scholarly journals Relative Dominance of Gag p24-Specific Cytotoxic T Lymphocytes Is Associated with Human Immunodeficiency Virus Control

2006 ◽  
Vol 80 (6) ◽  
pp. 3122-3125 ◽  
Author(s):  
Rosario Zuñiga ◽  
Aldo Lucchetti ◽  
Patricia Galvan ◽  
Shyla Sanchez ◽  
Carmen Sanchez ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Vaccine Development ◽  
Cytotoxic T Lymphocyte ◽  
Dominant Role ◽  
The United States ◽  
Effective Control ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT Conflicting data on the role of total virus- and protein-specific cytotoxic-T-lymphocyte (CTL) responses in the control of human immunodeficiency virus (HIV) disease progression exist. We present data generated from a Peruvian cohort of untreated, clade B-infected subjects, demonstrating that the proportion of Gag-specific, and in particular p24-reactive, CTL responses among the total virus-specific CTL activity is associated with individuals' CD4 counts and viral loads. Analyses in a second cohort in the United States confirm these findings and point towards a dominant role of Gag-specific immunity in effective control of HIV infection, providing important guidance for HIV vaccine development.

scholarly journals Rapid Definition of Five Novel HLA-A∗3002-Restricted Human Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Epitopes by Elispot and Intracellular Cytokine Staining Assays

2001 ◽  
Vol 75 (3) ◽  
pp. 1339-1347 ◽  
Author(s):  
Philip J. R. Goulder ◽  
, Marylyn M. Addo ◽  
Marcus A. Altfeld ◽  
Eric S. Rosenberg ◽  
Yanhua Tang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Intracellular Cytokine Staining ◽  
Initial Step ◽  
Peripheral Blood Mononuclear ◽  
Hla Restriction ◽  
Immunodeficiency Virus ◽  
Definition Of ◽  
Ctl Responses

ABSTRACT Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) play a major role in control of viral replication. To understand the contribution of this antiviral response, an initial step is to fully define the specific epitopes targeted by CTL. These studies focused on CTL responses restricted by HLA-A∗3002, one of the HLA-A molecules most prominent in African populations. To avoid the time-consuming effort and expense involved in culturing CTL prior to defining epitopes and restricting alleles, we developed a method combining Elispot assays with intracellular gamma interferon staining of peripheral blood mononuclear cells to first map the optimal epitopes targeted and then define the HLA restriction of novel epitopes. In two A∗3002-positive subjects whose CTL responses were characterized in detail, the strongest response in both cases was to an epitope in p17 Gag, RSLYNTVATLY (residues 76 to 86). Using this method, CTL epitopes for which there were no motif predictions were optimized and the HLA restriction was established within 48 to 72 h of receipt of blood. This simple and convenient approach should prove useful especially in the characterization of CTL responses specific to HIV and other viruses, particularly in localities where performing cytotoxicity assays would be problematic.

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 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 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 Positive and Negative Aspects of the Human Immunodeficiency Virus Protease: Development of Inhibitors versus Its Role in AIDS Pathogenesis

2000 ◽  
Vol 64 (4) ◽  
pp. 725-745 ◽  
Author(s):  
Kazuyoshi Ikuta ◽  
Satoko Suzuki ◽  
Haruko Horikoshi ◽  
Tetsu Mukai ◽  
Ronald B. Luftig
Keyword(s):  
Human Immunodeficiency Virus ◽  
Vaccine Development ◽  
Hiv Treatment ◽  
Hiv Protease ◽  
Status Report ◽  
Hiv Therapy ◽  
Highly Active ◽  
Introductory Overview ◽  
Immunodeficiency Virus

SUMMARY In this review we summarize multiple aspects of the human immunodeficiency virus (HIV) protease from both structural and functional viewpoints. After an introductory overview, we provide an up-to-date status report on protease inhibitors (PI). This proceeds from a discussion of PI structural design, to how PI are optimally utilized in highly active antiretroviral triple therapy (one PI along with two reverse transcriptase inhibitors), the emergence of PI resistance, and the natural role of secretory leukocyte PI. Then we switch to another focus: the interaction of HIV protease with other genes in acute and persistent infection, which in turn may have an effect on AIDS pathogenesis. We conclude with a discussion on future directions in HIV treatment, involving multiple-target anti-HIV therapy, vaccine development, and novel reactivation-inhibitory reagents.

scholarly journals Kinetics of Virus-Specific CD8+ T Cells and the Control of Human Immunodeficiency Virus Infection

2004 ◽  
Vol 78 (18) ◽  
pp. 10096-10103 ◽  
Author(s):  
Miles P. Davenport ◽  
Ruy M. Ribeiro ◽  
Alan S. Perelson
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Virus Infection ◽  
Human Immunodeficiency Virus Infection ◽  
Viral Replication ◽  
Cytotoxic T Lymphocyte ◽  
Viral Kinetics ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Kinetics Of

ABSTRACT Several primate models indicate that cytotoxic T lymphocyte-inducing vaccines may be unable to prevent human immunodeficiency virus infection but may have a long-term benefit in controlling viral replication and delaying disease progression. Here we show that analysis of the kinetics of antigen-specific CD8+ T-cell expansion suggests a delay in activation following infection that allows unimpeded early viral replication. Viral kinetics do not differ between controls and vaccinees during this delay phase. An increase in virus-specific CD8+ T-cell numbers around day 10 postinfection coincides with a slowing in viral replication in vaccinees and reduces peak viral loads by around 1 log. However, this response is too little too late to prevent establishment of persistent infection.

scholarly journals Control of Human Immunodeficiency Virus Type 1 Is Associated with HLA-B*13 and Targeting of Multiple Gag-Specific CD8+ T-Cell Epitopes

2007 ◽  
Vol 81 (7) ◽  
pp. 3667-3672 ◽  
Author(s):  
Isobella Honeyborne ◽  
Andrew Prendergast ◽  
Florencia Pereyra ◽  
Alasdair Leslie ◽  
Hayley Crawford ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
T Cell Epitopes ◽  
Immunodeficiency Virus

ABSTRACT To better understand relationships between CD8+ T-cell specificity and the immune control of human immunodeficiency virus type 1 (HIV-1), we analyzed the role of HLA-B*13, an allele associated with low viremia, in a cohort of 578 C clade-infected individuals in Durban, South Africa. Six novel B*13-restricted cytotoxic T lymphocyte epitopes were defined from analyses of 37 B*13-positive subjects, including three Gag epitopes. These B*13-restricted epitopes contribute to a broad Gag-specific CD8+ response that is associated with the control of viremia. These data are consistent with data from studies of other HLA-class I alleles associated with HIV control that have shown that the targeting of multiple Gag epitopes is associated with relative suppression of viremia.

scholarly journals Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703–positive individuals and their transmission recipients

2009 ◽  
Vol 206 (4) ◽  
pp. 909-921 ◽  
Author(s):  
Hayley Crawford ◽  
Wendy Lumm ◽  
Alasdair Leslie ◽  
Malinda Schaefer ◽  
Debrah Boeras ◽  
...  
Keyword(s):  
Viral Load ◽  
Hiv Replication ◽  
Rapid Disease Progression ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Ctl Responses

HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade–infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703–restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703–restricted CTL responses. In HLA-B*5703–mismatched recipients, the previously described early benefit of transmitted HLA-B*5703–associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.

Role of the General Pediatrician in the Management of Human Immunodeficiency Virus Infection in Children

1993 ◽  
Vol 14 (10) ◽  
pp. 371-379
Author(s):  
Thomas H. Rand ◽  
Alan Meyers
Keyword(s):  
Human Immunodeficiency Virus ◽  
Hiv Infection ◽  
The United States ◽  
Care Physician ◽  
Pediatric Hiv ◽  
Delivery Of Care ◽  
Advanced Immunodeficiency ◽  
Immunodeficiency Virus ◽  
Chronic Progressive Disease

Human immunodeficiency virus (HIV) infection is a chronic progressive disease affecting an estimated 20 000 children in the United States. Management of this infection and its complications is evolving rapidly and requires the coordinated services of a number of disciplines, which may be facilitated by centers having programs in pediatric HIV infection. However, much of the care for an HIV-infected child can be supervised by a primary care physician, particularly during the early phase of infection, when anticipatory health monitoring is emphasized. Many pediatricians have had no experience with HIV infection during residency training, and those who have may have cared only for inpatients who had advanced immunodeficiency. The trend in medical care for HIV infection is toward early detection and management, as in other chronic diseases of childhood. This review summarizes those aspects of HIV infection most likely to be encountered in general pediatric practice. There are several distinct problems in the delivery of care for infants and children who are infected with HIV: 1) At this time, HIV infection is a progressive, ultimately fatal disease. Interventions are directed at preserving function and quality of life. 2) HIV is an infectious disease. Preventing transmission should be addressed at every opportunity, both to point out activities having potential for transmission and to reassure families of the safety of other types of contact.

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