HIV-1-Specific Cytotoxic T Lymphocyte (CTL) Responses Against Immunodominant Optimal Epitopes Slow the Progression of AIDS in China

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T-lymphocyte (CTL) responses play a major role in the antiviral immune response, but the relative contribution of CTL responses restricted by different HLA class I molecules is less well defined. HLA-B60 or the related allele B61 is expressed in 10 to 20% of Caucasoid populations and is even more highly prevalent in Asian populations, but yet no CTL epitopes restricted by these alleles have been defined. Here we report the definition of five novel HLA-B60-restricted HIV-1-specific CTL epitopes, using peripheral blood mononuclear cells in enzyme-linked immunospot (Elispot) assays and using CTL clones and lines in cytolytic assays. The dominant HLA-B60-restricted epitope, Nef peptide KEKGGLEGL, was targeted by all eight subjects with B60 and also by both subjects with B61 studied. This study additionally establishes the utility of the Elispot assay as a more rapid and efficient method of defining novel CTL epitopes. This approach will help to define new CTL epitopes that may play an important role in the immune control of HIV-1.

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Elicitation of High-Frequency Cytotoxic T-Lymphocyte Responses against both Dominant and Subdominant Simian-Human Immunodeficiency Virus Epitopes by DNA Vaccination of Rhesus Monkeys

Journal of Virology ◽

10.1128/jvi.75.5.2462-2467.2001 ◽

2001 ◽

Vol 75 (5) ◽

pp. 2462-2467 ◽

Cited By ~ 65

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.

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Cytotoxic T-Lymphocyte (CTL) Responses Directed against Regulatory and Accessory Proteins in HIV-1 Infection

DNA and Cell Biology ◽

10.1089/104454902760330219 ◽

2002 ◽

Vol 21 (9) ◽

pp. 671-678 ◽

Cited By ~ 38

Author(s):

M.M. Addo ◽

X.G. Yu ◽

E.S. Rosenberg ◽

B.D. Walker ◽

M. Altfeld

Keyword(s):

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Accessory Proteins ◽

Hiv 1 ◽

Ctl Responses

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Immune Screening Identifies Novel T Cell Targets Encoded by Antisense Reading Frames of HIV-1

Journal of Virology ◽

10.1128/jvi.03435-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 4015-4019 ◽

Cited By ~ 12

Author(s):

Christoph T. Berger ◽

Anuska Llano ◽

Jonathan M. Carlson ◽

Zabrina L. Brumme ◽

Mark A. Brockman ◽

...

Keyword(s):

T Cell ◽

T Lymphocyte ◽

Cellular Immunity ◽

Cytotoxic T Lymphocyte ◽

Sequence Alignments ◽

Computational Approaches ◽

Anti Hiv ◽

Reading Frames ◽

Hiv 1 ◽

Ctl Responses

Cytotoxic-T lymphocyte (CTL) responses to epitopes in alternative HIV reading frames have been reported. However, the extent of CTL responses to putative proteins encoded in antisense reading frames is unknown. Using sequence alignments and computational approaches, we here predict five potential antisense HIV proteins and characterize common CTL responses against them. Results suggest that antisense-derived sequences are commonly transcribed and translated and could encode functional proteins that contain important targets of anti-HIV cellular immunity.

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Magnitude and Frequency of Cytotoxic T-Lymphocyte Responses: Identification of Immunodominant Regions of Human Immunodeficiency Virus Type 1 Subtype C

Journal of Virology ◽

10.1128/jvi.76.20.10155-10168.2002 ◽

2002 ◽

Vol 76 (20) ◽

pp. 10155-10168 ◽

Cited By ~ 83

Author(s):

V. Novitsky ◽

H. Cao ◽

N. Rybak ◽

P. Gilbert ◽

M. F. McLane ◽

...

Keyword(s):

Immune Responses ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Population Level ◽

Hiv Vaccine ◽

Subtype C ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT A systematic analysis of immune responses on a population level is critical for a human immunodeficiency virus type 1 (HIV-1) vaccine design. Our studies in Botswana on (i) molecular analysis of the HIV-1 subtype C (HIV-1C) epidemic, (ii) frequencies of major histocompatibility complex class I HLA types, and (iii) cytotoxic T-lymphocyte (CTL) responses in the course of natural infection allowed us to address HIV-1C-specific immune responses on a population level. We analyzed the magnitude and frequency of the gamma interferon ELISPOT-based CTL responses and translated them into normalized cumulative CTL responses. The introduction of population-based cumulative CTL responses reflected both (i) essentials of the predominant virus circulating locally in Botswana and (ii) specificities of the genetic background of the Botswana population, and it allowed the identification of immunodominant regions across the entire HIV-1C. The most robust and vigorous immune responses were found within the HIV-1C proteins Gag p24, Vpr, Tat, and Nef. In addition, moderately strong responses were scattered across Gag p24, Pol reverse transcriptase and integrase, Vif, Tat, Env gp120 and gp41, and Nef. Assuming that at least some of the immune responses are protective, these identified immunodominant regions could be utilized in designing an HIV vaccine candidate for the population of southern Africa. Targeting multiple immunodominant regions should improve the overall vaccine immunogenicity in the local population and minimize viral escape from immune recognition. Furthermore, the analysis of HIV-1C-specific immune responses on a population level represents a comprehensive systematic approach in HIV vaccine design and should be considered for other HIV-1 subtypes and/or different geographic areas.

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Identification of Novel HLA-A2-Restricted Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Epitopes Predicted by the HLA-A2 Supertype Peptide-Binding Motif

Journal of Virology ◽

10.1128/jvi.75.3.1301-1311.2001 ◽

2001 ◽

Vol 75 (3) ◽

pp. 1301-1311 ◽

Cited By ~ 67

Author(s):

Marcus A. Altfeld ◽

Brian Livingston ◽

Neha Reshamwala ◽

Phuong T. Nguyen ◽

Marylyn M. Addo ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

The Novel ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT Virus-specific cytotoxic T-lymphocyte (CTL) responses are critical in the control of human immunodeficiency virus type 1 (HIV-1) infection and will play an important part in therapeutic and prophylactic HIV-1 vaccines. The identification of virus-specific epitopes that are efficiently recognized by CTL is the first step in the development of future vaccines. Here we describe the immunological characterization of a number of novel HIV-1-specific, HLA-A2-restricted CTL epitopes that share a high degree of conservation within HIV-1 and a strong binding to different alleles of the HLA-A2 superfamily. These novel epitopes include the first reported CTL epitope in the Vpr protein. Two of the novel epitopes were immunodominant among the HLA-A2-restricted CTL responses of individuals with acute and chronic HIV-1 infection. The novel CTL epitopes identified here should be included in future vaccines designed to induce HIV-1-specific CTL responses restricted by the HLA-A2 superfamily and will be important to assess in immunogenicity studies in infected persons and in uninfected recipients of candidate HIV-1 vaccines.

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Control of HIV-1 Pathogenesis in Viremic Nonprogressors Is Independent of Gag-Specific Cytotoxic T Lymphocyte Responses

Journal of Virology ◽

10.1128/jvi.00346-18 ◽

2018 ◽

Vol 92 (12) ◽

Cited By ~ 3

Author(s):

Maria Salgado ◽

Albert Garcia-Minambres ◽

Judith Dalmau ◽

Esther Jiménez-Moyano ◽

Pompeyo Viciana ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Hiv Infection ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Viral Pathogenesis ◽

Elite Controllers ◽

Cell Counts ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT Viremic nonprogressors (VNPs) constitute a very scarce group of untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain stable CD4 + T cell counts despite high levels of HIV-1 replication. The specific factors associated with this atypical control of the HIV infection have been poorly described. Since specific T cell responses seem to be one of the main causes of HIV-1 control in elite controllers, we studied whether HIV-1 Gag-specific cytotoxic T lymphocyte (CTL) responses could also modulate disease control in VNPs. We characterized the immune responses from four VNPs compared to those of five standard progressors (SPs) during the first years of HIV-1 infection. We observed no differences in the breadth and frequency of Gag-specific cellular responses. Furthermore, we obtained 217 HIV-1 Gag clonal sequences in which the viral variability of Gag increased over 3 years of infection for synonymous and nonsynonymous mutations in both VNPs and SPs. VNPs evolution rates in gag were comparable to SPs. This observation is in line with a similar accumulation of CTL putative escape mutations in Gag epitopes targeted by CTL responses. Altogether, the absence of viral pathogenesis in VNP individuals seems to be independent of HIV-Gag-specific CTL responses. This novel information guides to the study of alternative mechanism of HIV-1 pathogenesis control. IMPORTANCE Control of HIV infection has been widely studied in elite controllers or long-term nonprogressor models. However, there is a less-known group of individuals, termed viremic nonprogressors (VNPs), who maintain stable CD4 + T cell counts despite high plasma viremia. The mechanisms involved in this remarkable control of HIV-1 pathogenesis clearly have implications for the development of new drugs and vaccines. We show here for the first time that VNPs have immune responses and HIV-gag evolution similar to those of standard progressors. Remarkably, we demonstrate that the mechanism of pathogenesis control in these individuals differs from some elite controllers that are reported to have improved immune control. This is noteworthy since it opens the door to new, as-yet-unknown mechanisms for HIV control. Our novel results advance the understanding of mechanisms involved in viremic nonprogression and suggest that there are alternative mechanisms to the adaptive immune responses for an effective control of viral pathogenesis.

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Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design

Journal of Virology ◽

10.1128/jvi.75.19.9210-9228.2001 ◽

2001 ◽

Vol 75 (19) ◽

pp. 9210-9228 ◽

Cited By ~ 77

Author(s):

V. Novitsky ◽

N. Rybak ◽

M. F. McLane ◽

P. Gilbert ◽

P. Chigwedere ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Subtype C ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT The most severe human immunodeficiency virus type 1 (HIV-1) epidemic is occurring in southern Africa. It is caused by HIV-1 subtype C (HIV-1C). In this study we present the identification and analysis of cumulative cytotoxic T-lymphocyte (CTL) responses in the southern African country of Botswana. CTLs were shown to be an important component of the immune response to control HIV-1 infection. The definition of optimal and dominant epitopes across the HIV-1C genome that are targeted by CTL is critical for vaccine design. The characteristics of the predominant virus that causes the HIV-1 epidemic in a certain geographic area and also the genetic background of the population, through the distribution of common HLA class I alleles, might impact dominant CTL responses in the vaccinee and in the general population. The enzyme-linked immunospot (Elispot) gamma interferon assay has recently been shown to be a reliable tool to map optimal CTL epitopes, correlating well with other methods, such as intracellular staining, tetramer staining, and the classical chromium release assay. Using Elispot with overlapping synthetic peptides across Gag, Tat, Rev, and Nef, we analyzed HIV-1C-specific CTL responses of HIV-1-infected blood donors. Profiles of cumulative Elispot-based CTL responses combined with diversity and sequence consensus data provide an additional characterization of immunodominant regions across the HIV-1C genome. Results of the study suggest that the construction of a poly-epitope subtype-specific HIV-1 vaccine that includes multiple copies of immunodominant CTL epitopes across the viral genome, derived from predominant HIV-1 viruses, might be a logical approach to the design of a vaccine against AIDS.

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Cross-Reactivity against Multiple HIV-1 Epitopes Is Characteristic of HIV-1-Specific Cytotoxic T Lymphocyte Clones

Journal of Virology ◽

10.1128/jvi.00617-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 2

Author(s):

Arumugam Balamurugan ◽

Hwee L. Ng ◽

Otto O. Yang

Keyword(s):

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Cross Reactivity ◽

Type I ◽

Mhc I ◽

Infected Cells ◽

High Concentrations ◽

High Level ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT Although a high level of promiscuity for heterologous epitopes is believed to exist for cellular immunity, limited data explore this issue for human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T lymphocyte (CTL) responses. Here, we found an unexpected degree of heterologous cross-reactivity against HIV-1 epitopes, in addition to the targeted index epitope. Most CTL clones screened cross-reacted against other known HIV-1 epitopes of the same major histocompatibility complex type I (MHC-I) restriction, up to 40% of tested nonindex epitopes in some cases. The observed cross-reactivity was universally lower avidity than recognition of the index epitope when examined for several A*02- and B*57-restricted CTL clones, demonstrating that the high concentrations of exogenous epitope typically used for screening of CTL responses are prone to detect such cross-reactivity spuriously. In agreement with this, we found that these cross-reactive responses do not appear to mediate CTL activity against HIV-1-infected cells. Overall, our data indicate that low-level cross-reactivity is remarkably common for HIV-1-specific CTLs. The role of this phenomenon is unclear, but low-avidity interactions have been shown to foster homeostatic proliferation of memory T cells. IMPORTANCE This study raises two issues related to HIV-1-specific CTL responses. These are key immune responses that retard disease progression in infected persons that are highly relevant to immunotherapies and vaccines for HIV-1. First, we make the novel observation that these responses are promiscuous and that CTLs targeting one epitope may cross-recognize other, completely distinct epitopes in the virus. While these are low-avidity interactions that do not appear to contribute directly to the antiviral activity of CTLs, this raises interesting biologic implications regarding the purpose of the phenomenon, such as providing a stimulus for these responses to persist long term. Second, the data raise a technical caveat to detection of CTL responses against particular epitopes, suggesting that some methodologies may unintentionally detect cross-reactivity and overestimate responses against an epitope.

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