[Impairments in neurocognitive functions in patients with long COVID: A systematic review]. / Stoornissen in neurocognitieve functies bij patiënten met long COVID: een systematische review.

BACKGROUND: Studies have shown impairments in neurocognitive functions which persist more than 3 months after COVID-19 (long COVID). It remains unclear what these impairments entail, how long they persist and what proportion of the patients exhibit them. AIM: To define the specific neurocognitive profile and to determine the proportion of deficits in at least one cognitive domain in patients with long COVID. METHOD: We conducted a systematic search in PubMed according to PRISMA 2020 guidelines with the following inclusion criteria: peer reviewed publications in which patients were assessed more than 3 months following acute COVID-19 by means of a test battery for different domains of neurocognition. RESULTS: We found a total of 1178 papers, of which 7 cohort studies and 1 case-control study were selected. The proportion of patients having deficits in at least one domain of neurocognition ranged from 23% to 100%. Most frequent impairments were found in attention and speed of information processing, anterograde memory, working memory and executive function. Quality of the included studies was moderate. CONCLUSION: Impairments in neurocognitive functions are highly prevalent among patients with long COVID and include various cognitive domains. We encourage further research to continue studying the complex interaction of COVID-19, neurocognitive impairments and neuropsychiatric syndromes.

High unrecognized SARS-CoV-2 exposure of newly admitted and hospitalized psychiatric patients.

BACKGROUND: Patients with pre-existing mental disorders are at higher risk for SARS-CoV-2 infection and adverse outcomes, and severe mental illness, including mood and psychosis spectrum disorders, is associated with increased mortality risk. Despite their increased risk profile, patients with severe mental illness have been understudied during the pandemic, with limited estimates of exposure in inpatient settings. OBJECTIVE: The aim of this study was to describe the SARS-CoV-2 seroprevalence and antibody titers, and pro-inflammatory cytokine concentrations of newly admitted or hospitalized psychiatric inpatients without known history of COVID-19 infection, using robust quantitative multi-antigen assessments, and compare patients' exposure to that of hospital staff. METHODS: This multi-centric, cross-sectional study compared SARS-CoV-2 seroprevalence and titers of 285 patients (University Psychiatric Centre Duffel [UPCD] N = 194; Assistance-Publique-Hopitaux de Paris [AP-HP] N = 91), and 192 hospital caregivers (UPCD N = 130; AP-HP N = 62) at two large psychiatric care facilities between January 1st and the May 30th 2021. Serum levels of SARS-CoV-2 antibodies against Spike proteins (full length), spike subunit 1 (S1), spike subunit 2 (S2), spike subunit 1 receptor binding domain (S1-RBD) and Nucleocapsid proteins were quantitatively determined using an advanced capillary Western Blot technique. To assess the robustness of the between-group seroprevalence differences, we performed sensitivity analyses with stringent cut-offs for seropositivity. We also assessed peripheral concentrations of IL-6, IL-8 and TNF-a using ELLA assays. Secondary analyses included comparisons of SARS-CoV-2 seroprevalence and titers between patient diagnostic subgroups, and between newly admitted (hospitalization ≤ 7 days) and hospitalized patients (hospitalization > 7 days) and correlations between serological and cytokines. RESULTS: Patients had a significantly higher SARS-CoV-2 seroprevalence (67.85 % [95% CI 62.20-73.02]) than hospital caregivers (27.08% [95% CI 21.29-33.77]), and had significantly higher global SARS-CoV-2 titers (F = 29.40, df = 2, p < 0.0001). Moreover, patients had a 2.51-fold (95% CI 1.95-3.20) higher SARS-CoV-2 exposure risk compared to hospital caregivers (Fisher's exact test, P < 0.0001). No difference was found in SARS-CoV-2 seroprevalence and titers between patient subgroups. Patients could be differentiated most accurately from hospital caregivers by their higher Spike protein titers (OR 136.54 [95% CI 43.08-481.98], P < 0.0001), lower S1 (OR 0.06 [95% CI 0.02-0.15], P < 0.0001) titers and higher IL-6 (OR 3.41 [95% CI 1.73-7.24], P < 0.0001) and TNF-α (OR 34.29 [95% CI 5.00-258.87], P < 0.0001) and lower titers of IL-8 (OR 0.13 [95% CI 0.05-0.30], P < 0.0001). Seropositive patients had significantly higher SARS-COV-2 antibody titers compared to seropositive hospital caregivers (F = 19.53, df = 2, P < 0.0001), while titers were not different in seronegative individuals. Pro-inflammatory cytokine concentrations were not associated with serological status. CONCLUSION: Our work demonstrated a very high unrecognized exposure to SARS-CoV-2 among newly admitted and hospitalized psychiatric inpatients, which is cause for concern in the context of highly robust evidence of adverse outcomes following COVID-19 in psychiatric patients. Attention should be directed toward monitoring and mitigating exposure to infectious agents within psychiatric hospitals.

The relationship between immune and cognitive dysfunction in mood and psychotic disorder: a systematic review and a meta-analysis.

BACKGROUND: In psychotic and mood disorders, immune alterations are hypothesized to underlie cognitive symptoms, as they have been associated with elevated blood levels of inflammatory cytokines, kynurenine metabolites, and markers of microglial activation. The current meta-analysis synthesizes all available clinical evidence on the associations between immunomarkers (IMs) and cognition in these psychiatric illnesses. METHODS: Pubmed, Web of Science, and Psycinfo were searched for peer-reviewed studies on schizophrenia spectrum disorder (SZ), bipolar disorder (BD), or major depressive disorder (MDD) including an association analysis between at least one baseline neuropsychological outcome measure (NP) and one IM (PROSPERO ID:CRD42021278371). Quality assessment was performed using BIOCROSS. Correlation meta-analyses, and random effect models, were conducted in Comprehensive Meta-Analysis version 3 investigating the association between eight cognitive domains and pro-inflammatory and anti-inflammatory indices (PII and AII) as well as individual IM. RESULTS: Seventy-five studies (n = 29,104) revealed global cognitive performance (GCP) to be very weakly associated to PII (r = -0.076; p = 0.003; I2 = 77.4) or AII (r = 0.067; p = 0.334; I2 = 38.0) in the combined patient sample. Very weak associations between blood-based immune markers and global or domain-specific GCP were found, either combined or stratified by diagnostic subgroup (GCP x PII: SZ: r = -0.036, p = 0.370, I2 = 70.4; BD: r = -0.095, p = 0.013, I2 = 44.0; MDD: r = -0.133, p = 0.040, I2 = 83.5). We found evidence of publication bias. DISCUSSION: There is evidence of only a weak association between blood-based immune markers and cognition in mood and psychotic disorders. Significant publication and reporting biases were observed and most likely underlie the inflation of such associations in individual studies.

The future of immunopsychiatry: Three milestones to clinical innovation.

Psychoneuroimmunology, the area of research dedicated to understanding the fundamental interactions between the central nervous system and the immune system, has given rise to the development of Immunopsychiatry, a new discipline which harnesses the immune system to produce beneficial outcomes for mental health problems. Immunopsychiatry has the potential to become a clinically relevant specialty area in psychiatric practice, but has not yet been adopted by the wider mental health community. This paper aims to map out the future trajectory of Immunopsychiatry on its road towards science-to-policy knowledge translation and clinical implementation. Three critical milestones which will need to be reached in order for Immunopsychiatry to fulfil its promise for clinical innovation are discussed: a clear definition of patients who fall within the immunopsychiatric continuum; demonstration of well-defined clinical benefit and incorporation in clinical guidelines; and convergence with other paradigms in biological psychiatry.

[Heterogeneity in psychiatry training in Europe: competition or collaboration?] / Heterogeniteit in de Europese opleidingen tot psychiater: competitie of samenwerking?

BACKGROUND: The European Union strives towards a mutual recognition of qualifications for medical specialists. Already in 1993, the European Union of Medical Specialists drafted non-binding quality criteria for every medical specialty. In psychiatry, however, European standardisation and quality control of the different national training programmes is currently still lacking.
AIM: To describe the heterogeneity of psychiatric postgraduate training in Europe and its ensuing challenges.
METHOD: We used the scientific literature and results from surveys conducted with European trainees between 2016 and 2018.
RESULTS: Psychiatric training differed throughout Europe in terms of format, content and working conditions. The minimum duration of training in the European Union ranged from 4 to 7 years. Regarding content, the position of psychotherapy differed significantly between countries. Finally, the differences in subjective learning experiences were influenced by organisational variables, such as working hours and availability of supervision.
CONCLUSION: Despite all efforts to harmonise psychiatry training in Europe, in practice there has been little progress towards this goal. Nevertheless, information on the differences in training variables between countries has become more readily available, and trainees may use this knowledge to actively shape their own education.

To which countries do European psychiatric trainees want to move to and why?

BACKGROUND: There is a shortage of psychiatrists worldwide. Within Europe, psychiatric trainees can move between countries, which increases the problem in some countries and alleviates it in others. However, little is known about the reasons psychiatric trainees move to another country. METHODS: Survey of psychiatric trainees in 33 European countries, exploring how frequently psychiatric trainees have migrated or want to migrate, their reasons to stay and leave the country, and the countries where they come from and where they move to. A 61-item self-report questionnaire was developed, covering questions about their demographics, experiences of short-term mobility (from 3 months up to 1 year), experiences of long-term migration (of more than 1 year) and their attitudes towards migration. RESULTS: A total of 2281 psychiatric trainees in Europe participated in the survey, of which 72.0% have 'ever' considered to move to a different country in their future, 53.5% were considering it 'now', at the time of the survey, and 13.3% had already moved country. For these immigrant trainees, academic was the main reason they gave to move from their country of origin. For all trainees, the overall main reason for which they would leave was financial (34.4%), especially in those with lower (<500€) incomes (58.1%), whereas in those with higher (>2500€) incomes, personal reasons were paramount (44.5%). CONCLUSIONS: A high number of psychiatric trainees considered moving to another country, and their motivation largely reflects the substantial salary differences. These findings suggest tackling financial conditions and academic opportunities.

MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates.

Studies on mucosal-associated invariant T cells (MAITs) in nonhuman primates (NHP), a physiologically relevant model of human immunity, are handicapped due to a lack of macaque MAIT-specific reagents. Here we show that while MR1 ligand-contact residues are conserved between human and multiple NHP species, three T-cell receptor contact-residue mutations in NHP MR1 diminish binding of human MR1 tetramers to macaque MAITs. Construction of naturally loaded macaque MR1 tetramers facilitated identification and characterization of macaque MR1-binding ligands and MAITs, both of which mirrored their human counterparts. Using the macaque MR1 tetramer we show that NHP MAITs activated in vivo in response to both Bacillus Calmette-Guerin vaccination and Mycobacterium tuberculosis infection. These results demonstrate that NHP and human MR1 and MAITs function analogously, and establish a preclinical animal model to test MAIT-targeted vaccines and therapeutics for human infectious and autoimmune disease.

Simian immunodeficiency virus (SIV) infection influences the level and function of regulatory T cells in SIV-infected rhesus macaques but not SIV-infected sooty mangabeys.

Differences in clinical outcome of simian immunodeficiency virus (SIV) infection in disease-resistant African sooty mangabeys (SM) and disease-susceptible Asian rhesus macaques (RM) prompted us to examine the role of regulatory T cells (Tregs) in these two animal models. Results from a cross-sectional study revealed maintenance of the frequency and absolute number of peripheral Tregs in chronically SIV-infected SM while a significant loss occurred in chronically SIV-infected RM compared to uninfected animals. A longitudinal study of experimentally SIV-infected animals revealed a transient increase in the frequency of Tregs from baseline values following acute infection in RM, but no change in the frequency of Tregs occurred in SM during this period. Further examination revealed a strong correlation between plasma viral load (VL) and the level of Tregs in SIV-infected RM but not SM. A correlation was also noted in SIV-infected RM that control VL spontaneously or in response to antiretroviral chemotherapy. In addition, immunofluorescent cell count assays showed that while Treg-depleted peripheral blood mononuclear cells from RM led to a significant enhancement of CD4+ and CD8+ T-cell responses to select pools of SIV peptides, there was no detectable T-cell response to the same pool of SIV peptides in Treg-depleted cells from SIV-infected SM. Our data collectively suggest that while Tregs do appear to play a role in the control of viremia and the magnitude of the SIV-specific immune response in RM, their role in disease resistance in SM remains unclear.

Expanded tissue targets for foamy virus replication with simian immunodeficiency virus-induced immunosuppression.

Foamy viruses (FV) are the oldest known genus of retroviruses and have persisted in nonhuman primates for over 60 million years. FV are efficiently transmitted, leading to a lifelong nonpathogenic infection. Transmission is thought to occur through saliva, but the detailed mechanism is unknown. Interestingly, this persistent infection contrasts with the rapid cytopathicity caused by FV in vitro, suggesting a host defense against FV. To better understand the tissue specificity of FV replication and host immunologic defense against FV cytopathicity, we quantified FV in tissues of healthy rhesus macaques (RM) and those severely immunosuppressed by simian immunodeficiency virus (SIV). Contrary to earlier findings, we find that all immunocompetent animals consistently have high levels of viral RNA in oral tissues but not in other tissues examined, including the small intestine. Strikingly, abundant viral transcripts were detected in the small intestine of all of the SIV-infected RM, which has been shown to be a major site of SIV (and human immunodeficiency virus)-induced CD4+ T-cell depletion. In contrast, there was a trend to lower viral RNA levels in oropharyngeal tissues of SIV-infected animals. The expansion of FV replication to the small intestine but not to other CD4+ T-cell-depleted tissues suggests that factors other than T-cell depletion, such as dysregulation of the jejunal microenvironment after SIV infection, likely account for the expanded tissue tropism of FV replication.

An anti-CD45RO immunotoxin kills HIV-latently infected cells from individuals on HAART with little effect on CD8 memory.

CD4+ CD45RO+ T cells are the major latent viral reservoir in HIV-infected individuals and hence a major obstacle in curing the disease. An anti-CD45RO immunotoxin (IT) can decrease the number of both productively and latently infected CD4+ T cells obtained from HIV-infected individuals with detectable viremia. In this study, we determined whether this IT could also kill latently infected replication-competent CD4+ T cells obtained from infected individuals without detectable plasma viremia. Our results demonstrate that ex vivo treatment with the anti-CD45RO IT significantly reduced the frequency of these cells. In contrast, the IT had only a modest effect on the cytomegalovirus-specific memory responses of CD8+ T cells. These results suggest that purging latent cells from infected individuals on highly active antiretroviral therapy with the anti-CD45RO IT might reduce the HIV latent reservoir without seriously compromising CD8+ T cell memory responses.

Impairment of Gag-specific CD8(+) T-cell function in mucosal and systemic compartments of simian immunodeficiency virus mac251- and simian-human immunodeficiency virus KU2-infected macaques.

The identification of several simian immunodeficiency virus mac251 (SIV(mac251)) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8(+) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIV(mac251) and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4(+) T cells. The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8(+) T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIV(mac251) that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIV(mac251)-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8(+) T-cell function.

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

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 naïve 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.

Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry.

Bone marrow hematogones (B-lymphocyte precursors) may cause problems in diagnosis because of their morphologic and immunophenotypic similarities to neoplastic lymphoblasts. The purposes of this prospective, multiparametric flow cytometry study were to quantify hematogones across age groups and a spectrum of clinical conditions, to identify factors that affect the relative quantity of hematogones, and to compare their immunophenotype with that of neoplastic lymphoblasts. A total of 662 consecutive marrow specimens were analyzed for hematogones using one of two 4-color antibody combinations; hematogones were identified in 528 (79.8%). There was a significant decline in hematogones with increasing age (P <.001), but a broad range was found at all ages and many adults had a relatively high number. Specimens processed by density gradient had a higher mean percent hematogones than those processed by erythrocyte lysis (P <.001). There was a direct decline in hematogones with increasing marrow involvement with neoplastic cells. A total of 8% of the 662 specimens contained 5% or more hematogones: 24.6% of specimens from patients aged less than 16 years and 6.3% from those 16 and older (P <.000 01). Increased hematogones were observed most often in patients with lymphoma, marrow regenerative states, immune cytopenias, and acquired immunodeficiency syndrome. Hematogones always exhibited a typical complex spectrum of antigen expression that defines the normal antigenic evolution of B-cell precursors and lacked aberrant expression. In contrast, lymphoblasts in 49 cases of precursor B-ALL showed maturation arrest and exhibited 1 to 11 immunophenotypic aberrancies. Four-color flow cytometry with optimal combinations of antibodies consistently distinguishes between hematogones and neoplastic lymphoblasts.

Immunophenotypic analysis of peripheral T-cell neoplasms. A multiparameter flow cytometric approach.

We retrospectively reviewed multiparameter flow cytometric analyses in 50 peripheral T-cell neoplasms (PTCNs). Results were interpreted within the context of a large cohort of nonneoplastic T-cell populations. All PTCN diagnoses were confirmed with morphologic and/or molecular analysis. Aberrant populations were defined as discrete immunophenotypic clusters exhibiting loss of or increased or diminished expression of T-cell antigens relative to internal immunophenotypically normal T-cell populations. An antigenic pattern was considered abnormal if it exceeded ranges for T-cell subsets in specific anatomic sites or was not normally encountered. Forty-six of 50 and 41 of 50 demonstrated 1 or more and 2 or more aberrations, respectively. The most common abnormally expressed antigen was CD3, followed by CD7, CD5, and CD2. Except for CD7, abnormally dim or bright antigen expression was more common than deletion. Only 3 cases were abnormal solely based on expansion of an otherwise immunophenotypically normal population; the remainder had patterns of antigen expression not seen in nonneoplastic populations. These data indicate that most PTCNs are aberrant by multiparameter flow analysis. However, results must be interpreted within the context of thorough knowledge of the immunophenotypic spectrum of nonneoplastic T cells.

CD4(+)CD8(dim) T lymphocytes exhibit enhanced cytokine expression, proliferation and cytotoxic activity in response to HCMV and HIV-1 antigens.

CD4(+)CD8(dim) T cells represent a minor subset of the total CD3(+) T cell population in peripheral blood. Although transient and persistent expansions of these cells have been reported in both healthy and diseased individuals, the functional properties of the CD4(+)CD8(dim) population are largely unknown. In this study, we examined antigen-specific cytokine and proliferative responses of the CD4(+)CD8(dim) subset. In whole blood cultures stimulated with the viral antigens HCMV and HIV-1, a significant fraction of the CD4(+)CD8(dim) subset exhibited cytokine expression and proliferation in response to antigen activation. Typically, the CD4(+)CD8(dim) population contained two- to eightfold higher frequencies of antigen-specific cytokine producing cells than the CD4(+)CD8(-) population. Phenotypic analysis of the cytokine expressing CD4(+)CD8(dim) population indicated that these cells are memory T cells, with a high frequency of this population expressing the cytotoxic markers CD56 and perforin. Furthermore, the CD4(+)CD8(dim) cytokine responses to CMV were shown to be MHC class II dependent. Significantly, purified CD4(+)CD8(dim) T cells were found to possess higher CMV-specific cytotoxic activity than purified CD4(+)CD8(-) T cells in a standard (51)Cr-release CTL assay. Thus, CD4(+)CD8(dim) T cells appear to be MHC class II dependent, are capable of cytolytic effector activity, and are highly enriched within the CD4(+) cell populations specific for HCMV and HIV-1.

Use of overlapping peptide mixtures as antigens for cytokine flow cytometry.

Intracellular cytokine staining and flow cytometry can be used to measure T-cell responses to defined antigens. Although CD8+ T-cell responses to soluble proteins are inefficiently detected by this approach, peptides can be used as antigens. Using overlapping peptides spanning an entire protein sequence, CD8+ T-cell responses can be detected to multiple epitopes, regardless of HLA type. In this study, overlapping peptide mixes of various lengths were compared and 15 amino acid peptides with 11 amino acid overlaps were found to stimulate both CD4+ and CD8+ T-cell responses. Such peptide mixes stimulated CD4+ T-cell responses equivalent to those observed with whole recombinant protein, while simultaneously stimulating CD8+ T-cell responses much higher than those observed with whole protein. Although 8-12 amino acid peptides produced the highest level of CD8+ T-cell responses, 15 amino acid peptides were still very effective. Peptides that were 20 amino acids in length, however, did not stimulate strong CD8+ T-cell responses at the same peptide dose. The cytokine responses to individual epitopes added up approximately to the response to the entire mix, demonstrating that large mixes can detect responses in a quantitative fashion. Unlike whole protein antigens, peptide mixes were effective at stimulating responses in both cryopreserved PBMC and blood stored for 24 h at room temperature. Thus, overlapping 15 amino acid peptide mixes may facilitate the analysis of antigen-specific CD4+ and CD8+ T-cell responses by cytokine flow cytometry, using clinical specimens that include shipped blood or cryopreserved PBMC.

Clonotypic structure of the human CD4+ memory T cell response to cytomegalovirus.

High steady-state frequencies of CMV-specific CD4(+) memory T cells are maintained in CMV-exposed subjects, and these cells are thought to play a key role in the immunologic control of this permanent infection. However, the essential components of this response are poorly defined. Here, we report the use of a step-wise application of flow cytometric and molecular techniques to determine the number and size of the TCR Vbeta-defined clonotypes within freshly obtained CMV-specific CD4(+) memory T cell populations of four healthy, CMV-exposed human subjects. This analysis revealed a stable clonotypic hierarchy in which 1-3 dominant clonotypes are maintained in concert with more numerous subdominant and minor clonotypes. These dominant clonotypes accounted for 10-50% of the overall CMV response, and comprised from 0.3 to 4.0% of peripheral blood CD4(+) T cells. Two subjects displayed immunodominant responses to single epitopes within the CMV matrix phosphoprotein pp65; these single epitope responses were mediated by a single dominant clonotype in one subject, and by multiple subdominant and minor clonotypes in the other. Thus, the CMV-specific CD4(+) T cell memory repertoire in normal subjects is characterized by striking clonotypic dominance and the potential for epitope focusing, suggesting that primary responsibility for immunosurveillance against CMV reactivation rests with a handful of clones recognizing a limited array of CMV determinants. These data have important implications for the understanding of mechanisms by which a genetically stable chronic viral pathogen such as CMV is controlled, and offer possible insight into the failure of such control for a genetically flexible pathogen like HIV-1.

Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy.

We measured the longitudinal responses to 95 HLA class I-restricted human immunodeficiency virus (HIV) epitopes and an immunodominant HLA A2-restricted cytomegalovirus (CMV) epitope in eight treatment-naive HIV-infected individuals, using intracellular cytokine staining. Patients were treated with highly active antiretroviral therapy (HAART) for a median of 78 weeks (range, 34 to 121 weeks). Seven of eight patients maintained an undetectable viral load for the duration of therapy. A rapid decline in HIV-specific CD8(+) T-cell response was observed at initiation of therapy. After an undetectable viral load was achieved, a slower decrease in HIV-specific CD8(+) T-cell response was observed that was well described by first-order kinetics. The median half-life for the rate of decay was 38.8 (20.3 to 68.0) weeks when data were expressed as percentage of peripheral CD8(+) T cells. In most cases, data were similar when expressed as the number of responding CD8(+) T cells per microliter of blood. In subjects who responded to more than one HIV epitope, rates of decline in response to the different epitopes were similar and varied by a factor of 2.2 or less. Discontinuation of treatment resulted in a rapid increase in HIV-specific CD8(+) T cells. Responses to CMV increased 1.6- and 2.8-fold within 16 weeks of initiation of HAART in two of three patients with a measurable CMV response. These data suggest that HAART quickly starts to restore CD8(+) T-cell responses to other chronic viral infections and leads to a slow decrease in HIV-specific CD8(+) T-cell response in HIV-infected patients. The slow decrease in the rate of CD8(+) T-cell response and rapid increase in response to recurrent viral replication suggest that the decrease in CD8(+) T-cell response observed represents a normal memory response to withdrawal of antigen.