scholarly journals Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load

2003 ◽  
Vol 77 (3) ◽  
pp. 2081-2092 ◽  
Author(s):  
M. M. Addo ◽  
X. G. Yu ◽  
A. Rathod ◽  
D. Cohen ◽  
R. L. Eldridge ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Protein Subunits ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Total Magnitude ◽  
Cellular Immune ◽  
Hiv 1

ABSTRACT Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/106 PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

scholarly journals Hierarchical Targeting of Subtype C Human Immunodeficiency Virus Type 1 Proteins by CD8+ T Cells: Correlation with Viral Load

2004 ◽  
Vol 78 (7) ◽  
pp. 3233-3243 ◽  
Author(s):  
Agatha Masemola ◽  
Tumelo Mashishi ◽  
Greg Khoury ◽  
Phineas Mohube ◽  
Pauline Mokgotho ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
T Cell ◽  
T Cell Responses ◽  
Subtype C ◽  
Viral Control ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.

scholarly journals Differential CD4+ versus CD8+ T-Cell Responses Elicited by Different Poxvirus-Based Human Immunodeficiency Virus Type 1 Vaccine Candidates Provide Comparable Efficacies in Primates

2008 ◽  
Vol 82 (6) ◽  
pp. 2975-2988 ◽  
Author(s):  
Petra Mooij ◽  
Sunita S. Balla-Jhagjhoorsingh ◽  
Gerrit Koopman ◽  
Niels Beenhakker ◽  
Patricia van Haaften ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
T Cell Responses ◽  
Vaccine Candidates ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Poxvirus vectors have proven to be highly effective for boosting immune responses in diverse vaccine settings. Recent reports reveal marked differences in the gene expression of human dendritic cells infected with two leading poxvirus-based human immunodeficiency virus (HIV) vaccine candidates, New York vaccinia virus (NYVAC) and modified vaccinia virus Ankara (MVA). To understand how complex genomic changes in these two vaccine vectors translate into antigen-specific systemic immune responses, we undertook a head-to-head vaccine immunogenicity and efficacy study in the pathogenic HIV type 1 (HIV-1) model of AIDS in Indian rhesus macaques. Differences in the immune responses in outbred animals were not distinguished by enzyme-linked immunospot assays, but differences were distinguished by multiparameter fluorescence-activated cell sorter analysis, revealing a difference between the number of animals with both CD4+ and CD8+ T-cell responses to vaccine inserts (MVA) and those that elicit a dominant CD4+ T-cell response (NYVAC). Remarkably, vector-induced differences in CD4+/CD8+ T-cell immune responses persisted for more than a year after challenge and even accompanied antigenic modulation throughout the control of chronic infection. Importantly, strong preexposure HIV-1/simian immunodeficiency virus-specific CD4+ T-cell responses did not prove deleterious with respect to accelerated disease progression. In contrast, in this setting, animals with strong vaccine-induced polyfunctional CD4+ T-cell responses showed efficacies similar to those with stronger CD8+ T-cell responses.

scholarly journals Magnitude of Functional CD8+ T-Cell Responses to the Gag Protein of Human Immunodeficiency Virus Type 1 Correlates Inversely with Viral Load in Plasma

2002 ◽  
Vol 76 (5) ◽  
pp. 2298-2305 ◽  
Author(s):  
Bradley H. Edwards ◽  
Anju Bansal ◽  
Steffanie Sabbaj ◽  
Janna Bakari ◽  
Mark J. Mulligan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
T Cell ◽  
Disease Progression ◽  
T Cell Responses ◽  
Cell Responses ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The importance of CD8+ T-cell responses in the control of human immunodeficiency virus type 1 (HIV-1) infection has been demonstrated, yet few studies have been able to correlate these responses with markers of HIV-1 disease progression. This study measured cell-mediated immune responses using peripheral blood mononuclear cells (PBMC) obtained from 27 patients with chronic HIV-1 infection, the majority of whom were off antiretroviral therapy. The ELISPOT assay was used to detect gamma interferon-secreting PBMC after stimulation with overlapping HIV-1 peptides spanning the Gag, Pol, Env, and Nef proteins in addition to the baculovirus-derived p24 and gp160 proteins. All volunteers had responses to at least one HIV-1-specific peptide. All but one of the subjects (96%) responded to the Gag peptide pool, and 86% responded to the Pol and/or Nef peptide pools. The magnitude and the breadth of T-cell responses directed to either the Gag or p24 peptide pools correlated inversely with viral load in plasma (r = −0.60, P < 0.001 and r = −0.52, P < 0.005, respectively) and directly with absolute CD4+ T-cell counts (r = 0.54, P < 0.01 and r = 0.39, P < 0.05, respectively) using the Spearman rank correlation test. Responses to the Pol and integrase peptide pools also correlated with absolute CD4+ T-cell counts (r = 0.45, P < 0.05 and r = 0.49, P < 0.01, respectively). No correlation with markers of disease progression was seen with specific T-cell responses directed toward the Env or Nef peptides. These data serve as strong evidence that major histocompatibility complex class I presentation of Gag peptides is an essential feature for any HIV-1 vaccine designed to elicit optimal CD8+ T-cell responses.

scholarly journals Comparative Immunogenicity in Rhesus Monkeys of DNA Plasmid, Recombinant Vaccinia Virus, and Replication-Defective Adenovirus Vectors Expressing a Human Immunodeficiency Virus Type 1 gag Gene

2003 ◽  
Vol 77 (11) ◽  
pp. 6305-6313 ◽  
Author(s):  
Danilo R. Casimiro ◽  
Ling Chen ◽  
Tong-Ming Fu ◽  
Robert K. Evans ◽  
Michael J. Caulfield ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Rhesus Monkeys ◽  
Adenovirus Vector ◽  
T Cell Responses ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Replication Defective Adenovirus

ABSTRACT Cellular immune responses, particularly those associated with CD3+ CD8+ cytotoxic T lymphocytes (CTL), play a primary role in controlling viral infection, including persistent infection with human immunodeficiency virus type 1 (HIV-1). Accordingly, recent HIV-1 vaccine research efforts have focused on establishing the optimal means of eliciting such antiviral CTL immune responses. We evaluated several DNA vaccine formulations, a modified vaccinia virus Ankara vector, and a replication-defective adenovirus serotype 5 (Ad5) vector, each expressing the same codon-optimized HIV-1 gag gene for immunogenicity in rhesus monkeys. The DNA vaccines were formulated with and without one of two chemical adjuvants (aluminum phosphate and CRL1005). The Ad5-gag vector was the most effective in eliciting anti-Gag CTL. The vaccine produced both CD4+ and CD8+ T-cell responses, with the latter consistently being the dominant component. To determine the effect of existing antiadenovirus immunity on Ad5-gag-induced immune responses, monkeys were exposed to adenovirus subtype 5 that did not encode antigen prior to immunization with Ad5-gag. The resulting anti-Gag T-cell responses were attenuated but not abolished. Regimens that involved priming with different DNA vaccine formulations followed by boosting with the adenovirus vector were also compared. Of the formulations tested, the DNA-CRL1005 vaccine primed T-cell responses most effectively and provided the best overall immune responses after boosting with Ad5-gag. These results are suggestive of an immunization strategy for humans that are centered on use of the adenovirus vector and in which existing adenovirus immunity may be overcome by combined immunization with adjuvanted DNA and adenovirus vector boosting.

scholarly journals Long-Term Specific Immune Responses Induced in Humans by a Human Immunodeficiency Virus Type 1 Lipopeptide Vaccine: Characterization of CD8+-T-Cell Epitopes Recognized

2003 ◽  
Vol 77 (20) ◽  
pp. 11220-11231 ◽  
Author(s):  
Hanne Gahéry-Ségard ◽  
Gilles Pialoux ◽  
Suzanne Figueiredo ◽  
Céline Igéa ◽  
Mathieu Surenaud ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We studied the effect of booster injections and the long-term immune response after injections of an anti-human immunodeficiency virus type 1 (HIV-1) lipopeptide vaccine. This vaccine was injected alone or with QS21 adjuvant to 28 HIV-uninfected volunteers. One month later, after a fourth injection of the vaccine, B- and T-cell anti-HIV responses were detected in >85% of the vaccinated volunteers. One year after this injection, a long-term immune response was observed in >50% of the volunteers. At this point, a positive QS21 effect was observed only in the sustained B-cell and CD4+-T-cell responses. To better characterize the CD8+-T-cell response, we used a gamma interferon enzyme-linked immunospot method and a bank of 59 HIV-1 epitopes. For the six most common HLA molecules (HLA-A2, -A3, -A11, -A24, -B7 superfamily, and -B8), an average of 10 (range, 3 to 15) HIV-1 epitopes were tested. CD8+-T-cell responses were evaluated according to the HLA class I molecules of the volunteers. Each assessment was based on 18 HIV-1 epitopes in average. We showed that 31 HIV-1 epitopes elicited specific CD8+-T-cell responses after vaccination. The most frequently recognized peptides were Nef 68-76 (-B7), Nef 71-79 (-B7), Nef 84-92 (-A11), Nef 135-143 (-B7), Nef 136-145 (-A2), Nef 137-145 (-A2), Gag 259-267 (-B8), Gag 260-268 (-A2), Gag 267-274 (-A2), Gag 267-277 (-B7), and Gag 276-283 (A24). We found that CD8+-T-cell epitopes were induced at a higher number after a fourth injection (P < 0.05 compared to three injections), which indicates an increase in the breadth of HIV CD8+-T-cell epitope recognition after the boost.

scholarly journals Impaired Quality of the Hepatitis B Virus (HBV)-Specific T-Cell Response in Human Immunodeficiency Virus Type 1-HBV Coinfection

2009 ◽  
Vol 83 (15) ◽  
pp. 7649-7658 ◽  
Author(s):  
J. Judy Chang ◽  
Sunee Sirivichayakul ◽  
Anchalee Avihingsanon ◽  
Alex J. V. Thompson ◽  
Peter Revill ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Hepatits B virus (HBV)-specific T cells play a key role both in the control of HBV replication and in the pathogenesis of liver disease. Human immunodeficiency virus type 1 (HIV-1) coinfection and the presence or absence of HBV e (precore) antigen (HBeAg) significantly alter the natural history of chronic HBV infection. We examined the HBV-specific T-cell responses in treatment-naïve HBeAg-positive and HBeAg-negative HIV-1-HBV-coinfected (n = 24) and HBV-monoinfected (n = 39) Asian patients. Peripheral blood was stimulated with an overlapping peptide library for the whole HBV genome, and tumor necrosis factor alpha and gamma interferon cytokine expression in CD8+ T cells was measured by intracellular cytokine staining and flow cytometry. There was no difference in the overall magnitude of the HBV-specific T-cell responses, but the quality of the response was significantly impaired in HIV-1-HBV-coinfected patients compared with monoinfected patients. In coinfected patients, HBV-specific T cells rarely produced more than one cytokine and responded to fewer HBV proteins than in monoinfected patients. Overall, the frequency and quality of the HBV-specific T-cell responses increased with a higher CD4+ T-cell count (P = 0.018 and 0.032, respectively). There was no relationship between circulating HBV-specific T cells and liver damage as measured by activity and fibrosis scores, and the HBV-specific T-cell responses were not significantly different in patients with either HBeAg-positive or HBeAg-negative disease. The quality of the HBV-specific T-cell response is impaired in the setting of HIV-1-HBV coinfection and is related to the CD4+ T-cell count.

scholarly journals Magnitude and Quality of Vaccine-Elicited T-Cell Responses in the Control of Immunodeficiency Virus Replication in Rhesus Monkeys

2008 ◽  
Vol 82 (17) ◽  
pp. 8812-8819 ◽  
Author(s):  
Yue Sun ◽  
Sampa Santra ◽  
Jörn E. Schmitz ◽  
Mario Roederer ◽  
Norman L. Letvin
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Rhesus Monkeys ◽  
T Cell Responses ◽  
Viral Control ◽  
Cell Responses ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Functional Profiles

ABSTRACT While a diversity of immunogens that elicit qualitatively different cellular immune responses are being assessed in clinical human immunodeficiency virus vaccine trials, the consequences of those varied responses for viral control remain poorly understood. In the present study, we evaluated the induction of virus-specific T-cell responses in rhesus monkeys using a series of diverse vaccine vectors. We assessed both the magnitude and the functional profile of the virus-specific CD8+ T cells by measuring gamma interferon, interleukin-2, and tumor necrosis factor alpha production. We found that the different vectors generated virus-specific T-cell responses of different magnitudes and with different functional profiles. Heterologous prime-boost vaccine regimens induced particularly high-frequency virus-specific T-cell responses with polyfunctional repertoires. Yet, immediately after a pathogenic simian-human immunodeficiency virus (SHIV) challenge, no significant differences were observed between these cohorts of vaccinated monkeys in the magnitudes or the functional profiles of their virus-specific CD8+ T cells. This finding suggests that the high viral load shapes the functional repertoire of the cellular immune response during primary infection. Nevertheless, in all vaccination regimens, higher frequency and more polyfunctional vaccine-elicited virus-specific CD8+ T-cell responses were associated with better viral control after SHIV challenge. These observations highlight the contributions of both the quality and the magnitude of vaccine-elicited cellular immune responses in the control of immunodeficiency virus replication.

scholarly journals Induction of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses in HIV Vaccine Trial Participants Who Subsequently Acquire HIV-1 Infection

2006 ◽  
Vol 80 (19) ◽  
pp. 9779-9788 ◽  
Author(s):  
Helen Horton ◽  
Colin Havenar-Daughton ◽  
Deborah Lee ◽  
Erin Moore ◽  
Jianhong Cao ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Responses ◽  
Cell Immunity ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Hiv 1

ABSTRACT Candidate human immunodeficiency virus type 1 (HIV-1) vaccines designed to elicit T-cell immunity in HIV-1-uninfected persons are under investigation in phase I to III clinical trials. Little is known about how these vaccines impact the immunologic response postinfection in persons who break through despite vaccination. Here, we describe the first comprehensive characterization of HIV-specific T-cell immunity in vaccine study participants following breakthrough HIV-1 infection in comparison to 16 nonvaccinated subjects with primary HIV-1 infection. Whereas none of the 16 breakthrough infections possessed vaccine-induced HIV-1-specific T-cell responses preinfection, 85% of vaccinees and 86% of nonvaccinees with primary HIV-1 infection developed HIV-specific T-cell responses postinfection. Breakthrough subjects' T cells recognized 43 unique HIV-1 T-cell epitopes, of which 8 are newly described, and 25% were present in the vaccine. The frequencies of gamma interferon (IFN-γ)-secreting cells recognizing epitopes within gene products that were and were not encoded by the vaccine were not different (P = 0.64), which suggests that responses were not anamnestic. Epitopes within Nef and Gag proteins were the most commonly recognized in both vaccinated and nonvaccinated infected subjects. One individual controlled viral replication without antiretroviral therapy and, notably, mounted a novel HIV-specific HLA-C14-restricted Gag LYNTVATL-specific T-cell response. Longitudinally, HIV-specific T cells in this individual were able to secrete IFN-γ and tumor necrosis factor alpha, as well as proliferate and degranulate in response to their cognate antigenic peptides up to 5 years postinfection. In conclusion, a vaccinee's ability to mount an HIV-specific T-cell response postinfection is not compromised by previous immunization, since the CD8+ T-cell responses postinfection are similar to those seen in vaccine-naïve individuals. Finding an individual who is controlling infection highlights the importance of comprehensive studies of breakthrough infections in vaccine trials to determine whether host genetics/immune responses and/or viral characteristics are responsible for controlling viral replication.

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.

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