Central Role of Reverting Mutations in HLA Associations with Human Immunodeficiency Virus Set Point

ABSTRACT Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8+ T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert posttransmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = −0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = −0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.

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HLA-I Associated Adaptation Dampens CD8 T-Cell Responses in HIV Ad5-Vectored Vaccine Recipients

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz368 ◽

2019 ◽

Vol 220 (10) ◽

pp. 1620-1628 ◽

Cited By ~ 1

Author(s):

Sushma Boppana ◽

Sarah Sterrett ◽

Jacob Files ◽

Kai Qin ◽

Andrew Fiore-Gartland ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Hiv Vaccine ◽

Viral Control ◽

Cell Responses ◽

Efficacy Trials ◽

Immunodeficiency Virus ◽

Vectored Vaccine

Abstract HLA-I–associated human immunodeficiency virus (HIV) adaptation is known to negatively affect disease progression and CD8 T-cell responses. We aimed to assess how HLA-I–associated adaptation affects HIV vaccine–induced CD8 T-cell responses in 2 past vaccine efficacy trials. We found that vaccine-encoded adapted epitopes were less immunogenic than vaccine-encoded nonadapted epitopes, and adapted epitope-specific responses were less polyfunctional than nonadapted epitope-specific responses. Along those lines, vaccine recipients with higher HLA-I adaptation to the Gag vaccine insert mounted less polyfunctional CD8 T-cell responses at the protein level. Breadth of response, which correlated with viral control in recipients who became infected, is also dampened by HLA-I adaptation. These findings suggest that HLA-I–associated adaptation is an important consideration for strategies aiming to induce robust CD8 T-cell responses.

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Pseudovirion Particle Production by Live Poxvirus Human Immunodeficiency Virus Vaccine Vector Enhances Humoral and Cellular Immune Responses

Journal of Virology ◽

10.1128/jvi.79.9.5537-5547.2005 ◽

2005 ◽

Vol 79 (9) ◽

pp. 5537-5547 ◽

Cited By ~ 17

Author(s):

Xuemin Chen ◽

Michael T. Rock ◽

Jason Hammonds ◽

James Tartaglia ◽

Ayumi Shintani ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Particle Production ◽

T Cell Responses ◽

Particle Formation ◽

Hiv Vaccine ◽

Hiv Vaccines ◽

Cell Responses ◽

Immunodeficiency Virus

ABSTRACT Live-vector-based human immunodeficiency virus (HIV) vaccines are an integral part of a number of HIV vaccine regimens currently under evaluation. Live vectors that carry an intact gag gene are capable of eliciting HIV pseudovirion particle formation from infected host cells. The impact of pseudovirion particle formation on the immune response generated by live HIV vaccine vectors has not been established. In this study, a canarypox HIV vaccine candidate vector expressing HIV gag and env genes, vCP205, was modified by the introduction of a glycine-to-alanine coding change in the N-terminal myristylation site of gag to create Myr− vCP205. This substitution effectively eliminated particle formation without altering the level of protein production. vCP205 and Myr− vCP205 were then directly compared for the ability to induce HIV-specific immune responses in mice. The particle-competent vector vCP205 elicited higher levels of CD8+ T-cell responses, as indicated by gamma interferon enzyme-linked immunospot (ELISPOT) assay and intracellular cytokine staining. Humoral responses to Gag and Env were also markedly higher from animals immunized with the particle-competent vector. Furthermore, HIV-specific CD4+ T-cell responses were greater among animals immunized with the particle-competent vector. Using a human dendritic cell model of antigen presentation in vitro, vCP205 generated greater ELISPOT responses than Myr− vCP205. These results demonstrate that pseudovirion particle production by live-vector HIV vaccines enhances HIV-specific cellular and humoral immune responses.

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Maintenance of Viral Suppression in Human Immunodeficiency Virus Controllers Despite Waning T-Cell Responses During Antiretroviral Therapy

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa294 ◽

2020 ◽

Vol 222 (11) ◽

pp. 1837-1842 ◽

Cited By ~ 1

Author(s):

Nikolaus Jilg ◽

Pilar Garcia-Broncano ◽

Michael Peluso ◽

Florencia P Segal ◽

Ronald J Bosch ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Antiretroviral Therapy ◽

T Cell Activation ◽

Cell Activation ◽

T Cell Responses ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Undetectable Viremia ◽

Hiv Controllers

Abstract AIDS Clinical Trials Group study A5308 found reduced T-cell activation and exhaustion in human immunodeficiency virus (HIV) controllers start antiretroviral therapy (ART). We further assessed HIV-specific T-cell responses and post-ART viral loads. Before ART, the 31% of participants with persistently undetectable viremia had more robust HIV-specific T-cell responses. During ART, significant decreases were observed in a broad range of T-cell responses. Eight controllers in A5308 and the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort showed no viremia above the level of quantification in the first 12 weeks after ART discontinuation. ART significantly reduced HIV-specific T-cell responses in HIV controllers but did not adversely affect controller status after ART discontinuation.

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T Cell Responses During Human Immunodeficiency Virus (HIV)-1 Infection

Control of Innate and Adaptive Immune Responses during Infectious Diseases ◽

10.1007/978-1-4614-0484-2_8 ◽

2011 ◽

pp. 141-169

Author(s):

Claire A. Chougnet ◽

Barbara L. Shacklett

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

T Cell Responses ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Hiv 1

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Differential Pathogen-Specific Immune Reconstitution in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Children

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy668 ◽

2019 ◽

Vol 219 (9) ◽

pp. 1407-1417 ◽

Cited By ~ 1

Author(s):

Maximilian Muenchhoff ◽

Emily Adland ◽

Julia Roider ◽

Henrik Kløverpris ◽

Alasdair Leslie ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Antiretroviral Therapy ◽

Immune Reconstitution ◽

T Cell Responses ◽

Cell Phenotype ◽

Memory Phenotype ◽

Cell Responses ◽

Immune Exhaustion ◽

Immunodeficiency Virus

Abstract Background Susceptibility to coinfections in human immunodeficiency virus (HIV)-infected patients remains increased despite antiretroviral therapy (ART). To elucidate mechanisms involved in immune reconstitution, we studied immune activation, immune exhaustion, and HIV- and copathogen-specific T-cell responses in children before and after ART. Methods We prospectively enrolled 25 HIV-infected children to study HIV-, cytomegalovirus (CMV)-, and tuberculosis (TB)-specific T-cell responses before and 1 year after initiation of ART using intracellular cytokine (interleukin-2, interferon-γ, tumor necrosis factor-α) staining assays after in vitro stimulation. We further measured expression of activation, immune exhaustion, and memory phenotype markers and studied proliferative responses after antigen stimulation. Results We observed differential, pathogen-specific changes after 1 year of ART in cytokine profiles of CD4 T-cell responses that were associated with shifts in memory phenotype and decreased programmed cell death 1 (PD-1) expression. The proliferative capacity of HIV- and PPD-specific responses increased after 1 year of ART. Of note, the recovery of CMV- and TB-specific responses was correlated with a decrease in PD-1 expression (r = 0.83, P = .008 and r = 0.81, P = .0007, respectively). Conclusions Reconstitution of immune responses on ART is associated with alterations in T-cell phenotype, function, and PD-1 expression that are distinct for HIV, TB, and CMV. The PD-1 pathway represents a potential target for immunotherapy in HIV-infected patients on ART with insufficient immune reconstitution.

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A High Viral Burden Predicts the Loss of CD8 T-Cell Responses Specific for Subdominant Gag Epitopes during Chronic Human Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.01566-07 ◽

2007 ◽

Vol 81 (24) ◽

pp. 13809-13815 ◽

Cited By ~ 13

Author(s):

Christof Geldmacher ◽

Clive Gray ◽

Martha Nason ◽

Jeffrey R. Currier ◽

Antelmo Haule ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Baseline Viral Load ◽

Viral Control ◽

Cell Responses ◽

Immunodeficiency Virus

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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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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Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.78.2.841-854.2004 ◽

2004 ◽

Vol 78 (2) ◽

pp. 841-854 ◽

Cited By ~ 40

Author(s):

Kristina Abel ◽

Lisa La Franco-Scheuch ◽

Tracy Rourke ◽

Zhong-Min Ma ◽

Veronique de Silva ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Rhesus Macaques ◽

T Cell Responses ◽

Lymphoid Tissues ◽

Mrna Levels ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Ifn Γ

ABSTRACT Although gamma interferon (IFN-γ) is a key mediator of antiviral defenses, it is also a mediator of inflammation. As inflammation can drive lentiviral replication, we sought to determine the relationship between IFN-γ-related host immune responses and challenge virus replication in lymphoid tissues of simian-human immunodeficiency virus 89.6 (SHIV89.6)-vaccinated and unvaccinated rhesus macaques 6 months after challenge with simian immunodeficiency virus SIVmac239. Vaccinated-protected monkeys had low tissue viral RNA (vRNA) levels, vaccinated-unprotected animals had moderate tissue vRNA levels, and unvaccinated animals had high tissue vRNA levels. The long-term challenge outcome in vaccinated monkeys was correlated with the relative balance between SIV-specific IFN-γ T-cell responses and nonspecific IFN-γ-driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN-γ mRNA levels and a high frequency of IFN-γ-secreting T cells responding to in vitro SIVgag peptide stimulation; thus, it is likely that they could develop effective anti-SIV cytotoxic T lymphocytes in vivo. In contrast, both high tissue IFN-γ mRNA levels and strong in vitro SIV-specific IFN-γ T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN-γ mRNA levels but weak in vitro anti-SIV IFN-γ T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN-γ mRNA levels were associated with increased Mig/CXCL9, IP-10/CXCL10, and CXCR3 mRNA levels, suggesting that increased Mig/CXCL9 and IP-10/CXCL10 expression resulted in recruitment of CXCR3+ activated T cells. Thus, IFN-γ-driven inflammation promotes SIV replication in vaccinated-unprotected and unvaccinated monkeys. Unlike all unvaccinated monkeys, most monkeys vaccinated with SHIV89.6 did not develop IFN-γ-driven inflammation, but they did develop effective antiviral CD8+-T-cell responses.

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