Dynamics of Cytomegalovirus (CMV)–Specific T Cells in HIV‐1–Infected Individuals Progressing to AIDS with CMV End‐Organ Disease

Bronke, C.; Palmer, N.; Jansen, Christine A.; Westerlaken, Geertje H. A.; Polstra, Abeltje M.; Reiss, Peter; Bakker, Margreet; Miedema, Frank; Tesselaar, Kiki; Baarle, Debbie van

doi:10.1086/427828

Cited by 56 publications

(62 citation statements)

References 23 publications

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“…ϩ IFN-␥ ϩ T cells before onset of CMV clinical disease (40). Furthermore, these data are consistent with recent reports in mice, showing that the presence of activated, virus-specific CD4 ϩ effector memory T cells in the lung confer protection against secondary viral challenge (41,42).…”

Section: Figuresupporting

confidence: 91%

Persistent Cytomegalovirus-Specific Memory Responses in the Lung Allograft and Blood following Primary Infection in Lung Transplant Recipients

Shlobin

West

Lechtzin

et al. 2006

The Journal of Immunology

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Primary CMV infection in lung transplant recipients (LTRs) is associated with increased mortality. We studied 22 donor CMV-positive, recipient-negative (D+R−) LTRs for the development of posttransplant CMV-specific immunity. We found that 13 of 22 D+R− LTRs (59.1%) seroconverted (CMV IgG Ab+). Using pooled peptides of the immunodominant CMV Ags pp65 and IE1, we detected CMV-specific CD8+IFN-γ+ T cells in the PBMC of 90% of seroconverted individuals following primary infection by intracellular cytokine staining. In contrast, few seroconverters had detectable CMV-specific CD4+IFN-γ+ T cells during viral latency. However, the majority of IgG+ LTRs demonstrated CMV-specific CD4+ and CD8+ T cell proliferative responses from PBMC, with CD4+IFN-γ+ T cells detectable upon re-expansion. Examination of lung allograft mononuclear cells obtained by bronchoalveolar lavage revealed both CMV-specific CD4+ and CD8+IFN-γ+ T cells, including patients from whom CD4+IFN-γ+ T cells were simultaneously undetectable in the PBMC, suggesting differential effector memory populations between these compartments. Moreover, both responses in the PBMC and lung allograft were found to persist, despite substantial immunosuppression, long after primary infection. Clinical correlation in this cohort demonstrated that the acquisition of CMV immunity was associated with freedom from CMV disease (p ≤ 0.009) and preservation of allograft function (p ≤ 0.02) compared with those who failed to develop CMV immunity. Together, our data reveal immunologic heterogeneity in D+R− LTRs, with the development and persistence of primary CMV responses that may provide clinical benefit.

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Section: Figuresupporting

confidence: 91%

Persistent Cytomegalovirus-Specific Memory Responses in the Lung Allograft and Blood following Primary Infection in Lung Transplant Recipients

Shlobin

West

Lechtzin

et al. 2006

The Journal of Immunology

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“…The low percentage of IFN-␥ secretion by CMV ORF-specific CD8 ϩ T cells by some donors has been observed in other studies (34,59,60). The changing pattern of cytokine secretion by antigen-specific T cells has been proposed as a measure of the differentiation status of the memory T cell population (61)(62)(63)(64).…”

Section: Fig 8 Ul82-and Us3 -Cd8mentioning

confidence: 65%

Diverse Specificities, Phenotypes, and Antiviral Activities of Cytomegalovirus-Specific CD8⁺T Cells

Jackson

Mason

Okecha

et al. 2014

J Virol

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CD8؉ T cells specific for pp65, IE1, and IE2 are present at high frequencies in human cytomegalovirus (HCMV)-seropositive individuals, and these have been shown to have phenotypes associated with terminal differentiation, as well as both cytokine and proliferative dysfunctions, especially in the elderly. However, more recently, T cell responses to many other HCMV proteins have been described, but little is known about their phenotypes and functions. Consequently, in this study, we chose to determine the diversity of HCMVspecific CD8؉ T cell responses to the products of 11 HCMV open reading frames (ORFs) in a cohort of donors aged 20 to 80 years old as well as the ability of the T cells to secrete gamma interferon (IFN-␥). Finally, we also tested their functional antiviral capacity using a novel viral dissemination assay. We identified substantial CD8 ؉ T cell responses by IFN-␥ enzyme-linked immunospot (ELISPOT) assays to all 11 of these HCMV proteins, and across the cohort, individuals displayed a range of responses, from tightly focused to highly diverse, which were stable over time. CD8؉ T cell responses to the HCMV ORFs were highly differentiated and predominantly CD45RA ؉ , CD57 ؉ , and CD28 ؊ , across the cohort. These highly differentiated cells had the ability to inhibit viral spread even following direct ex vivo isolation. Taken together, our data argue that HCMV-specific CD8 ؉ T cells have effective antiviral activity irrespective of the viral protein recognized across the whole cohort and despite viral immune evasion. IMPORTANCEHuman cytomegalovirus (HCMV) is normally carried without clinical symptoms and is widely prevalent in the population; however, it often causes severe clinical disease in individuals with compromised immune responses. HCMV is never cleared after primary infection but persists in the host for life. In HCMV carriers, the immune response to HCMV includes large numbers of virus-specific immune cells, and the virus has evolved many mechanisms to evade the immune response. While this immune response seems to protect healthy people from subsequent disease, the virus is never eliminated. It has been suggested that this continuous surveillance by the immune system may have deleterious effects in later life. The study presented in this paper examined immune responses from a cohort of donors and shows that these immune cells are effective at controlling the virus and can overcome the virus' lytic cycle immune evasion mechanisms.

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“…HIV associated changes in the quantity or quality of opportunistic pathogen-specific CD4 T cell responses could potentially contribute to increased susceptibility to a given pathogen. For example, clinical complications caused by CMV closely correlates with depletion of CMV-specific CD4 T cell responses [54][55][56].…”

Section: Dynamics Of Mtb-specific Cd4 Th1 Cell Responses After Hiv Inmentioning

confidence: 99%

Interaction between HIV and Mycobacterium tuberculosis: HIV-1-induced CD4 T-cell depletion and the development of active tuberculosis

Geldmacher¹,

Höelscher²,

Zumla³

2017

Preprint

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Dynamics of Cytomegalovirus (CMV)–Specific T Cells in HIV‐1–Infected Individuals Progressing to AIDS with CMV End‐Organ Disease

Cited by 56 publications

References 23 publications

Persistent Cytomegalovirus-Specific Memory Responses in the Lung Allograft and Blood following Primary Infection in Lung Transplant Recipients

Persistent Cytomegalovirus-Specific Memory Responses in the Lung Allograft and Blood following Primary Infection in Lung Transplant Recipients

Diverse Specificities, Phenotypes, and Antiviral Activities of Cytomegalovirus-Specific CD8⁺T Cells

Interaction between HIV and Mycobacterium tuberculosis: HIV-1-induced CD4 T-cell depletion and the development of active tuberculosis

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Dynamics of Cytomegalovirus (CMV)–Specific T Cells in HIV‐1–Infected Individuals Progressing to AIDS with CMV End‐Organ Disease

Cited by 56 publications

References 23 publications

Persistent Cytomegalovirus-Specific Memory Responses in the Lung Allograft and Blood following Primary Infection in Lung Transplant Recipients

Persistent Cytomegalovirus-Specific Memory Responses in the Lung Allograft and Blood following Primary Infection in Lung Transplant Recipients

Diverse Specificities, Phenotypes, and Antiviral Activities of Cytomegalovirus-Specific CD8+T Cells

Interaction between HIV and Mycobacterium tuberculosis: HIV-1-induced CD4 T-cell depletion and the development of active tuberculosis

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Diverse Specificities, Phenotypes, and Antiviral Activities of Cytomegalovirus-Specific CD8⁺T Cells