scholarly journals Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

2012 ◽  
Vol 86 (18) ◽  
pp. 9802-9816 ◽  
Author(s):  
Melissa M. Norström ◽  
Marcus Buggert ◽  
Johanna Tauriainen ◽  
Wendy Hartogensis ◽  
Mattia C. Prosperi ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
High Resolution ◽  
Disease Progression ◽  
T Cell Responses ◽  
Low Risk ◽  
Early Infection ◽  
Cell Responses ◽  
Cell Counts ◽  
Hiv 1

HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1in vivoevolution and epitope-specific CD8+T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.

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 Virus-Specific CD8+ T-Cell Responses Better Define HIV Disease Progression than HLA Genotype

2010 ◽  
Vol 84 (9) ◽  
pp. 4461-4468 ◽  
Author(s):  
Warren L. Dinges ◽  
Julia Richardt ◽  
David Friedrich ◽  
Emilie Jalbert ◽  
Yi Liu ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
T Cell Responses ◽  
T Cell Response ◽  
Rapid Progression ◽  
Cell Responses ◽  
Conserved Regions ◽  
Cell Counts ◽  
Hla Genotype ◽  
Hiv 1

ABSTRACT HLA alleles B57/58, B27, and B35 have the strongest genetic associations with HIV-1 disease progression. The mechanisms of these relationships may be host control of HIV-1 infection via CD8+ T-cell responses. We examined these immune responses in subjects from the Seattle Primary Infection Cohort with these alleles. CD8+ T-cell responses to conserved HIV epitopes within B57/58 alleles (TW10 and KF11) and B27 alleles (KK10 and FY10) delayed declines in CD4+ T-cell counts (4 to 8 times longer), while responses to variable epitopes presented by B35 alleles (DL9 and IL9) resulted in more rapid progression. The plasma viral load was higher in B57/58+ and B27+ subjects lacking the conserved B57/58- and B27-restricted responses. The presence of certain B57/58-, B27-, and B35-restricted HIV-specific CD8+ T-cell responses after primary HIV-1 infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8+ T cells and not the presence of a particular HLA allele that determine disease progression. Further, the most effective host CD8+ T-cell responses to HIV-1 were prevalent within an HLA allele, represented a high total allele fraction of the host CD8+ T-cell response, and targeted conserved regions of HIV-1. These data suggest that vaccine immunogens should contain only conserved regions of HIV-1.

scholarly journals Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression

2010 ◽  
Vol 84 (22) ◽  
pp. 12018-12029 ◽  
Author(s):  
Mandla Mlotshwa ◽  
Catherine Riou ◽  
Denis Chopera ◽  
Debra de Assis Rosa ◽  
Roman Ntale ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Temporal Patterns ◽  
Viral Escape ◽  
Subtype C ◽  
Cell Responses ◽  
Ifn Γ ◽  
Hiv 1

ABSTRACT Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-γ-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.

scholarly journals Higher Homologous and Lower Cross-Reactive Gag-Specific T-Cell Responses in Human Immunodeficiency Virus Type 2 (HIV-2) Than in HIV-1 Infection

2008 ◽  
Vol 82 (17) ◽  
pp. 8619-8628 ◽  
Author(s):  
Wim Jennes ◽  
Makhtar Camara ◽  
Tandakha Dièye ◽  
Souleymane Mboup ◽  
Luc Kestens
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
T Cell Responses ◽  
Cell Responses ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 2 (HIV-2) infection results in slower CD4+ T-cell decline, lower plasma viral load levels, and hence slower progression of the disease than does HIV-1 infection. Although the reasons for this are not clear, it is possible that HIV-2 replication is more effectively controlled by host responses. We used aligned pools of overlapping HIV-1 and HIV-2 Gag peptides in an enhanced gamma interferon enzyme-linked immunospot assay to compare the levels of homologous and cross-reactive Gag-specific T-cell responses between HIV-1- and HIV-2-infected patients. HIV-2-infected patients showed broader and stronger homologous Gag-specific T-cell responses than HIV-1-infected patients. In contrast, the cross-reactive T-cell responses in HIV-2-infected patients were both narrower and weaker than those in HIV-1-infected patients, in line with overall weaker correlations between homologous and heterologous T-cell responses among HIV-2-infected patients than among HIV-1-infected patients. Cross-reactive responses in HIV-2-infected patients tended to correlate directly with HIV-1/HIV-2 Gag sequence similarities; this was not found in HIV-1-infected patients. The CD4+ T-cell counts of HIV-2-infected patients correlated directly with homologous responses and inversely with cross-reactive responses; this was not found in HIV-1-infected patients. Our data support a model whereby high-level HIV-2-specific T-cell responses control the replication of HIV-2, thus limiting viral diversification and priming of HIV-1 cross-reactive T-cell responses over time. However, we cannot exclude the possibility that HIV-2 replication is controlled by other host factors and that HIV-2-specific T-cell responses are better maintained in the context of slow viral divergence and a less damaged immune system. Understanding the nature of immune control of HIV-2 infection could be crucial for HIV vaccine design.

scholarly journals Immunodominance of HIV-1 Specific CD8+ T-Cell Responses Is Related to Disease Progression Rate in Vertically Infected Adolescents

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e21135 ◽  
Author(s):  
Elizabeth R. Sharp ◽  
Christian B. Willberg ◽  
Peter J. Kuebler ◽  
Jacob Abadi ◽  
Glenn J. Fennelly ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Progression Rate ◽  
Cell Responses ◽  
Disease Progression Rate ◽  
Hiv 1

scholarly journals Recognition of a Defined Region within p24 Gag by CD8+ T Cells during Primary Human Immunodeficiency Virus Type 1 Infection in Individuals Expressing Protective HLA Class I Alleles

2007 ◽  
Vol 81 (14) ◽  
pp. 7725-7731 ◽  
Author(s):  
Hendrik Streeck ◽  
Mathias Lichterfeld ◽  
Galit Alter ◽  
Angela Meier ◽  
Nickolas Teigen ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
T Cell Responses ◽  
Hla Class I ◽  
Class I ◽  
Hla B27 ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-specific immune responses during primary HIV-1 infection appear to play a critical role in determining the ultimate speed of disease progression, but little is known about the specificity of the initial HIV-1-specific CD8+ T-cell responses in individuals expressing protective HLA class I alleles. Here we compared HIV-1-specific T-cell responses between subjects expressing the protective allele HLA-B27 or -B57 and subjects expressing nonprotective HLA alleles using a cohort of over 290 subjects identified during primary HIV-1 infection. CD8+ T cells of individuals expressing HLA-B27 or -B57 targeted a defined region within HIV-1 p24 Gag (amino acids 240 to 272) early in infection, and responses against this region contributed over 35% to the total HIV-1-specific T-cell responses in these individuals. In contrast, this region was rarely recognized in individuals expressing HLA-B35, an HLA allele associated with rapid disease progression, or in subjects expressing neither HLA-B57/B27 nor HLA-B35 (P < 0.0001). The identification of this highly conserved region in p24 Gag targeted in primary infection specifically in individuals expressing HLA class I alleles associated with slower HIV-1 disease progression provides a rationale for vaccine design aimed at inducing responses to this region restricted by other, more common HLA class I alleles.

scholarly journals HIV-1 Epitope-Specific CD8+T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently

2006 ◽  
Vol 176 (10) ◽  
pp. 6130-6146 ◽  
Author(s):  
Emma L. Turnbull ◽  
A. Ross Lopes ◽  
Nicola A. Jones ◽  
David Cornforth ◽  
Phillipa Newton ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Hiv 1

Loss of HIV-1-specific T-cell responses associated with very rapid HIV-1 disease progression

AIDS ◽  
2007 ◽  
Vol 21 (7) ◽  
pp. 889-891 ◽  
Author(s):  
Hendrik Streeck ◽  
Becky Schweighardt ◽  
Heiko Jessen ◽  
Rachel L Allgaier ◽  
Terri Wrin ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
T Cell Responses ◽  
Cell Responses ◽  
Hiv 1

scholarly journals CD8+T-Cell Responses before and after Structured Treatment Interruption in Ugandan Adults Who Initiated ART with CD4+T Cells <200 Cell/μL: The DART Trial STI Substudy

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Jennifer Serwanga ◽  
Susan Mugaba ◽  
Auma Betty ◽  
Edward Pimego ◽  
Sarah Walker ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Treatment Interruption ◽  
Significant Decline ◽  
Continuous Treatment ◽  
Cell Responses ◽  
Cell Counts ◽  
Before And After ◽  
Ifn Γ ◽  
Hiv 1

Objective. To better understand attributes of ART-associated HIV-induced T-cell responses that might be therapeutically harnessed.Methods. CD8+T-cell responses were evaluated in some HIV-1 chronically infected participants of the fixed duration STI substudy of the DART trial. Magnitudes, breadths, and functionality of IFN-γ and Perforin responses were compared in STI (n=42) and continuous treatment (CT) (n=46) before and after a single STI cycle when the DART STI trial was stopped early due to inferior clinical outcome in STI participants.Results. STI and CT had comparable magnitudes and breadths of monofunctional CD8+IFNγ+and CD8+Perforin+responses. However, STI was associated with significant decline in breadth of bi-functional (CD8+IFNγ+Perforin+) responses;P=.02, Mann-Whitney test.Conclusions. STI in individuals initiated onto ART at <200 CD4+T-cell counts/μl significantly reduced occurrence of bifunctional CD8+IFNγ+/Perforin+responses. These data add to others that found no evidence to support STI as a strategy to improve HIV-specific immunity during ART.

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