Quantitation of HIV-1-Specific Cytotoxic T Lymphocytes and Plasma Load of Viral RNA

Ogg, Graham S.; Jin, Xia; Bonhoeffer, Sebastian; Dunbar, P. Rod; Nowak, Martin A.; Monard, Simon; Segal, Jeremy P.; Cao, Yunzhen; Rowland‐Jones, Sarah; Cerundolo, Vincenzo; Hurley, Arlene; Markowitz, Martin; Ho, David D.; Nixon, Douglas F.; McMichael, Andrew J.

doi:10.1126/science.279.5359.2103

Cited by 1,304 publications

(950 citation statements)

References 29 publications

Supporting

Mentioning

870

Contrasting

Unclassified

Order By: Relevance

“…To address this question, the distribution of FIV proviral DNA was quanti®ed in the lymphoid tissues throughout the study and compared with the virusspeci®c cellular immune responses. By analogy with studies on virus kinetics following HIV-1 infection, the relatively high proviral burden maintained in the blood until the termination of the study was rather surprising, as it is recognised that HIV-1 proviral burdens are low in the blood of human patients during the asymptomatic phase of the disease (Ogg et al, 1998) with sequestration of HIV-1 to lymph nodes (Embretson et al, 1993;Pantaleo et al, 1993). Our ®ndings may re¯ect the intraperitoneal route of challenge used in this study, coupled with the use of a highly pathogenic isolate of FIV.…”

Section: Discussionmentioning

confidence: 99%

“…Human immunode®ciency virus (HIV)-1 infection is also characterised by the rapid development of virus-speci®c CTL and non-cytolytic CD8 T cell responses (Koup et al, 1994;Borrow et al, 1994;Mackewicz et al, 1994a,b;Levy et al, 1996). Epidemiological studies have highlighted the very signi®cant role that strong and persistent cell-mediated immune responses have in the control of retroviral replication and in the maintenance of the symptom-free state (Koup et al, 1994;Borrow et al, 1994;Rinaldo et al, 1995;Ogg et al, 1998;Paxton et al, 1996). These observations have resulted in attempts to modify the outcome of infection in human patients by the adoptive transfer of CD8 T cells of predetermined viral antigen speci®city (Koenig et al, 1995;Brodie et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Involvement of cytolytic and non-cytolytic T cells in the control of feline immunodeficiency virus infection

Flynn

Dunham

Mueller

et al. 2002

Veterinary Immunology and Immunopathology

View full text Add to dashboard Cite

The appearance of non-cytolytic T cells that suppressed feline immunode®ciency virus (FIV) replication in vitro, and FIV-speci®c cytotoxic T cell (CTL) responses was compared in a group of seven, speci®c pathogen free (SPF) domestic cats following primary infection with the Glasgow 8 isolate of FIV (FIV ). FIV proviral burdens were quanti®ed in the blood and lymphoid tissues by real-time PCR. Non-cytolytic T cell suppression of FIV replication was measured by co-cultivating lymphoblasts prepared from the cats at different time-points during infection with FIV-infected MYA-1 cells in vitro. Non-cytolytic suppressor activity was detected as early as 1 week after infection, and was evident in all the lymphoid tissues examined. Further, this activity was present in subpopulations of T cells in the blood with normal (CD8 hi ) or reduced (CD8 lo ) expression of the CD8 molecule, and temporal modulations in non-cytolytic suppressor activity were unrelated to the circulating CD8 T cell numbers. Virus-speci®c CTL responses, measured by 51 Cr release assays, were not detected until 4 weeks after infection, with the emergence of FIV-speci®c effector CTLs in the blood. Throughout infection the response was predominantly directed towards FIV Gag-expressing target cells, and by 47 weeks after infection CTL responses had become localised in the lymph nodes and spleen. The results suggest that both non-cytolytic T cell suppression of FIV replication and FIV-speci®c CTL responses are important cellular immune mechanisms in the control of FIV replication in infected asymptomatic cats. #

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Involvement of cytolytic and non-cytolytic T cells in the control of feline immunodeficiency virus infection

Flynn

Dunham

Mueller

et al. 2002

Veterinary Immunology and Immunopathology

View full text Add to dashboard Cite

show abstract

“…Identification and characterization of antigen-specific T lymphocytes during the course of an immune response was tedious and indirect until the advent in the application of recombinant MHC class I-peptide complexes and their tetrameric arrays, which enable the detection of rare populations of antigenspecific T cells [40,41]. Until recently, there was no tool that enabled phenotypic analysis of antigen (MHC-peptide) presentation, the other player in the cognate interaction between TCR and their ligands.…”

Section: Discussionmentioning

confidence: 99%

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

et al. 2008

View full text Add to dashboard Cite

MHC class I molecules are important components of immune surveillance. There are no available methods to directly visualize and determine the quantity and distribution of MHC/ peptide complexes on individual cells or to detect such complexes on antigen-presenting cells in tissues. MHC-restricted recombinant antibodies with the same specificity of T cell receptors (TCR) may become a valuable tool to address these questions. They may also serve as valuable targeting molecules that mimic the specificity of cytotoxic T cells. We isolated by phage display a panel of human recombinant Fab antibodies with peptidespecific, MHC-restricted TCR-like reactivity directed toward HLA-A2-restricted T cell epitopes derived from a novel antigen termed TCRc alternative reading frame protein (TARP) which is expressed on prostate and breast cancer cells. We have characterized one of these recombinant antibodies and demonstrated its capacity to directly detect specific HLA-A2/ TARP T cell epitopes on antigen-presenting cells that have complexes formed by naturally occurring active intracellular processing of the antigen, as well as on the surface of tumor cells. Moreover, by genetic fusion we armed the TCR-like antibody with a potent toxin and demonstrated that it can serve as a targeting moiety killing tumor cells in a peptide-specific, MHC-restricted manner similar to cytotoxic T lymphocytes. Key words: Immunotoxin Á MHC Á Recombinant antibody Á T-cell receptor IntroductionMost patients with metastatic prostate and breast cancers are provided with the limited benefits from standard chemo-and hormone-based therapies. During the recent years, much effort has been invested in developing new approaches, such as immunotherapy, to improve the therapeutic abilities, by combining the tumor specificity of cell-mediated immunity with the freedom from toxic chemotherapies.Recent immunotherapy approaches employ the principle that CD8 + CTL recognize and kill tumor cells that display peptides from tumor-associated antigens presented by MHC class I molecules. Several tumor antigens and HLA allele-specific peptides from prostate cancer-associated antigens have been identified as CD8 + T cell epitopes, including HLA-A2-binding peptides derived from prostate-specific antigen (PSA) [1,2], prostate-specific membrane antigen (PSMA) [3], prostate stem cell antigen (PSCA) [4,5], and prostate acid phosphatase 6, which are all now components of current vaccine trials [5][6][7][8][9][10][11].Identification of new tumor-specific antigens is an essential step for the successful development of immunotherapy ap- [12][13][14]. One of these, T cell receptor gamma alternate reading frame protein (TARP), is expressed on breast and prostate cancer cells [15,16]. It was shown that TARP was expressed on >90% of cancer specimens examined [9,15]. In order to define new breast and prostate CD8 + T cell tumor antigens, two wild-type HLA-A2 epitopes from TARP were identified [17]. The wild-type sequences were also improved by sequence modifications to produce epitopeenha...

show abstract

“…During primary infection in humans the reduction of the original viral burst is associated with the emergence of HIV-specific cytotoxic CD8 + T lymphocytes (CTL). 19 , 33 , 34 , 39–53 Their role in controlling viremia was confirmed by systemic CD8 depletion in SIV/SHIV infected macaques, which resulted in a rapid increase in viremia, 54–57 demonstrating a CD8-dependent immunological mechanisms of viral control. 58–67 Failure to contain viral replication in macaques correlated with the emergence of viral mutants that escaped from CTL immune surveillance.…”

Section: Introductionmentioning

confidence: 89%

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

Valentı́n

et al. 2018

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

HIV sequence diversity and the propensity of eliciting immunodominant responses targeting inessential variable regions are hurdles in the development of an effective AIDS vaccine. We developed a DNA vaccine comprising conserved elements (CE) of SIV p27Gag and HIV-1 Env and found that priming vaccination with CE DNA is critical to efficiently overcome the dominance imposed by Gag and Env variable regions. Here, we show that DNA vaccinated macaques receiving the CE prime/CE+full-length DNA co-delivery booster vaccine regimens developed broad, potent and durable cytotoxic T cell responses targeting conserved protein segments of SIV Gag and HIV Env. Gag CE-specific T cells showed robust anamnestic responses upon infection with SIVmac239 which led to the identification of CE-specific cytotoxic lymphocytes able to recognize epitopes covering distinct CE on the surface of SIV infected cells in vivo. Though not controlling infection overall, we found an inverse correlation between Gag CE-specific CD8+ T cell responses and peak viremia. The T cell responses induced by the HIV Env CE immunogen were recalled in some animals upon SIV infection, leading to the identification of two cross-reactive epitopes between HIV and SIV Env based in sequence homology. These data demonstrate that a vaccine combining Gag and Env CE DNA subverted the normal immunodominance patterns, eliciting immune responses that included subdominant, highly conserved epitopes. These vaccine regimens augment cytotoxic T cell responses to highly conserved epitopes in the viral proteome and maximize response breadth. The vaccine-induced CE-specific T cells were expanded upon SIV infection, indicating that the predicted CE epitopes incorporated in the DNA vaccine are processed and exposed by infected cells in their natural context within the viral proteome.

show abstract

Quantitation of HIV-1-Specific Cytotoxic T Lymphocytes and Plasma Load of Viral RNA

Cited by 1,304 publications

References 29 publications

Involvement of cytolytic and non-cytolytic T cells in the control of feline immunodeficiency virus infection

Involvement of cytolytic and non-cytolytic T cells in the control of feline immunodeficiency virus infection

Targeting TARP, a novel breast and prostate tumor‐associated antigen, with T cell receptor‐like human recombinant antibodies

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

Contact Info

Product

Resources

About