Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome - State of the art: Report of the 2nd international meeting at the Charité Fatigue Center.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment. During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies. Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies.

The KORE-INNOVATION trial, a prospective controlled multi-site clinical study to implement and assess the effects of an innovative peri-operative care pathway for patients with ovarian cancer: rationale, methods and trial design.

BACKGROUND: Advanced ovarian cancer is managed by extensive surgery, which could be associated with high morbidity. A personalized pre-habilitation strategy combined with an 'enhanced recovery after surgery' (ERAS) pathway may decrease post-operative morbidity. PRIMARY OBJECTIVE: To analyze the effects of a combined multi-modal pre-habilitation and ERAS strategy on severe post-operative morbidity for patients with ovarian cancer (primary diagnosis or first recurrence) undergoing cytoreductive surgery. STUDY HYPOTHESIS: A personalized multi-modal pre-habilitation algorithm entailing a physical fitness intervention, nutritional and psycho-oncological support, completed by an ERAS pathway, reduces post-operative morbidity. TRIAL DESIGN: This is a prospective, controlled, non-randomized, open, interventional two-center clinical study. Endpoints will be compared with a three-fold control: (a) historic control group (data from institutional ovarian cancer databases); (b) prospective control group (assessed before implementing the intervention); and (c) matched health insurance controls. INCLUSION CRITERIA: Patients with ovarian, fallopian, or primary peritoneal cancer undergoing primary surgical treatment (primary ovarian cancer or first recurrence) can be included. The intervention group receives an additional multi-level study treatment: (1) standardized frailty assessment followed by (2) a personalized tri-modal pre-habilitation program and (3) peri-operative care according to an ERAS pathway. EXCLUSION CRITERIA: Inoperable disease or neoadjuvant chemotherapy, simultaneous diagnosis of simultaneous primary tumors, in case of interference with the overall prognosis (except for breast cancer); dementia or other conditions that impair compliance or prognosis. PRIMARY ENDPOINT: Reduction of severe post-operative complications (according to Clavien- Dindo Classification (CDC) III-V) within 30 days after surgery. SAMPLE SIZE: Intervention group (n=414, of which approximately 20% insure with the participating health insurance); historic control group (n=198); prospective control group (n=50), health insurance controls (for those intervention patients who are members of the participating health insurance). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The intervention phase started in December 2021 and will continue until June 2023. As of March 2023, 280 patients have been enrolled in the intervention group. The expected completion of the entire study is September 2024. TRIAL REGISTRATION: NCT05256576.

Long-term complications of prone position ventilation with relevance for acute and postacute rehabilitation: a systematic review of the literature.

INTRODUCTION: Prone positioning ventilation (PPV) is an effective treatment for patients with moderate to severe acute respiratory distress syndrome (ARDS). Despite the benefits of PPV, different kinds of short and long-term consequences have been noted. This review summarizes long-term complications of PPV that impact treatment strategies and outcomes in acute and postacute rehabilitation. EVIDENCE ACQUISITION: PubMed/Medline, Cochrane Library, Cochrane COVID-19 Study Register databases and the Google Scholar search engine were systematically searched for studies investigating long-term complications of PPV. The final search date for all sources/databases was January 31, 2022. For our methodological appraisal, we conducted a systematic review of articles without any restrictions on types of articles or publication dates. Only articles published in English and available as full texts were eligible for inclusion. After the screening process, data of interest were extracted from eligible sources: PPV sequelae and conclusions (i.e. possible effects on the course of rehabilitation and therapy strategies). EVIDENCE SYNTHESIS: A total of 59 studies are included in this review. Long-term consequences are mainly pressure ulcers and nerve lesions that exist after discharge from the Intensive Care Unit (ICU). Publications rarely recommend treatment strategies for long-term complications after PPV. Due to the quality of the included studies, no robust conclusions as to effective strategies can be drawn. CONCLUSIONS: Further high-quality research is required, considering the different long-term complications after PPV and their impact on rehabilitation in order to draw conclusions about viable physical therapies. Crucially, however, prone positioning (PP) sequelae pose new challenges to physicians and therapists in acute and postacute rehabilitation medicine as well as follow-up care.

[Acute rehabilitation after COVID-19 infection : A selected case series]. / Akutrehabilitation nach COVID­19­Infektion : Eine ausgewählte Fallserie.

BACKGROUND: While the first wave of the coronavirus disease 2019 (COVID-19) pandemic mainly affected the old, currently younger patients also become infected and hospitalized. After severe and critical COVID-19 infections and also after surviving acute phase symptoms, these patients often show symptoms (e.g. exertional dyspnea), organ damage (e.g. of the lungs, the cardiovascular system) as well as psychological impairments. OBJECTIVE: The severe courses after critical cases of COVID-19 represent challenges for rehabilitation and require more than ever rehabilitative treatment approaches even in acute hospitals. METHODS: This article presents a selected case series of patients with a typical constellation of pre-existing conditions due to immunosuppression plus critical course of COVID-19 and indications for acute rehabilitation. RESULTS: This case series depicts the long duration of hospitalization with high numbers of hours on ventilation in the intensive care unit. At the time of transfer to acute rehabilitation these patients are immobile and have severe limitations in all activities of daily life, so that an inpatient rehabilitation in an acute hospital is indicated and the usual means of continuation of rehabilitation were not feasible. The sequelae of lying prone and complications, such as exertional desaturation in the early stage of convalescence are detected in the acute phase of early rehabilitation. CONCLUSION: After severe COVID-19 infections new challenges for rehabilitation are to be expected, so that rehabilitative treatment approaches with an interdisciplinary early rehabilitation in an acute hospital are urgently needed. Finally, acute rehabilitation not only enables a seamless treatment chain for these patients but also the flow of patients from the intensive care unit to ensure the functioning of local infrastructures.

Factors Predicting Limb Volume Reduction Using Compression Bandaging Within Decongestive Lymphatic Therapy in Lymphedema: A Multicountry Prospective Study.

Objectives: To identify predictive factors associated with limb volume reduction using different decongestive lymphatic therapy (DLT) systems in patients with lymphoedema, over a period of up to 28 days. Methods: A multicountry (Canada, France, Germany, the United Kingdom) prospective cohort study using (DLT): skin care, exercise, compression bandaging, and manual lymphatic drainage for up to 4 weeks. Reduction in limb volume comparing DLT with (1) standard multilayer bandaging with inelastic material, and with (2) multilayer bandaging with Coban2, together with the identification of factors associated with limb volume changes. Results: Out of 264 patients with upper or lower limb lymphedema, 133 used Coban2 and 131 used standard care. Following DLT, mean limb volume reduction was 941 mL using Coban2 compared with 814 mL using standard care. A difference of 127 mL was found (95% confidence interval -275 to 529 mL, p = 0.53). Of the 176 patients with leg swelling, 166 (94.3%) had a limb volume measurement after 28 days and were included in the risk factor analysis. Of these, 132 (79.5%) were female, with overall mean age of 60.1 years (standard deviation = 14.7), with secondary lymphedema in 102/163 (62.6%). Duration of lymphedema was >10 years in 75/161 (46.6%) and 99/166 (59.7%) were International Society of Lymphology late-stage II/III, indicating longstanding and/or a high frequency of patients with advanced stages of lymphedema. Ninety-one (54.8%) received Coban2 and 75 (45.2%) had standard care. Multivariable factors for a greater leg volume reduction were large initial leg volume (p < 0.001), DLT treatment duration of 4 weeks compared with 2 weeks (p = 0.01), and peripheral arterial disease (p = 0.015). Conclusion: Limb volume changes were found to be similar between groups. Lack of standardization of DLT makes interpretation of effectiveness problematic. There is an urgent need for randomized-controlled trials. Despite this, severe lymphedema with a large limb volume responded well to DLT in this study.

Quality of Life and Costs Within Decongestive Lymphatic Therapy in Patients with Leg Lymphedema: A Multicountry, Open-Label, Prospective Study.

Background: Little is known of the impact in terms of health-related quality of life (HRQoL) and cost-effectiveness with decongestive therapy. Objectives: To examine changes in limb volume, quality of life (QoL), and treatment cost of methods of decongestive lymphatic therapy (DLT). Methods: Patients with chronic edema/lymphedema of the leg were invited to participate in a study of DLT in four countries (United Kingdom, France, Germany, and Canada). In each country two sites were selected. One site used their standard method of DLT in their service, including compression with multilayer bandaging with inelastic material. The other site used a system that included 3M™ Coban 2™ as the bandage treatment alongside other standard components of DLT. Patients were followed for either 2 or 4 weeks depending on the local protocols. At entry, at 2 weeks, and at 4 weeks, patients were assessed by using a health index (EQ-5D), a disease-specific HRQoL tool (LYMQOL) and resource usage was recorded over the treatment period. Results: Of the 165 patients with cost data, 90 were treated with Coban 2 and 75 with standard care compression bandaging. There was good evidence of an improvement in EQ-5D of 0.077 (p < 0.001) in all patients. LYMQOL showed significant improvements (p < 0.001) with lower scores. There were no major differences between the two arms of the study with respect to HRQoL. The number of treatment episodes was higher in those treated with standard care (8.15 vs. 6.37), but the overall treatment cost was higher with Coban 2 (£890.7) compared with standard care (£723.0). Conclusion: QoL improved in the standard care and Coban 2 group bandages, and there was no demonstrable difference between the care systems. Further work is required to examine the role of the individual parts of DLT that provide the greatest benefit to patients and the health systems that support them.

Differential contractile response of critically ill patients to neuromuscular electrical stimulation.

BACKGROUND: Neuromuscular electrical stimulation (NMES) has been investigated as a preventative measure for intensive care unit-acquired weakness. Trial results remain contradictory and therefore inconclusive. As it has been shown that NMES does not necessarily lead to a contractile response, our aim was to characterise the response of critically ill patients to NMES and investigate potential outcome benefits of an adequate contractile response. METHODS: This is a sub-analysis of a randomised controlled trial investigating early muscle activating measures together with protocol-based physiotherapy in patients with a SOFA score ≥ 9 within the first 72 h after admission. Included patients received protocol-based physiotherapy twice daily for 20 min and NMES once daily for 20 min, bilaterally on eight muscle groups. Electrical current was increased up to 70 mA or until a contraction was detected visually or on palpation. Muscle strength was measured by a blinded assessor at the first adequate awakening and ICU discharge. RESULTS: One thousand eight hundred twenty-four neuromuscular electrical stimulations in 21 patients starting on day 3.0 (2.0/6.0) after ICU admission were included in this sub-analysis. Contractile response decreased from 64.4% on day 1 to 25.0% on day 7 with a significantly lower response rate in the lower extremities and proximal muscle groups. The electrical current required to elicit a contraction did not change over time (day 1, 50.2 [31.3/58.8] mA; day 7, 45.3 [38.0/57.5] mA). The electrical current necessary for a contractile response was higher in the lower extremities. At the first awakening, patients presented with significant weakness (3.2 [2.5/3.8] MRC score). When dividing the cohort into responders and non-responders (> 50% vs. ≤ 50% contractile response), we observed a significantly higher SOFA score in non-responders. The electrical current necessary for a muscle contraction in responders was significantly lower (38.0 [32.8/42.9] vs. 54.7 [51.3/56.0] mA, p < 0.001). Muscle strength showed higher values in the upper extremities of responders at ICU discharge (4.4 [4.1/4.6] vs. 3.3 [2.8/3.8] MRC score, p = 0.036). CONCLUSION: Patients show a differential contractile response to NMES, which appears to be dependent on the severity of illness and also relevant for potential outcome benefits. TRIAL REGISTRATION: ISRCTN ISRCTN19392591 , registered 17 February 2011.

[Interdisciplinary Acute Medical Rehabilitation after Sepsis - A Retrospective Analysis]. / Fachübergreifende Frührehabilitation nach Sepsis ­ Eine retrospektive Analyse .

BACKGROUND: Surviving sepsis may have consequences of high impact for the patients' further life regarding functioning in mobility and activities of daily living, among other fields. Patients consecutively have a great need of rehabilitation interventions beginning with early mobilization in the Intensive Care Unit ICU. Acute medical rehabilitation is a concept of early rehabilitation still in the acute care hospital, normally beginning after a direct transferal from the ICU. Its aim is to improve the patients' functioning in mobility and activities of daily living (ADL) to enable further post-acute rehabilitation interventions. METHODS: In this retrospective analysis a sample of patients who received acute medical rehabilitation after surviving a sepsis or severe sepsis was followed. The study targeted the question if basic functions of mobility and ADL could be improved by acute medical rehabilitation. Furthermore, the need for aid supply was evaluated, as well as the type of discharge or transferal after acute care. RESULTS: The increase of mobility and ADL capability before and after acute medical rehabilitation was highly significant (p<0.001 each) and showed very large effect sizes (d=1.3, 1.4 respectively). Aid supply was organized for 92% of patients. A majority of patients could receive consecutive post-acute rehabilitation after re-gaining function. DISCUSSION: The data shows the enormous gain in functioning that can be reached with an acute medical rehabilitation intervention after ICU treatment of sepsis.

[Competence Based Catalogue of Learning Objectives for Rehabilitation, Physical Medicine, Naturopathic Treatment - Revised Version - Joint Recommendations of the German Society of Rehabilitation Science and the German Society of Physical Medicine and Rehabilitation]. / Kompetenzbasierter Lernzielkatalog "Rehabilitation, Physikalische Medizin, Naturheilverfahren" (RPMN) ­ revidierte Fassung.

Since the first publication of learning objectives for the interdisciplinary subject "Rehabilitation, Physical Medicine, Naturopathic Treatment" in undergraduate medical education in 2004 a revision is reasonable due to heterogenous teaching programmes in the faculties and the introduction of the National Competence Based Catalogue of Learning Objectives in Medicine as well as the "Masterplan Medical Education 2020". Therefore the German Society of Rehabilitation Science and the German Society of Physical Medicine and Rehabilitation started a structured consensus process using the DELPHI-method to reduce the learning objectives and arrange them more clearly. Objectives of particular significance are emphasised. All learning objectives are assigned to the cognitive and methodological level 1 or to the action level 2. The learning objectives refer to the less detailed National Competence Based Catalogue of Learning Objectives in Medicine. The revised learning objectives will contribute to further progress in competence based and more homogenous medical teaching in core objectives of Rehabilitation, Physical Medicine, and Naturopathic Treatment in the faculties.

Introduction of the Charité Mobility Index (CHARMI) - A Novel Clinical Mobility Assessment for Acute Care Rehabilitation.

INTRODUCTION: Mobility is an essential part of a person's functioning and independence. It encompasses locomotive functions, but also the more basic functions of positioning and transferring. Despite the availability of several mobility-related assessment instruments to date, there is a need for assessment instruments with the specific capability to display the full range of mobilisation. Our aim was to develop and validate a scoring instrument with hierarchical composition where every score value stands for a defined mobility level. PARTICIPANTS AND METHODS: A previously developed and validated pilot instrument was applied to assess patients (n = 113) admitted to an acute rehabilitation programme. Mobility was assessed during admission, subsequently at weekly intervals and at discharge to acquire a detailed status of mobility at multiple time points and individual mobilisation profiles over time. The scoring instrument was then remodelled based on clinical criteria to establish an easy-to-use scoring system with hierarchical composition. Psychometric properties were calculated using an independent sample of 87 consecutive patients. RESULTS: Content validity could be affirmed. The psychometric tests demonstrated excellent convergent validity with the three mobility items of the Barthel Index (r = 0.93), despite an adequately lower correlation with the whole Barthel Index (r = 0.63). Adequate floor and ceiling effects (20%) and a large responsiveness to change (ǀdǀ = 1.7, p < 0.001) between admission and discharge values were demonstrated. Inter-rater reliability was excellent (κ = 0.88). CONCLUSIONS: The Charité Mobility Index (CHARMI) is a promising, easy-to-use hierarchical scoring instrument assessing the full individual spectrum from immobility to unlimited mobility, including positioning, transfer and locomotion items. It allows for monitoring of mobilisation.

GIA-Aneurysmorrhaphy and Dermal Detachment: A Novel Technique to Repair Arteriovenous Fistula Aneurysms.

This report describes a simplified technique for management of aneurysmal arteriovenous fistulas along with results of initial clinical experience in 12 patients. Various techniques have been described which seek to repair the arteriovenous fistula and lengthen its duration of use. Here, we introduce the GIA-aneurysmorrhaphy and dermal detachment (GADD) procedure, a novel technique which requires minimal dissection to decompress tension on the overlying skin. Transverse incisions were made proximally and distally to the aneurysmal segment, which was then bluntly dissected along its length on either side. A GIA stapler is then fired along the longitudinal axis, narrowing the lumen of the fistula and separating the aneurysm from the skin. After the operation, the arteriovenous fistulae were used continuously until death (1 patient for 12 months), until thrombosis (1 patient for 13 months), or continue to be in use (9 patients, mean patency 18 months). One patient underwent conversion to open aneurysmorrhaphy due to intraoperative fistula occlusion. Five patients resumed hemodialysis immediately, while the remaining resumed hemodialysis within 3 months. The most common complication was cellulitis (3 patients). The GADD procedure as described in this report offers an effective and low-risk option for the management of venous aneurysms with threatened skin in hemodialysis patients.

Psychological and sociodemographic predictors of premature discontinuation of a 1-year multimodal outpatient weight-reduction program: an attrition analysis.

OBJECTIVE: Attrition rates of up to 77% have been reported in conservative weight-reduction programs for the treatment of obesity. In view of the cost of such programs to the health system, there is a need to identify the variables that predict premature discontinuation of treatment. Previous studies have focused mainly on somatic and sociodemographic parameters. The prospective influence of psychological factors has not been systematically investigated to date. METHODS: A total of 164 patients (138 of whom were women) with a mean age of 45 years and a mean body mass index of 39.57 participated in a 1-year outpatient weight-reduction program at the Charité - Universitätsmedizin Berlin University Hospital. The program included movement therapy, dietary advice, psychoeducational and behavioral interventions, relaxation procedures, and consultations with a specialist in internal medicine and a psychologist. Patients also underwent regular laboratory and psychological testing. The results were evaluated using a t-test, χ(2)-test, and logistic regression analysis. RESULTS: Seventy-one of the 164 patients (61 women, mean age = 43 years, mean body mass index = 39.53) withdrew before the end of the program (attrition rate = 43.3%). While there were no differences between the somatic and metabolic characteristics of those who withdrew and those who remained, the sociodemographic and psychological factors had some relevance. In particular, "expectation of self-efficacy" (Fragebogen zu Selbstwirksamkeit, Optimismus und Pessimismus [SWOP]), "not working," "tiredness" (Berliner Stimmungsfragebogen [BSF]), "pessimism" (SWOP) and "positive reframing" (Brief-COPE) were found to play a role in whether participants subsequently dropped out of the treatment. "Support coping" (Brief-COPE) and "older age" prior to the start of treatment were identified as variables that promoted treatment adherence. CONCLUSION: The results are discussed in light of previous findings and with regard to whether the modules of the weight-reduction program should be adapted.

The effect of clothes on sphygmomanometric and oscillometric blood pressure measurement.

AIM: We determined the effect of wearing clothes under the manometer's cuff on blood pressure in manual auscultatory sphygmomanometric and automatic oscillometric blood pressure measurement. METHODS: Two hundred and one subjects were examined with the auscultatory sphygmomanometric and the automatic oscillometric method, each with and without sleeved arm in random order. The auscultatory readings were blinded for the subjects' state of clothing. Common shirts and sweaters (thinner than 2 mm) were used. RESULTS: Based on confidence intervals of the differences between sleeved and non-sleeved arm measurements and equivalence test, sleeves did not lead to statistically significant effects. Measurements with and without sleeve can be accepted equal within an a priori defined interval of equivalence of +/-4 mmHg. DISCUSSION: This study shows that measuring blood pressure with the manometer's cuff over the subject's sleeve does not differ significantly from non-sleeved arm measurements. This is true for a sample that includes normotensive as well as hypertensive persons with a wide age range. For clinical practice, the not significant mean differences of 0.5-1.1 mmHg are interpreted as not relevant. In this study with a statistical power to find a difference of 4 mmHg, blood pressure measurements were found to be equivalent with and without clothes thinner than 2 mm.

Major histocompatibility complex class I alleles associated with slow simian immunodeficiency virus disease progression bind epitopes recognized by dominant acute-phase cytotoxic-T-lymphocyte responses.

Certain major histocompatibility complex class I (MHC-I) alleles are associated with delayed disease progression in individuals infected with human immunodeficiency virus (HIV) and in macaques infected with simian immunodeficiency virus (SIV). However, little is known about the influence of these MHC alleles on acute-phase cellular immune responses. Here we follow 51 animals infected with SIV(mac)239 and demonstrate a dramatic association between Mamu-A*01 and -B*17 expression and slowed disease progression. We show that the dominant acute-phase cytotoxic T lymphocyte (CTL) responses in animals expressing these alleles are largely directed against two epitopes restricted by Mamu-A*01 and one epitope restricted by Mamu-B*17. One Mamu-A*01-restricted response (Tat(28-35)SL8) and the Mamu-B*17-restricted response (Nef(165-173)IW9) typically select for viral escape variants in early SIV(mac)239 infection. Interestingly, animals expressing Mamu-A*1 and -B*17 have less variation in the Tat(28-35)SL8 epitope during chronic infection than animals that express only Mamu-A*01. Our results show that MHC-I alleles that are associated with slow progression to AIDS bind epitopes recognized by dominant CTL responses during acute infection and underscore the importance of understanding CTL responses during primary HIV infection.

Characterization of the peptide-binding specificity of Mamu-B*17 and identification of Mamu-B*17-restricted epitopes derived from simian immunodeficiency virus proteins.

The SIV-infected rhesus macaque is an excellent model to examine candidate AIDS virus vaccines. These vaccines should elicit strong CD8(+) responses. Previous definition of the peptide-binding motif and optimal peptides for Mamu-A*01 has created a demand for Mamu-A*01-positive animals. We have now studied a second MHC class I molecule, Mamu-B*17, that is present in 12% of captive-bred Indian rhesus macaques. The peptide-binding specificity of the Mamu-B*17 molecule was characterized using single substitution analogs of two Mamu-B*17-binding peptides and libraries of naturally occurring sequences of viral or bacterial origin. Mamu-B*17 uses position 2 and the C terminus of its peptide ligands as dominant anchor residues. The C terminus was found to have a very narrow specificity for the bulky aromatic residue W, with other aromatic residues (F and Y) being only occasionally tolerated. Position 2 is associated with a broad chemical specificity, readily accommodating basic (H and R), bulky hydrophobic (F and M), and small aliphatic (A) residues. Using this motif, we identified 50 peptides derived from SIV(mac)239 that bound Mamu-B*17 with an affinity of 500 nM or better. ELISPOT and intracellular cytokine-staining assays showed that 16 of these peptides were antigenic. We have, therefore, doubled the number of MHC class I molecules for which SIV-derived binding peptides have been characterized. This allows for the quantitation of immune responses through tetramers and analysis of CD8(+) function by intracellular cytokine-staining assays and ELISPOT. Furthermore, it is an important step toward the design of a multiepitope vaccine for SIV and HIV.

Tat-vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication.

The regulatory proteins of human immunodeficiency virus may represent important vaccine targets. Here we assessed the role of Tat-specific cytotoxic T lymphocytes (CTL) in controlling pathogenic simian immunodeficiency virus SIVmac239 replication after using a DNA-prime, vaccinia virus Ankara-boost vaccine regimen. Despite the induction of Tat-specific CTL, there was no significant reduction in either peak or viral set point compared to that of controls.

Dominance of CD8 responses specific for epitopes bound by a single major histocompatibility complex class I molecule during the acute phase of viral infection.

Cytotoxic T-lymphocyte (CTL) responses are thought to control human immunodeficiency virus replication during the acute phase of infection. Understanding the CD8(+) T-cell immune responses early after infection may, therefore, be important to vaccine design. Analyzing these responses in humans is difficult since few patients are diagnosed during early infection. Additionally, patients are infected by a variety of viral subtypes, making it hard to design reagents to measure their acute-phase immune responses. Given the complexities in evaluating acute-phase CD8(+) responses in humans, we analyzed these important immune responses in rhesus macaques expressing a common rhesus macaque major histocompatibility complex class I molecule (Mamu-A*01) for which we had developed a variety of immunological assays. We infected eight Mamu-A*01-positive macaques and five Mamu-A*01-negative macaques with the molecularly cloned virus SIV(mac)239 and determined all of the simian immunodeficiency virus-specific CD8(+) T-cell responses against overlapping peptides spanning the entire virus. We also monitored the evolution of particular CD8(+) T-cell responses by tetramer staining of peripheral lymphocytes as well as lymph node cells in situ. In this first analysis of the entire CD8(+) immune response to autologous virus we show that between 2 and 12 responses are detected during the acute phase in each animal. CTL against the early proteins (Tat, Rev, and Nef) and against regulatory proteins Vif and Vpr dominated the acute phase. Interestingly, CD8(+) responses against Mamu-A*01-restricted epitopes Tat(28-35)SL8 and Gag(181-189)CM9 were immunodominant in the acute phase. After the acute phase, however, this pattern of reactivity changed, and the Mamu-A*01-restricted response against the Gag(181-189)CM9 epitope became dominant. In most of the Mamu-A*01-positive macaques tested, CTL responses against epitopes bound by Mamu-A*01 dominated the CD8(+) cellular immune response.