associated with a net loss of breadth (P < 0.001) and a decrease in the total magnitude of the Gag-specific T-cell response in general (P = 0.03). Most importantly, the baseline viral load predicted the subsequent change in the breadth of Gag recognition over time (P < 0.0001, r 2 = 0.41). Compared to maintained responses, lost responses were low in magnitude (P < 0.0001) and subdominant in the hierarchy of Gag-specific responses. The present study indicates that chronic exposure of the human immune system to high levels of HIV viremia is a determinant of virus-specific CD8 T-cell loss.

CD8 T-Cell Infiltration in Extravascular Tissues of Patients With Human Immunodeficiency Virus Infection. Interleukin-15 Upmodulates Costimulatory Pathways Involved in the Antigen-Presenting Cells–T-Cell Interaction

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1277-1286 ◽  
Author(s):  
Carlo Agostini ◽  
Renato Zambello ◽  
Monica Facco ◽  
Alessandra Perin ◽  
Francesco Piazza ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Binding Proteins ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Antigen Presenting

Interleukin (IL)-15 regulates the proliferative activity of the CD8+ T-cell pool in human immunodeficiency virus (HIV)-infected patients, thereby contributing to the maintenance of the CD8+ T-cell–mediated immune response against HIV in extravascular tissues, including the lung. However, the effects of IL-15 on antigen-presenting cells (APC) during HIV infection are still unclear. In this study, we evaluated whether IL-15 regulates the macrophage stimulatory pathways governing inflammatory events that take place in the lung of patients with HIV infection. As a first step we evaluated the in vitro effects of IL-15 on lung macrophages retrieved from the respiratory tract of eight normal subjects. Although macrophages from uninfected individuals expressed the IL-15 binding proteins (IL-15R and the common γc) at resting conditions, they did not express IL-15 messenger RNA (mRNA). However, a 24-hour stimulation with IL-15 induced the expression of interferon-γ (IFN-γ) and IL-15 itself, suggesting a role for this cytokine in the activation of the pulmonary macrophage pool during inflammation. As a confirmation of the role of IL-15 in this setting, at resting conditions, alveolar macrophages of patients with HIV infection and T-cell alveolitis expressed IL-15, IFN-γ, and IL-15 binding proteins; showed an upmodulation of costimulatory molecules, B7 and CD72, which are involved in the APC of macrophages; and behaved as effective accessory cells because they elicited a strong proliferation of T cells. The accessory effect was inhibited by pretreatment with anti-CD72, anti-B7 (CD80 and CD86), and anti–IL-15 monoclonal antibodies (MoAb). We then investigated the relationship between IL-15 and the expression of costimulatory molecules by macrophages. A 24-hour stimulation of IL-15R+/γc+ macrophages with IL-15 upregulated the expression of CD80 and CD86. The evidence that IL-15 upregulates the expression of coligands that favor the contact between T cells and APC, per se, triggers T-cell activation and proliferation and acts as a chemoattractant for T cells, suggests that IL-15 plays a key role in Tc1-mediated defense mechanisms taking place in extravascular tissues of patients with HIV disease.

scholarly journals HIVgp120 activates autoreactive CD4-specific T cell responses by unveiling of hidden CD4 peptides during processing.

1995 ◽  
Vol 181 (6) ◽  
pp. 2253-2257 ◽  
Author(s):  
S Salemi ◽  
A P Caporossi ◽  
L Boffa ◽  
M G Longobardi ◽  
V Barnaba
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antigen Processing ◽  
T Cell Response ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
T Cell Priming ◽  
Antigen Presenting ◽  
First Time ◽  
Self Peptides

T cells are made tolerant only to those self-peptides that are presented in sufficient amounts by antigen-presenting cells. They ignore cryptic self-determinants, such as either those not generated by processing machinery or generated in insufficient amounts. It is anticipated that mechanisms that either change antigen processing or increase the yield of previously "invisible" peptides may be capable of inducing T cell priming and, if they are self-maintained, may sustain autoimmune diseases. Herein, we demonstrate for the first time a mechanism by which the gp120 human immunodeficiency virus-I, by downregulating plasma membrane CD4 and increasing its processing, unveils hidden CD4 epitopes, inducing an autoimmune-specific T cell response.

scholarly journals CD8+ T lymphocytes provide helper activity for IgE synthesis in human immunodeficiency virus-infected patients with hyper-IgE.

1995 ◽  
Vol 181 (1) ◽  
pp. 423-428 ◽  
Author(s):  
R Paganelli ◽  
E Scala ◽  
I J Ansotegui ◽  
C M Ausiello ◽  
E Halapi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cd4 Cells ◽  
In Vitro Synthesis ◽  
Immunodeficiency Virus ◽  
Ige Synthesis

Increased levels of serum IgE and eosinophilia have been described in human immunodeficiency virus (HIV) infection, almost exclusively in patients with CD4+ cell count &lt; 200 cells/microliters. IgE production is regulated by CD4+ T helper type 2 (Th-2) lymphocytes, producing interleukin 4 (IL-4) and expressing a ligand for the B cell-specific CD40 molecule (CD40 ligand [L]). A shift to a Th-2-like pattern of cytokine secretion has been postulated to be associated with progression toward acquired immunodeficiency syndrome (AIDS). We studied three AIDS patients with very high levels of IgE and almost complete depletion of CD4+ lymphocytes, suggesting that IgE synthesis could not be driven by CD4+ cells. IgE in vitro synthesis by cells from such patients was, however, inhibited by anti-IL-4. We show that both CD8+ T cell lines and the majority of CD8+ T cells clones derived from these patients produce IL-4, IL-5, and IL-6 in half of the cases together with interferon gamma (IFN-gamma). 44% of CD8+ T cell clones expressed a CD40L, and the supernatants of the clones were capable of inducing IgE synthesis by normal B cells costimulated with anti-CD40. CD8+ T cells in these patients therefore functionally mimic Th-2 type cells and may account for hyper-IgE and eosinophilia in the absence of CD4+ cells. The presence of such CD8+ cells may also provide a source of IL-4 directing the development of predominant Th-2 responses in HIV infection.

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 Selection, Transmission, and Reversion of an Antigen-Processing Cytotoxic T-Lymphocyte Escape Mutation in Human Immunodeficiency Virus Type 1 Infection

2004 ◽  
Vol 78 (13) ◽  
pp. 7069-7078 ◽  
Author(s):  
Todd M. Allen ◽  
Marcus Altfeld ◽  
Xu G. Yu ◽  
Kristin M. O'Sullivan ◽  
Mathias Lichterfeld ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Antigen Processing ◽  
Cytotoxic T Lymphocyte ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8+ T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.

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 Human Immunodeficiency Virus (HIV)–Specific Effector CD8 T Cell Activity in Patients with Primary HIV Infection

2002 ◽  
Vol 185 (6) ◽  
pp. 755-765 ◽  
Author(s):  
Galit Alter ◽  
Alefia Merchant ◽  
Christos M. Tsoukas ◽  
Danielle Rouleau ◽  
Roger P. LeBlanc ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
Primary Hiv Infection ◽  
Immunodeficiency Virus ◽  
Specific Effector
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