scholarly journals Control of HIV-1 in Elite Suppressors despite Ongoing Replication and Evolution in Plasma Virus

2010 ◽  
Vol 84 (14) ◽  
pp. 7018-7028 ◽  
Author(s):  
Karen A. O'Connell ◽  
Timothy P. Brennan ◽  
Justin R. Bailey ◽  
Stuart C. Ray ◽  
Robert F. Siliciano ◽  
...  
Keyword(s):  
Selective Pressure ◽  
De Novo ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
Latent Reservoir ◽  
Elite Controllers ◽  
Plasma Virus ◽  
Longitudinal Plasma ◽  
Elite Suppressors ◽  
Hiv 1

ABSTRACT A subset of HIV-1-infected patients known as elite controllers or suppressors (ES) control the virus naturally. We have previously demonstrated sequence discordance between proviral and plasma gag clones in ES, much of which can be attributed to selective pressure from the host (J. R. Bailey, T. M. Williams, R. F. Siliciano, and J. N. Blankson, J. Exp. Med. 203:1357-1369, 2006). However, it is not clear whether ongoing viral replication continues in ES once the control of viremia has been established or whether selective pressure impacts this evolution. The cytotoxic T-lymphocyte (CTL) response in ES often targets Gag and frequently is superior to that of HIV-1 progressors, partially due to the HLA class I alleles B*57/5801 and B*27, which are overrepresented in ES. We therefore examined longitudinal plasma and proviral gag sequences from HLA-B*57/5801 and -B*27 ES. Despite the highly conserved nature of gag, we observed clear evidence of evolution in the plasma virus, largely due to synonymous substitutions. In contrast, evolution was rare in proviral clones, suggesting that ongoing replication in ES does not permit the significant reseeding of the latent reservoir. Interestingly, there was little continual evolution in CTL epitopes, and we detected de novo CTL responses to autologous viral mutants. Thus, some ES control viremia despite ongoing replication and evolution.

scholarly journals Maintenance of viral suppression in HIV-1–infected HLA-B*57+ elite suppressors despite CTL escape mutations

2006 ◽  
Vol 203 (5) ◽  
pp. 1357-1369 ◽  
Author(s):  
Justin R. Bailey ◽  
Thomas M. Williams ◽  
Robert F. Siliciano ◽  
Joel N. Blankson
Keyword(s):  
T Cell ◽  
Viral Suppression ◽  
Selective Pressure ◽  
De Novo ◽  
Interleukin 2 ◽  
Cd8 T Cell ◽  
Plasma Virus ◽  
Low Level ◽  
Ctl Escape ◽  
Elite Suppressors

Rare human immunodeficiency virus 1–infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57–restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57–restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon-γ responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57–restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.

scholarly journals Evidence of CD8+ T-Cell-Mediated Selective Pressure on Human Immunodeficiency Virus Type 1 nef in HLA-B*57+ Elite Suppressors

2008 ◽  
Vol 83 (1) ◽  
pp. 88-97 ◽  
Author(s):  
Justin R. Bailey ◽  
Timothy P. Brennan ◽  
Karen A. O'Connell ◽  
Robert F. Siliciano ◽  
Joel N. Blankson
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Selective Pressure ◽  
Plasma Virus ◽  
Viral Loads ◽  
Immunodeficiency Virus ◽  
Elite Suppressors ◽  
Hiv 1

ABSTRACT Elite suppressors (ES) are human immunodeficiency virus type 1 (HIV-1)-infected patients who maintain viral loads of <50 copies/ml without treatment. The observation that the HLA-B*57 allele is overrepresented in these patients implies that HIV-1-specific CD8+ T cells play a key role in suppressing viral replication. We have previously shown that while CD8+ T-cell escape mutations are rarely seen in proviral Gag sequences in resting CD4+ T cells from peripheral blood, they are present in every clone amplified from the low levels of free virus in the plasma of HLA-B*57+ ES. In this study, we compared the pattern of mutations in Nef sequences amplified from peripheral blood CD4+ T cells and from plasma virus. We show that Nef mutations are present in plasma virus but are rare in the cellular sequences and provide evidence that these plasma Nef variants represent novel escape mutants. The results provide further evidence of CD8+ T-cell-mediated selective pressure on plasma virus in ES and suggest that there must be ongoing HIV-1 replication in spite of the very low viral loads seen for these patients.

scholarly journals Identification of Dominant Optimal HLA-B60- and HLA-B61-Restricted Cytotoxic T-Lymphocyte (CTL) Epitopes: Rapid Characterization of CTL Responses by Enzyme-Linked Immunospot Assay

2000 ◽  
Vol 74 (18) ◽  
pp. 8541-8549 ◽  
Author(s):  
Marcus A. Altfeld ◽  
Alicja Trocha ◽  
Robert L. Eldridge ◽  
Eric S. Rosenberg ◽  
Mary N. Phillips ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
Peripheral Blood Mononuclear ◽  
Antiviral Immune Response ◽  
Ctl Epitopes ◽  
Hla Class I Molecules ◽  
Hiv 1 ◽  
Ctl Responses

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.

Minor contribution of HLA class I-associated selective pressure to the variability of HIV-1 accessory protein Vpu

2012 ◽  
Vol 421 (2) ◽  
pp. 291-295 ◽  
Author(s):  
Zafrul Hasan ◽  
Jonathan M. Carlson ◽  
Hiroyuki Gatanaga ◽  
Anh Q. Le ◽  
Chanson J. Brumme ◽  
...  
Keyword(s):  
Selective Pressure ◽  
Hla Class I ◽  
Class I ◽  
Accessory Protein ◽  
Minor Contribution ◽  
Hiv 1

scholarly journals Modest de novo Reactivation of Single HIV-1 Proviruses in Peripheral CD4+ T Cells by Romidepsin

2021 ◽  
Vol 1 ◽  
Author(s):  
Kathrine Kjær ◽  
Steffen Leth ◽  
Christina V. Konrad ◽  
Jesper D. Gunst ◽  
Rasmus Nymann ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
De Novo ◽  
Viral Rna ◽  
Viral Reservoir ◽  
Latent Reservoir ◽  
Host Immune System ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
Hiv 1

A cure for human immunodeficiency virus (HIV-1) is restricted by the continued presence of a latent reservoir of memory CD4+ T cells with proviruses integrated into their DNA despite suppressive antiretroviral therapy (ART). A predominant strategy currently pursued in HIV-1 cure-related research is the “kick and kill” approach, where latency reversal agents (LRAs) are used to reactivate transcription from integrated proviruses. The premise of this approach is that “kicking” latent virus out of hiding allows the host immune system to recognize and kill infected cells. Clinical trials investigating the efficacy of LRAs, such as romidepsin, have shown that these interventions do induce transient spikes in viral RNA in HIV-1-infected individuals. However, since these trials failed to significantly reduce viral reservoir size or significantly delay time to viral rebound during analytical treatment interruptions, it is questioned how much each individual latent provirus is actually “kicked” to produce viral transcripts and/or proteins by the LRA. Here, we developed sensitive and specific digital droplet PCR-based assays with single-provirus level resolution. Combining these assays allowed us to interrogate the level of viral RNA transcripts from single proviruses in individuals on suppressive ART with or without concomitant romidepsin treatment. Small numbers of proviruses in peripheral blood memory CD4+ T cells were triggered to become marginally transcriptionally active upon romidepsin treatment. These novel assays can be applied retrospectively and prospectively in HIV-1 cure-related clinical trials to gain crucial insights into LRA efficacy at the single provirus level.

scholarly journals A Novel Assay Allows Genotyping of the Latent Reservoir for Human Immunodeficiency Virus Type 1 in the Resting CD4+ T Cells of Viremic Patients

2005 ◽  
Vol 79 (8) ◽  
pp. 5185-5202 ◽  
Author(s):  
Daphne Monie ◽  
Rachel P. Simmons ◽  
Richard E. Nettles ◽  
Tara L. Kieffer ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Latent Reservoir ◽  
Drug Resistant ◽  
Plasma Virus ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A latent reservoir for human immunodeficiency virus type 1 (HIV-1) consisting of integrated provirus in resting memory CD4+ T cells prevents viral eradication in patients on highly active antiretroviral therapy (HAART). It is difficult to analyze the nature and dynamics of this reservoir in untreated patients and in patients failing therapy, because it is obscured by an excess of unintegrated viral DNA that constitutes the majority of viral species in resting CD4+ T cells from viremic patients. Therefore, we developed a novel culture assay that stimulates virus production from latent, integrated HIV-1 in resting CD4+ T cells in the presence of antiretroviral drugs that prevent the replication of unintegrated virus. Following activation, resting CD4+ T cells with integrated HIV-1 DNA produced virus particles for several days, with peak production at day 5. Using this assay, HIV-1 pol sequences from the resting CD4+ T cells of viremic patients were found to be genetically distinct from contemporaneous plasma virus. Despite the predominance of a relatively homogeneous population of drug-resistant viruses in the plasma of patients failing HAART, resting CD4+ T cells harbored a diverse array of wild-type and archival drug-resistant viruses that were less fit than plasma virus in the context of current therapy. These results provide the first direct evidence that resting CD4+ T cells serve as a stable reservoir for HIV-1 even in the setting of high levels of viremia. The ability to analyze archival species in viremic patients may have clinical utility in detecting drug-resistant variants not present in the plasma.

scholarly journals Effective Downregulation of HLA-A*2 and HLA-B*57 by Primary Human Immunodeficiency Virus Type 1 Isolates Cultured from Elite Suppressors

2009 ◽  
Vol 83 (13) ◽  
pp. 6941-6946 ◽  
Author(s):  
Eric Nou ◽  
Yan Zhou ◽  
Damaris D. Nou ◽  
Joel N. Blankson
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Hla Class I ◽  
Elite Controllers ◽  
Hla Class I Molecules ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Elite controllers or suppressors (ES) are human immunodeficiency virus type 1 (HIV-1)-infected patients who control viral replication to <50 copies/ml without antiretroviral therapy. Downregulation of HLA class I molecules is an important mechanism used by HIV-1 to evade the immune system. In this study, we showed that primary isolates from ES are as effective as isolates obtained from patients with progressive HIV-1 disease at downregulating HLA-A*2 and HLA-B*57 molecules on primary CD4+ T cells. Thus, a diminished ability of viral isolates from ES to evade HIV-specific immune responses probably does not contribute to the control of viral replication in these patients.

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.

scholarly journals HIV-1 Gag Cytotoxic T Lymphocyte Epitopes Vary in Presentation Kinetics Relative to HLA Class I Downregulation

2013 ◽  
Vol 87 (15) ◽  
pp. 8726-8734 ◽  
Author(s):  
A. Balamurugan ◽  
A. Ali ◽  
J. Boucau ◽  
S. Le Gall ◽  
H. L. Ng ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
Class I ◽  
Hiv 1
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