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Journal ArticleDOI

Design and tests of an HIV vaccine.

01 Jul 2002-British Medical Bulletin (Oxford University Press)-Vol. 62, Iss: 1, pp 87-98

TL;DR: Experiments in macaques and man suggest that a prime boost regimen using DNA and recombinant pox virus is highly effective at stimulating cellular immunity, but the difficulty of inducing broad cellular responses able to protect against all clades of HIV, remains an important issue.

AbstractIt is likely that a successful vaccine against HIV will need to stimulate the innate immune system, generate high levels of neutralising antibody, strong cellular immune responses, and mucosal immunity. Early efforts to develop HIV vaccines attempted to use the virus glycoprotein, gp120, to induce neutralising antibody, but did not take into account the trimeric structure of the native glycoprotein or the complex nature of the CD4 and chemokine receptor binding sites. Recently, attention has been focused on cellular immune responses, particularly T-cell cytotoxicity, based on evidence from the SIV model and from exposed and uninfected humans. Recent experiments in macaques and man suggest that a prime boost regimen using DNA and recombinant pox virus is highly effective at stimulating cellular immunity. However, in addition to the problems of generating neutralising antibodies and mucosal immunity, the difficulty of inducing broad cellular responses able to protect against all clades of HIV, remains an important issue.

Topics: Cellular immunity (63%), HIV vaccine (62%), Vaccination (54%), Chemokine receptor binding (54%), Immune system (54%)

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Citations
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Journal ArticleDOI
TL;DR: 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 are identified.
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.

291 citations


Cites background from "Design and tests of an HIV vaccine...."

  • ...Since the first description of HIV-specific CTL, numerous studies have supported the important role of this arm of the cellular immune system, and a considerable number of vaccine development efforts are directed toward the design of CTLbased vaccination strategies (10, 39, 54)....

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Journal ArticleDOI
TL;DR: The present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.
Abstract: Strong CD4 + and CD8 + T cell responses are considered important immune components for controlling HIV infection, and their priming may be central to an effective HIV vaccine. We describe in this study an approach by which multiple CD4 + and CD8 + T cell epitopes are processed and presented from an exogenously added HIV-1 Gag-p24 peptide of 32 aa complexed to heat shock protein (HSP) gp96. CD8 + T cell recognition of the HSP/peptide complex, but not the peptide alone, was inhibited by brefeldin A, suggesting an endoplasmic reticulum-dependent pathway. This is the first report to describe efficient processing and simultaneous presentation of overlapping class I- and class II-restricted epitopes from the same extracellularly added precursor peptide complexed to HSP. Given previous reports of the strong immunogenicity of HSP/peptide complexes, the present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.

103 citations


Cites background from "Design and tests of an HIV vaccine...."

  • ...Hence, recent vaccine approaches have focused on inducing cellular immune responses mediated by CD8 as well as CD4 T cells (2)....

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Journal ArticleDOI
TL;DR: The results show that pertussis vaccination has a significant causal effect in reducing disease severity and the relations between the MLE of the causal estimand and two commonly used estimators for vaccine effects on postinfection outcomes are shown.
Abstract: The effects of vaccine on postinfection outcomes, such as disease, death, and secondary transmission to others, are important scientific and public health aspects of prophylactic vaccination. As a result, evaluation of many vaccine effects condition on being infected. Conditioning on an event that occurs posttreatment (in our case, infection subsequent to assignment to vaccine or control) can result in selection bias. Moreover, because the set of individuals who would become infected if vaccinated is likely not identical to the set of those who would become infected if given control, comparisons that condition on infection do not have a causal interpretation. In this article we consider identifiability and estimation of causal vaccine effects on binary postinfection outcomes. Using the principal stratification framework, we define a postinfection causal vaccine efficacy estimand in individuals who would be infected regardless of treatment assignment. The estimand is shown to be not identifiable under the standard assumptions of the stable unit treatment value, monotonicity, and independence of treatment assignment. Thus selection models are proposed that identify the causal estimand. Closed-form maximum likelihood estimators (MLEs) are then derived under these models, including those assuming maximum possible levels of positive and negative selection bias. These results show the relations between the MLE of the causal estimand and two commonly used estimators for vaccine effects on postinfection outcomes. For example, the usual intent-to-treat estimator is shown to be an upper bound on the postinfection causal vaccine effect provided that the magnitude of protection against infection is not too large. The methods are used to evaluate postinfection vaccine effects in a clinical trial of a rotavirus vaccine candidate and in a field study of a pertussis vaccine. Our results show that pertussis vaccination has a significant causal effect in reducing disease severity.

65 citations


Cites background from "Design and tests of an HIV vaccine...."

  • ...Another example arises in HIV, where researchers are considering both antibody and T-cell–based vaccines (McMichael, Mwau, and Hanke 2002; Nabel 2001) under the hypothesis that the former will protect from infection and the latter will protect from disease or death....

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Journal ArticleDOI
TL;DR: This exercise provides an example showing how the combined use of intrinsic disorder predictions and relational databases provides an improved understanding of the functional and structural behaviour of viral proteins.
Abstract: To examine the usefulness of protein disorder predictions as a tool for the comparative analysis of viral proteins, a relational database has been constructed. The database includes proteins from influenza A and HIV-related viruses. Annotations include viral protein sequence, disorder prediction, structure, and function. Location of each protein within a virion, if known, is also denoted. Our analysis reveals a clear relationship between proximity to the RNA core and the percentage of predicted disordered residues for a set of influenza A virus proteins. Neuraminidases (NA) and hemagglutinin (HA) of major influenza A pandemics tend to pair in such a way that both proteins tend to be either ordered-ordered or disordered-disordered by prediction. This may be the result of these proteins evolving from being lipid-associated. High abundance of intrinsic disorder in envelope and matrix proteins from HIV-related viruses likely represents a mechanism where HIV virions can escape immune response despite the availability of antibodies for the HIV-related proteins. This exercise provides an example showing how the combined use of intrinsic disorder predictions and relational databases provides an improved understanding of the functional and structural behaviour of viral proteins.

60 citations


Cites background from "Design and tests of an HIV vaccine...."

  • ...Structures and functions of a large number of viral proteins are not yet totally understood [1-5]....

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Journal ArticleDOI
TL;DR: Analysis of the PID patterns in matrix proteins of viruses related and unrelated to HIV-1 might have important implications in the search for HIV vaccines since disorder in the matrix protein might provide a mechanism for immune evasion.
Abstract: Background: A previous study (Goh G.K.-M., Dunker A.K., Uversky V.N. (2008) Protein intrinsic disorder toolbox for comparative analysis of viral proteins. BMC Genomics. 9 (Suppl. 2), S4) revealed that HIV matrix protein p17 possesses especially high levels of predicted intrinsic disorder (PID). In this study, we analyzed the PID patterns in matrix proteins of viruses related and unrelated to HIV-1. Results: Both SIV mac and HIV-1 p17 proteins were predicted by PONDR VLXT to be highly disordered with subtle differences containing 50% and 60% disordered residues, respectively. SIVmac is very closely related to HIV-2. A specific region that is predicted to be disordered in HIV1 is missing in SIV mac . The distributions of PID patterns seem to differ in SIV mac and HIV-1 p17 proteins. A high level of PID for the matrix does not seem to be mandatory for retroviruses, since Equine Infectious Anemia Virus (EIAV), an HIV cousin, has been predicted to have low PID level for the matrix; i.e. its matrix protein p15 contains only 21% PID residues. Surprisingly, the PID percentage and the pattern of predicted disorder distribution for p15 resemble those of the influenza matrix protein M1 (25%). Conclusion: Our data might have important implications in the search for HIV vaccines since disorder in the matrix protein might provide a mechanism for immune evasion.

57 citations


Cites background from "Design and tests of an HIV vaccine...."

  • ...A major difficulty facing the search for HIV vaccines is a puzzling problem of the inability of HIV protein-binding antibodies in eliciting effective broad immune response [17]....

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References
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Journal ArticleDOI
05 Feb 1999-Science
TL;DR: The results confirm the importance of cell-mediated immunity in controlling HIV-1 infection and support the exploration of vaccination approaches for preventing infection that will elicit these immune responses.
Abstract: Clinical evidence suggests that cellular immunity is involved in controlling human immunodeficiency virus-1 (HIV-1) replication. An animal model of acquired immune deficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to show that virus replication is not controlled in monkeys depleted of CD8+ lymphocytes during primary SIV infection. Eliminating CD8+ lymphocytes from monkeys during chronic SIV infection resulted in a rapid and marked increase in viremia that was again suppressed coincident with the reappearance of SIV-specific CD8+ T cells. These results confirm the importance of cell-mediated immunity in controlling HIV-1 infection and support the exploration of vaccination approaches for preventing infection that will elicit these immune responses.

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27 Mar 1998-Science
TL;DR: With the use of the tetrameric complexes, a significant inverse correlation was observed between HIV-specific CTL frequency and plasma RNA viral load and suggest a considerable cytopathic effect of the virus in vivo.
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1,475 citations


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TL;DR: It is demonstrated that CD8 cells play a crucial role in suppressing SIV replication in vivo and are examined using an anti-CD8 monoclonal antibody, OKT8F.
Abstract: To determine the role of CD8(+) T cells in controlling simian immunodeficiency virus (SIV) replication in vivo, we examined the effect of depleting this cell population using an anti-CD8 monoclonal antibody, OKT8F. There was on average a 99.9% reduction of CD8 cells in peripheral blood in six infected Macaca mulatta treated with OKT8F. The apparent CD8 depletion started 1 h after antibody administration, and low CD8 levels were maintained until day 8. An increase in plasma viremia of one to three orders of magnitude was observed in five of the six macaques. The injection of a control antibody to an infected macaque did not induce a sustained viral load increase, nor did it significantly reduce the number of CD8(+) T cells. These results demonstrate that CD8 cells play a crucial role in suppressing SIV replication in vivo.

1,428 citations


Journal ArticleDOI
18 Jun 1998-Nature
TL;DR: The spatial organization of conserved neutralization epitopes on gp120 is described, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody.
Abstract: The human immunodeficiency virus HIV-1 establishes persistent infections in humans which lead to acquired immunodeficiency syndrome (AIDS). The HIV-1 envelope glycoproteins, gp120 and gp41, are assembled into a trimeric complex that mediates virus entry into target cells. HIV-1 entry depends on the sequential interaction of the gp120 exterior envelope glycoprotein with the receptors on the cell, CD4 and members of the chemokine receptor family. The gp120 glycoprotein, which can be shed from the envelope complex, elicits both virus-neutralizing and non-neutralizing antibodies during natural infection. Antibodies that lack neutralizing activity are often directed against the gp120 regions that are occluded on the assembled trimer and which are exposed only upon shedding. Neutralizing antibodies, by contrast, must access the functional envelope glycoprotein complex and typically recognize conserved or variable epitopes near the receptor-binding regions. Here we describe the spatial organization of conserved neutralization epitopes on gp120, using epitope maps in conjunction with the X-ray crystal structure of a ternary complex that includes a gp120 core, CD4 and a neutralizing antibody. A large fraction of the predicted accessible surface of gp120 in the trimer is composed of variable, heavily glycosylated core and loop structures that surround the receptor-binding regions. Understanding the structural basis for the ability of HIV-1 to evade the humoral immune response should assist in the design of a vaccine.

1,271 citations


Journal ArticleDOI
17 Jan 2002-Nature
TL;DR: The replication-defective adenovirus is a promising vaccine vector for development of an HIV-1 vaccine and elicited by a replication-incompetent Ad5 vector, used either alone or as a booster inoculation after priming with a DNA vector.
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1,233 citations


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