CMV-specific CD4 T-cell Responses Research Articles

Cytomegalovirus-Specific CD4+ T-cell Responses and CMV-IgG Levels Are Associated With Neurocognitive Impairment in People Living With HIV

Mechanisms leading to neurocognitive impairment (NCI) in people living with HIV (PLWHIV) on stable combination antiretroviral therapy (cART) remain unknown. We investigated the association between immunity against cytomegalovirus (CMV), HIV-specific variables, and NCI in PLWHIV on stable cART and with low comorbidity. Fifty-two PLWHIV on stable cART and 31 HIV-uninfected controls matched on age, sex, education, and comorbidity were tested with a neurocognitive test battery, and CMV-immunoglobulin G (CMV-IgG) levels were measured. In PLWHIV, CMV-specific (CMV-pp65 and CMV-gB) CD4 and CD8 T-cell responses were measured using intracellular cytokine staining and flow cytometry. NCI was defined as a global deficit scale score (GDS score) ≥0.5. GDS scores and domain-specific scores defined severity of NCI. Logistic and linear multivariable regression analyses were used. NCI was detected in 30.8% of PLWHIV, and HIV was associated with an adjusted odds ratio (aOR) of 5.18 [95% confidence interval (CI): 1.15 to 23.41, P = 0.033] for NCI. In PLWHIV, higher CMV-specific CD4 T-cell responses increased the probability of NCI with an aOR of 1.68 (95% CI: 1.10 to 2.57) for CMV-pp65 or an aOR of 3.73 (95% CI: 1.61 to 16.98) for CMV-gB, respectively. Similar associations were not found with CMV-IgG or CMV-specific CD8 T cells, but when assessing severity of NCI, higher CMV-IgG (per 100 U/mL) was associated with worse GDS scores (β = 0.08) (0.01-0.16), P = 0.044), specifically in the domain of speed of information processing (β = 0.20 (0.04-0.36, P = 0.019). PLWHIV had increased risk of NCI. Excess risk may be associated with CMV-specific CD4 T-cell responses and CMV-IgG. Larger longitudinal studies investigating the impact of immunity against CMV on risk of NCI are warranted.

Cytomegalovirus infection modulates the phenotype and functional profile of the T-cell immune response to mycobacterial antigens in older life

Infection with Cytomegalovirus is associated with accelerated immunosenescence. Expansions of CMV-specific T cell responses have previously been demonstrated to affect the ability of T cells to respond to other infections. Most people above 60years of age display M. tuberculosis-specific immunity because of vaccination, exposure, or both. T-cell responses can be assessed by measuring intracellular IFN-γ in vitro after tuberculin stimulation. Here we investigated tuberculin-specific CD4 T-cell responses in independently living healthy older people in the South of England using flow-cytometry. Individuals were investigated for tuberculin and CMV-specific T-cell immunity using in vitro antigen stimulation followed by intracellular staining for IFN-γ, TNF-α, IL2, as well as degranulation and CD154 upregulation. We also examined a control group of younger individuals (20–35years of age). There was no significant difference between older and young people in regards to tuberculin responsiveness of CD4 T-cells; however, older people seemed to show more outliers. Increased responsiveness to tuberculin was significantly correlated to CMV responsiveness but not age. In older donors, the memory phenotype of tuberculin-induced T-cells was significantly skewed towards a more terminal differentiation phenotype in CMV-infected compared to uninfected individuals and the degree of skewing correlated quantitatively with the size of the CMV-specific CD4 T-cell response. This is a fundamental advance over previous reports of changes of the tuberculin-specific CD4 T-cell response with CMV serostatus. Our results show that how the immune system responds to CMV has a fundamental impact on the phenotype and function of the immune response to mycobacterial antigens in older life.

Restoration of CD4 T‐cell responses to cytomegalovirus is short‐lived in severely immunodeficient HIV‐infected patients responding to highly active antiretroviral therapy

To define the level of pathogen-specific immune reconstitution persisting over 3 to 5 years of highly active antiretroviral therapy (HAART) in HIV-infected patients who began therapy with CD4 T-cell counts below 50 cells/microL. Cytomegalovirus (CMV)-specific T-cell responses were analysed in adult HIV-1-infected patients with nadir CD4 T-cell counts below 50 cells/microL before HAART. CMV-specific CD4 T-cell responses were measured by interferon-gamma enzyme-linked immunospot assay (ELISpot assay), lymphoproliferation and interferon-gamma levels in cell culture supernatants. CD4 T-cell responses to CMV were low in untreated patients and remained low during the first year on HAART, but increased progressively to levels similar to those found in HIV-seronegative CMV-seropositive controls at 3 years. Responses then declined markedly and at 5 years were lower than controls. This could not be explained by changes in CD4 or CD8 T-cell counts or plasma HIV RNA levels. Interferon-gamma and interleukin-5 responses to a mitogen were maintained or elevated. CMV-specific CD4 T-cell responses were found to decline after 3-5 years on HAART and may provide inadequate long-term protection against CMV disease in patients who are severely immunodeficient prior to treatment.

Analysis of HIV-1– and CMV-specific memory CD4 T-cell responses during primary and chronic infection

CD4 T-cell-specific memory antiviral responses to human immunodeficiency virus type 1 (HIV-1) and cytomegalovirus (CMV) were investigated in 16 patients with documented primary HIV-1 infection (4 of the 16 subjects also had primary CMV infection) and compared with those observed in patients with chronic HIV-1 and CMV coinfection. Virus-specific memory CD4 T cells were characterized on the basis of the expression of the chemokine receptor CCR7. HIV-1- and CMV-specific interferon-gamma-secreting CD4 T cells were detected in patients with primary and chronic HIV-1 and CMV coinfection and were mostly contained in the cell population lacking expression of CCR7. The magnitude of the primary CMV-specific CD4 T-cell response was significantly greater than that of chronic CMV infection, whereas there were no differences between primary and chronic HIV-1-specific CD4 T-cell responses. A substantial proportion of CD4(+)CCR7(-) T cells were infected with HIV-1. These results advance the characterization of antiviral memory CD4 T-cell response and the delineation of the potential mechanisms that likely prevent the generation of a robust CD4 T-cell immune response during primary infection.

Sustained high frequencies of specific CD4 T cells restricted to a single persistent virus.

Replication of cytomegalovirus (CMV) is largely controlled by the cellular arm of the immune response. In this study the CMV-specific CD4 T-cell response was characterized in a cohort of apparently healthy individuals. In 11% of all individuals, extremely high frequencies, between 10 and 40%, were found. High-level frequencies of CMV-specific CD4 T cells persisted over several months and were not the result of an acute infection. Specific T cells were oligoclonal and were phenotypically and functionally characterized as mature effector cells, with both cytokine-secreting and proliferative potential. These high-level frequencies do not seem to compromise the immune response towards heterologous infections, and no signs of immunopathology were observed. Whereas a large temporary expansion of virus-specific T cells is well known to occur during acute infection, we now show that extremely high frequencies of virus-specific T cells may continuously exist in chronic CMV infection without overtly compromising the remaining protective immunity.