Faculty Opinions recommendation of Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection.

ABSTRACT Human immunodeficiency virus (HIV)-specific CD8 T-cell responses targeting products encoded within the Gag open reading frame have frequently been associated with better viral control and disease outcome during the chronic phase of HIV infection. To further clarify this relationship, we have studied the dynamics of Gag-specific CD8 T-cell responses in relation to plasma viral load and time since infection in 33 chronically infected subjects over a 9-month period. High baseline viral loads were associated with a net loss of breadth (P < 0.001) and a decrease in the total magnitude of the Gag-specific T-cell response in general (P = 0.03). Most importantly, the baseline viral load predicted the subsequent change in the breadth of Gag recognition over time (P < 0.0001, r 2 = 0.41). Compared to maintained responses, lost responses were low in magnitude (P < 0.0001) and subdominant in the hierarchy of Gag-specific responses. The present study indicates that chronic exposure of the human immune system to high levels of HIV viremia is a determinant of virus-specific CD8 T-cell loss.

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Analysis of Total Human Immunodeficiency Virus (HIV)-Specific CD4+ and CD8+ T-Cell Responses: Relationship to Viral Load in Untreated HIV Infection

Journal of Virology ◽

10.1128/jvi.75.24.11983-11991.2001 ◽

2001 ◽

Vol 75 (24) ◽

pp. 11983-11991 ◽

Cited By ~ 541

Author(s):

Michael R. Betts ◽

David R. Ambrozak ◽

Daniel C. Douek ◽

Sebastian Bonhoeffer ◽

Jason M. Brenchley ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Viral Load ◽

T Cell ◽

Hiv Infection ◽

Highly Active Antiretroviral Therapy ◽

T Cell Responses ◽

T Cell Response ◽

Cell Responses ◽

Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus (HIV)-specific T-cell responses are thought to play a key role in viral load decline during primary infection and in determining the subsequent viral load set point. The requirements for this effect are unknown, partly because comprehensive analysis of total HIV-specific CD4+ and CD8+T-cell responses to all HIV-encoded epitopes has not been accomplished. To assess these responses, we used cytokine flow cytometry and overlapping peptide pools encompassing all products of the HIV-1 genome to study total HIV-specific T-cell responses in 23 highly active antiretroviral therapy naı̈ve HIV-infected patients. HIV-specific CD8+ T-cell responses were detectable in all patients, ranging between 1.6 and 18.4% of total CD8+ T cells. HIV-specific CD4+ T-cell responses were present in 21 of 23 patients, although the responses were lower (0.2 to 2.94%). Contrary to previous reports, a positive correlation was identified between the plasma viral load and the total HIV-, Env-, and Nef-specific CD8+ T-cell frequency. No correlation was found either between viral load and total or Gag-specific CD4+ T-cell response or between the frequency of HIV-specific CD4+ and CD8+ T cells. These results suggest that overall frequencies of HIV-specific T cells are not the sole determinant of immune-mediated protection in HIV-infection.

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Proliferative Capacity of Epitope-Specific CD8 T-Cell Responses Is Inversely Related to Viral Load in Chronic Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.01754-06 ◽

2006 ◽

Vol 81 (1) ◽

pp. 434-438 ◽

Cited By ~ 74

Author(s):

Cheryl L. Day ◽

Photini Kiepiela ◽

Alasdair J. Leslie ◽

Mary van der Stok ◽

Kriebashne Nair ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Epitopes ◽

Viral Control ◽

Cell Responses ◽

Immunodeficiency Virus

ABSTRACT The relationship between the function of human immunodeficiency virus (HIV)-specific CD8 T-cell responses and viral load has not been defined. In this study, we used a panel of major histocompatibility complex class I tetramers to examine responses to frequently targeted CD8 T-cell epitopes in a large cohort of antiretroviral-therapy-naïve HIV type 1 clade C virus-infected persons in KwaZulu Natal, South Africa. In terms of effector functions of proliferation, cytokine production, and degranulation, only proliferation showed a significant correlation with viral load. This robust inverse relationship provides an important functional correlate of viral control relevant to both vaccine design and evaluation.

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

Journal of Virology ◽

10.1128/jvi.78.7.3233-3243.2004 ◽

2004 ◽

Vol 78 (7) ◽

pp. 3233-3243 ◽

Cited By ~ 160

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.

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Heteroclitic peptides enhance human immunodeficiency virus-specific CD8+ T cell responses

Vaccine ◽

10.1016/j.vaccine.2012.09.067 ◽

2012 ◽

Vol 30 (49) ◽

pp. 6997-7004 ◽

Cited By ~ 6

Author(s):

Krista H. Gladney ◽

Julia Pohling ◽

Natasha A. Hollett ◽

Katrin Zipperlen ◽

Maureen E. Gallant ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Heteroclitic Peptides

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

Journal of Virology ◽

10.1128/jvi.76.5.2298-2305.2002 ◽

2002 ◽

Vol 76 (5) ◽

pp. 2298-2305 ◽

Cited By ~ 260

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.

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