Influence of HIV infection on cytomegalovirus-specific immunity: T-cell responses to pp65 and IE1 before and after HAART may reflect altered cytomegalovirus biology

ABSTRACTAntigen-specific CD4+T helper cell responses have long been recognized to be a critical component of effective vaccine immunity. CD4+T cells are necessary to generate and maintain humoral immune responses by providing help to antigen-specific B cells for the production of antibodies. In HIV infection, CD4+T cells are thought to be necessary for the induction of Env-specific broadly neutralizing antibodies. However, few studies have investigated the role of HIV-specific CD4+T cells in association with HIV neutralizing antibody activity in vaccination or natural infection settings. Here, we conducted a comprehensive analysis of HIV-specific CD4+T cell responses in a cohort of 34 untreated HIV-infected controllers matched for viral load, with and without neutralizing antibody breadth to a panel of viral strains. Our results show that the breadth and magnitude of Gag-specific CD4+T cell responses were significantly higher in individuals with neutralizing antibodies than in those without neutralizing antibodies. The breadth of Gag-specific CD4+T cell responses was positively correlated with the breadth of neutralizing antibody activity. Furthermore, the breadth and magnitude of gp41-specific, but not gp120-specific, CD4+T cell responses were significantly elevated in individuals with neutralizing antibodies. Together, these data suggest that robust Gag-specific CD4+T cells and, to a lesser extent, gp41-specific CD4+T cells may provide important intermolecular help to Env-specific B cells that promote the generation or maintenance of Env-specific neutralizing antibodies.IMPORTANCEOne of the earliest discoveries related to CD4+T cell function was their provision of help to B cells in the development of antibody responses. Yet little is known about the role of CD4+T helper responses in the setting of HIV infection, and no studies to date have evaluated the impact of HIV-specific CD4+T cells on the generation of antibodies that can neutralize multiple different strains of HIV. Here, we addressed this question by analyzing HIV-specific CD4+T cell responses in untreated HIV-infected persons with and without neutralizing antibodies. Our results indicate that HIV-infected persons with neutralizing antibodies have significantly more robust CD4+T cell responses targeting Gag and gp41 proteins than individuals who lack neutralizing antibodies. These associations suggest that Gag- and gp41-specific CD4+T cell responses may provide robust help to B cells for the generation or maintenance of neutralizing antibodies in natural HIV-infection.

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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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Dynamics of T Cell Responses in HIV Infection

The Journal of Immunology ◽

10.4049/jimmunol.169.1.607-a ◽

2002 ◽

Vol 169 (1) ◽

pp. 607.2-607

Author(s):

Victor Appay ◽

Laura Papagno ◽

Celsa A. Spina ◽

Pokrath Hansasuta ◽

Abigail King ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

T Cell Responses ◽

Cell Responses

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Treg Downregulation Was Associated with Augmentation of T Cell Responses Against Immunogenic Antigens and Clinical Responses in Patients with Hematological Malignancies after Donor Lymphocyte Infusion (DLI)

Blood ◽

10.1182/blood-2018-99-111783 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3423-3423

Author(s):

Jochen Greiner ◽

Marlies Götz ◽

Michael Schmitt ◽

Hartmut Döhner ◽

Markus Wiesneth ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Response ◽

Research Funding ◽

T Cell Responses ◽

Donor Lymphocyte Infusion ◽

Cytotoxic T Cell ◽

Epitope Recognition ◽

Cell Responses ◽

Before And After

Abstract In order to maintain remission and to prolong overall-survival after allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion (DLI), cytotoxic T-cell responses against malignant cells play a pivotal role, however they are not well characterized so far. In this study, we focused on the detection of immune responses in patients before and after DLI. A broader epitope-specific T cell activity is associated with clinical response of patients treated with DLI and a concurrent reduction of regulatory T cell frequency may contribute to clinical response in patients after DLI. For a better characterization of the T cell responses, frequency and diversity of leukemia-associated antigen (LAA)-specific cytotoxic T cells was assessed using ELISpot and pMHC multimer assays. Furthermore, the frequency of regulatory T cells (Treg) before and after DLI was analyzed. Results were correlated to the clinical course of the patients. Independently of their clinical response, 7/11 patients (63.6%) showed an immunological response through an increase in the number of recognized epitopes over the course of DLI. There was a significant increase (p=0.02) in epitope recognition comparing early screening and maximum response after DLI and a significant increase in the mean augmentation from 1 to 4 of the spotted epitopes in the course of DLI was detected in the cohort of clinical responders (R) compared to non-responders (NR) who did not show any dynamics in epitope recognition with a median of 3 to 4 recognized LAA. The proportion of the CD4+CD25highFoxP3+ Treg within the CD4+CD25high T cell fraction decreased significantly in R from a median of 72.9% to 54.6% when comparing the variation at the time points before and after DLI (p=0.04). In NR there was no significant change in the Treg fraction in the course of DLI. In general, significantly more LAA-derived T cell epitopes (p=0.02) were recognized in R when compared to NR. Moreover, the frequency of Treg in R decreased significantly (p=0.008) while remaining stable in NR. Taken together, an increase of specific CTL responses against several LAA after DLI was detected. This study suggests that decreasing numbers of Treg as well as enhanced LAA diversity in T cell responses contribute to clinical outcome of patients treated with DLI. Disclosures Döhner: AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding.

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Long-term follow-up of SARS-CoV-2 convalescents reveals distinct magnitude of spike-specific immunity after viral re-exposure and vaccination

10.21203/rs.3.rs-677167/v1 ◽

2021 ◽

Author(s):

Percy Knolle ◽

Nina Körber ◽

Alina Priller ◽

Sarah Yazici ◽

Tanja Bauer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

T Cell Immunity ◽

Cell Responses ◽

Specific Immunity ◽

Cell Immunity

Abstract Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is controlled by the host´s immune response1-4, but longitudinal follow-up studies of virus-specific immunity to evaluate protection from re-infection are lacking. Here, we report the results from a prospective study that started during the first wave of the COVID-19 pandemic in spring 2020, where we identified 91 convalescents from mild SARS-CoV-2 infection among 4554 health care workers. We followed the dynamics and magnitude of spike-specific immunity in convalescents during the spontaneous course over ≥ 9 months, after SARS-CoV-2 re-exposure and after BNT162b2 mRNA vaccination. Virus-neutralizing antibodies and spike-specific T cell responses with predominance of IL-2-secreting polyfunctional CD4 T cells continuously declined over 9 months, but remained detectable at low levels. After a single vaccination, convalescents simultaneously mounted strong antibody and T cell responses against the SARS-CoV-2 spike proteins. In naïve individuals, a prime vaccination induced preferentially IL-2-secreting CD4 T cells that preceded production of spike-specific virus-neutralizing antibodies after boost vaccination. Response to vaccination, however, was not homogenous. Compared to four individuals among 455 naïve vaccinees (0.9%), we identified 5/82 (6.1%) convalescents with a delayed response to vaccination. These convalescents had originally developed dysfunctional spike-specific immune responses after SARS-CoV-2 infection, and required prime and boost vaccination to develop strong spike-specific immunity. Importantly, during the second wave of the COVID-19 pandemic in fall/winter of 2021 and prior to vaccination we detected a surge of virus-neutralizing antibodies consistent with re-exposure to SARS-CoV-2 in 6 out of 82 convalescents. The selective increase in virus-neutralizing antibodies occurred without systemic re-activation of spike-specific T cell immunity, whereas a single BNT162b2 mRNA vaccination sufficed to induce strong spike-specific antibody and systemic T cell responses in the same individuals. These results support the notion that BNT162b2 mRNA vaccination synchronizes spike-specific immunity in all convalescents of mild SARS-CoV-2 infection and may provide additional protection from re-infection by inducing more rigorous stimulation of spike-specific T cell immunity than re-exposure with SARS-CoV-2.

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P07-07. Non-progressive paediatric HIV infection is associated with virus attenuation and increase in CD8+ specific T cell responses over time

Retrovirology ◽

10.1186/1742-4690-6-s3-p105 ◽

2009 ◽

Vol 6 (S3) ◽

Author(s):

JG Prado ◽

A Prendergast ◽

C Thobakgale ◽

C Juarez ◽

A Tudor-Williams ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

T Cell Responses ◽

Paediatric Hiv ◽

Cell Responses ◽

Paediatric Hiv Infection ◽

Over Time

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Effect of HIV Infection and Antiretroviral Therapy on Hepatitis B Virus (HBV)–Specific T Cell Responses in Patients Who Have Resolved HBV Infection

The Journal of Infectious Diseases ◽

10.1086/428502 ◽

2005 ◽

Vol 191 (7) ◽

pp. 1169-1179 ◽

Cited By ~ 25

Author(s):

R. Monica Lascar ◽

A. Ross Lopes ◽

Richard J. Gilson ◽

Claire Dunn ◽

Ruth Johnstone ◽

...

Keyword(s):

Hepatitis B Virus ◽

T Cell ◽

Antiretroviral Therapy ◽

Hepatitis B ◽

Hiv Infection ◽

T Cell Responses ◽

Hbv Infection ◽

Cell Responses ◽

B Virus

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The Breadth of Expandable Memory CD8+T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers

Journal of Virology ◽

10.1128/jvi.01527-15 ◽

2015 ◽

Vol 89 (21) ◽

pp. 10735-10747 ◽

Cited By ~ 20

Author(s):

Zaza M. Ndhlovu ◽

Eleni Stampouloglou ◽

Kevin Cesa ◽

Orestes Mavrothalassitis ◽

Donna Marie Alvino ◽

...

Keyword(s):

T Cells ◽

Viral Load ◽

T Cell ◽

T Lymphocytes ◽

Hiv Infection ◽

T Cell Responses ◽

T Cell Response ◽

Elite Controllers ◽

Cell Responses ◽

Specific Memory

ABSTRACTPrevious studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated thein vivorelevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8+T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P= 0.01) as well as treated progressors (P= 0.0003). Nef- and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P= 0.9 for Nef as determined by a Kruskal-Wallis test;P= 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r= −0.6;P= 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8+T cell feature that would be desirable in a vaccine-induced T cell response.IMPORTANCEMany studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8+T lymphocytes, is at least partially involved in the durable control of HIV replication. HIV controllers maintain a large proportion of Gag-specific expandable memory CD8+T cells involved in ongoing viral suppression. These data suggest that induction of this cell subset by future HIV vaccines may be important for narrowing possible routes of rapid escape from vaccine-induced CD8+T cell responses.

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