Lower Extremity Somatosensory Evoked Potentials Predict Functional Outcomes in Complete Traumatic Cervical Spinal Cord Injury.

BACKGROUND: Traumatic cervical spinal cord injury (tCSCI) is often a debilitating injury, making early prognosis important for medical and surgical planning. Currently, the best early predictors of prognosis are physical examination, imaging studies, and patient demographics. Despite these factors, patient outcomes continue to vary significantly. The purpose of this study was to evaluate the prognostic value of somatosensory evoked potentials (SSEPs) with functional outcomes in tCSCI patients. METHODS: A retrospective study was conducted on prospectively collected data from 2 academic institutions. Patients 18 years and older who had tCSCI and underwent posterior cervical decompression and stabilization with intraoperative neuromonitoring were reviewed. The outcomes of interest were the American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade and ASIA motor score at follow-up. Outcomes measures were assessed via student t-tests, chi-squared tests, and multivariable regression analysis. RESULTS: A total of 79 patients were included. In complete injuries, detectable lower extremity SSEPs were associated with higher ASIA motor scores at follow-up (P = 0.002), greater increases in ASIA motor scores at follow-up (P = 0.009), and a greater likelihood of clinically important improvement in ASIA motor score (P = 0.024). Incomplete, AIS grade C injuries has higher rates of grade conversion (P = 0.019) and clinically important improvement in ASIA motor score (P = 0.010), compared to AIS grade A or B injuries. CONCLUSIONS: The detection of lower extremity SSEP signals during initial surgical treatment of tCSCI is associated with greater improvement in ASIA motor scores postoperatively. The association is most applicable to patients with complete injury.

Perioperative Opioid Use in Anterior Cruciate Ligament Reconstruction Patients.

Anterior cruciate ligament reconstruction (ACLR) is one of the most commonly performed outpatient orthopaedic procedures, yet there is little data about perioperative opioid prescribing practices. The purposes of this study were to quantify the perioperative opioid prescriptions filled by patients who underwent ACLR and to identify factors associated with greater postoperative opioid use. Patients who underwent ACLR at a single institution between June 2015 and May 2017 were studied using a regional prescription monitoring database to identify all preoperative and postoperative outpatient opioid prescriptions up to 2 years postoperatively. The number of morphine milligram equivalents of each opioid was calculated to determine total morphine milligram equivalents (TMEs) filled preoperatively, at discharge, and refilled postoperatively. Patients who refilled an opioid prescription postoperatively were compared with those who did not. Ninety-nine of 269 (36.8%) total patients refilled an opioid prescription postoperatively. Thirty-three patients (12.3%) required a refill after 2 weeks postoperatively, and no patients refilled after 21 months postoperatively. Fifty-seven patients (21%) received an opioid prescription in the 2 years following surgery that was unrelated to their ACL reconstruction. Increased age, higher body mass index (BMI), government insurance, current or prior tobacco use history, preoperative opioid use, and greater number of medical comorbidities were significantly associated with refilling a prescription opioid. Higher BMI and government insurance were independent predictors of refilling. Higher preoperative TMEs and surgeon were independent predictor of greater refill TMEs. In the opioid-naïve subgroup of 177 patients, only higher BMI was a predictor of refilling, and only greater comorbidities was a predictor of greater refill TMEs. The results demonstrate that preoperative opioid use was associated with postoperative opioid refills and higher refill TMEs in a dose-dependent fashion. A higher percentage of patients received an opioid prescription for reasons unrelated to the ACL reconstruction than refilled a prescription after the first 2 weeks postoperatively.

Higher preoperative expectations predict better outcomes in shoulder surgery patients.

PURPOSE: The purpose of this study is to determine if preoperative expectations (PE) are an independent predictor of greater 2-year outcomes and greater improvement from baseline in shoulder surgery patients. METHODS: Two-hundred and sixteen patients who underwent shoulder surgery at one institution were studied. Patients completed both preoperative and 2-year follow-up questionnaires including PROMIS (Patient-Reported Outcome Measurement Information System) computer-adaptive testing in six domains, American Shoulder and Elbow Surgeons (ASES) score, shoulder numeric pain scale (NPS), and the Marx Shoulder Activity Rating Scale (MARS). PE were measured using the Musculoskeletal Outcomes and Data Evaluation Management System (MODEMS) expectations domain, and satisfaction was measured via the Surgical Satisfaction Questionnaire (SSQ-8). RESULTS: The mean PE score was 86.2 ± 17.8. Greater PE were associated with significantly better 2-year scores for ASES, NPS, MARS, SSQ8, and PROMIS domains of Physical Function, Fatigue, Pain Interference Fatigue and Social Satisfaction. Multivariable analyses demonstrated that greater PE were an independent predictor of both better 2-year scores and greater improvement for PROMIS SS (p < 0.001), ASES (p = 0.007), and shoulder NPS (p = 0.011). CONCLUSION: Greater PE are positively associated with numerous patient-based outcomes 2 years after surgery. With regards to pain relief, shoulder function, and social satisfaction, higher PE are also predictive of better outcome scores and more improvement. This study suggests that preoperative assessment of shoulder surgery PE is important, and that counseling patients to optimize realistic expectations may lead to superior outcomes. LEVEL OF EVIDENCE: III.

Perioperative opioid use and Press Ganey patient satisfaction scores after anterior cruciate ligament reconstruction.

BACKGROUND: Satisfaction measures such as Press Ganey (PG) scores are increasingly used to determine reimbursement. PURPOSE: To investigate the relationship between PG satisfaction scores and perioperative opioid use in patients undergoing anterior cruciate ligament reconstruction (ACLR). METHODS: Patients undergoing ACLR were retrospectively identified. Perioperative opioid prescription data were collected using the electronic medical record. RESULTS: Positive correlations existed between immediate preoperative total morphine equivalents (TMEs) and PG scores. There was a negative correlation between "Pain Control" and preoperative TMEs. CONCLUSION: PG scores were correlated with preoperative and intraoperative opioid administration but not postoperative opioid administration.

Predictors of met expectations two years after knee surgery.

INTRODUCTION: The purpose of this study is to determine which patient factors predict two-year postoperative met expectations in a cohort of patients undergoing knee surgery. Additionally, this study aims to measure the association between met expectations and postoperative outcomes. METHODS: 319 patients undergoing knee surgery at one institution were studied. Patients completed patient-reported outcome questionnaires prior to surgery and again two years postoperatively. Preoperative Expectations and postoperative Met Expectations were measured using the Musculoskeletal Outcomes and Data Evaluation Management System (MODEMS) Expectations domain. RESULTS: The mean Met Expectations score was significantly lower than the preoperative Expectations Score. Worse two-year Met Expectations were associated with older age, higher BMI, greater comorbidities, more previous surgeries, black race, unemployment, lower income, government insurance, Worker's Compensation, smoking, and no injury prior to surgery. Greater Met Expectations were correlated with better scores on all two-year outcome measures as well as greater improvement on most outcome measures. Race, insurance status, function, mental health, and knee pain were found to be independent predictors of Met Expectations. CONCLUSION: This study identified multiple patient factors and outcome measures that were associated with Met Expectations two years after knee surgery.

Preoperative expectations and early postoperative met expectations of extremity orthopaedic surgery.

BACKGROUND: Preoperative patient expectations and met expectations are likely associated with the outcome of treatment. However, there is a lack of data regarding the preoperative expectations and early postoperative met expectations of patients undergoing extremity orthopaedic surgery. The purpose of this study was to identify the predictors of early postoperative met expectations in a cohort of patients undergoing extremity orthopaedic surgery and to assess the relationship between patient expectations and patient-reported outcome (PRO) measures. We hypothesized that patients with higher preoperative expectation scores and higher postoperative met expectation scores would have better early postoperative outcomes. METHODS: Four hundred thirty-five patients age seventeen and older who underwent extremity orthopaedic surgery at one institution were prospectively enrolled in this study. Each patient completed a preoperative questionnaire that included an assessment of demographics, pain, function, general health, treatment expectations, activity level, and Patient-Reported Outcome Measurement Information System (PROMIS) computer adaptive testing. Expectations were evaluated using the Expectations Domain of the Musculoskeletal Outcomes Data Evaluation and Management System (MODEMS) questionnaire. Patients completed a follow-up questionnaire two weeks after surgery that also assessed MODEMS met expectations and satisfaction (Surgical Satisfaction Questionnaire (SSQ-8)). RESULTS: The mean preoperative expectation score was 86.95 ± 16.59, and the mean postoperative met expectation score was 55.02 ± 27.63 (0-100 scale with 100 representing the highest level of expectations). Greater met expectations were significantly associated with white race (p = 0.025), college degree (p = 0.011), and higher income (p = 0.002). Greater met expectations were also significantly associated with greater postoperative physical function, social satisfaction, activity level, and subjective improvement, as well as lower pain interference, joint pain, body pain, fatigue, anxiety, and depression (p < 0.01 for each). Multivariable analysis results found that less postoperative joint pain and greater postoperative social satisfaction, improvement, and physical function were all significant independent predictors of greater met expectations at two weeks postoperative (p < 0.01 for each). CONCLUSION: Greater preoperative expectations are associated with better activity and less pain two weeks after surgery. Met expectations of extremity orthopaedic surgery were associated with postoperative physical function, social satisfaction, activity, pain, anxiety, depression, and subjective improvement. These results may have implications for preoperative counseling and risk factor modification.

Patients undergoing shoulder surgery have high preoperative expectations.

PURPOSE: The primary aims of this study were to (1) assess the preoperative expectations of patients undergoing shoulder surgery, and (2) determine the relationship between preoperative patient demographics, PROs, and preoperative patient expectations. It was hypothesized that younger patients with worse function and worse health status had higher expectations of shoulder surgery. METHODS: Data from a total of 319 patients (319 shoulders) from 2015-2018 were analyzed. Patients completed a series of questionnaires covering demographics and patient-reported outcome measures. Expectations of treatment were evaluated using the Musculoskeletal Outcomes Data Evaluation and Management System. Bivariate analyses were performed to determine the significance of identified associations. RESULTS: The study population consisted of 186 males and 133 females. The mean age was 46.9 (± 17.2), and the mean BMI was 30.1 (± 6.8). Overall, patients had high expectations of shoulder surgery, with a mean score of 84.7 (± 19.3). The most commonly performed procedure in the study population was arthroscopic rotator cuff repair. There was a significant association between pre-treatment expectations and ethnicity, previous shoulder surgery, employment status, income level, tobacco use, preoperative opioid use, depression, and ASA score. CONCLUSION: The findings suggest that patients undergoing shoulder surgery have high overall preoperative expectations, which were significantly associated with ethnicity, surgical history, opioid use, and employment status, and with multiple patient-reported outcome measures including physical function, pain interference, fatigue, and depression. Nevertheless, by discussing expectations preoperatively, orthopaedic surgeons can help patients develop high but realistic expectations to improve outcomes and satisfaction. LEVEL OF EVIDENCE: IV.

Nursing students' experience with fall risk assessment in older adults.

The purpose of this study was to examine the perceptions of nursing students regarding barriers and facilitators to integrating falls risk evaluation and management into practice as well as effective strategies for learning falls prevention. The qualitative research method of thematic analysis was adopted to collect data through semi-structured interviews with senior nursing students. Open and axial coding was used to analyze the data and those with greatest support generated final categories. Thematic analysis identified five central themes (learning to do a fall risk assessment, addressing health beliefs of older adults, barriers to fall assessment, and overcoming barriers) that describe nursing student perceptions of incorporating fall prevention into practice. Results of this study indicate that an online program enhanced with opportunity for hands-on practice provides an effective strategy for learning fall prevention that can be incorporated into nursing practice. Further research is needed to understand how to overcome barriers to integrating fall prevention into practice.

A Genome-Wide Screen with Nicotinamide to Identify Sirtuin-Dependent Pathways in Saccharomyces cerevisiae.

Sirtuins are evolutionarily conserved NAD-dependent deacetylases that catalyze the cleavage of NAD(+) into nicotinamide (NAM), which can act as a pan-sirtuin inhibitor in unicellular and multicellular organisms. Sirtuins regulate processes such as transcription, DNA damage repair, chromosome segregation, and longevity extension in yeast and metazoans. The founding member of the evolutionarily conserved sirtuin family, SIR2, was first identified in budding yeast. Subsequent studies led to the identification of four yeast SIR2 homologs HST1, HST2, HST3, and HST4. Understanding the downstream physiological consequences of inhibiting sirtuins can be challenging since most studies focus on single or double deletions of sirtuins, and mating defects in SIR2 deletions hamper genome-wide screens. This represents an important gap in our knowledge of how sirtuins function in highly complex biological processes such as aging, metabolism, and chromosome segregation. In this report, we used a genome-wide screen to explore sirtuin-dependent processes in Saccharomyces cerevisiae by identifying deletion mutants that are sensitive to NAM. We identified 55 genes in total, 36 of which have not been previously reported to be dependent on sirtuins. We find that genome stability pathways are particularly vulnerable to loss of sirtuin activity. Here, we provide evidence that defects in sister chromatid cohesion renders cells sensitive to growth in the presence of NAM. The results of our screen provide a broad view of the biological pathways sensitive to inhibition of sirtuins, and advance our understanding of the function of sirtuins and NAD(+) biology.

Combined molecular MRI and immuno-spin-trapping for in vivo detection of free radicals in orthotopic mouse GL261 gliomas.

Free radicals play a major role in gliomas. By combining immuno-spin-trapping (IST) and molecular magnetic resonance imaging (mMRI), in vivo levels of free radicals were detected within mice bearing orthotopic GL261 gliomas. The nitrone spin trap DMPO (5,5-dimethyl pyrroline N-oxide) was administered prior to injection of an anti-DMPO probe (anti-DMPO antibody covalently bound to a bovine serum albumin (BSA)-Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-biotin MRI contrast agent) to trap tumor-associated free radicals. mMRI detected the presence of anti-DMPO adducts by either a significant sustained increase (p<0.001) in MR signal intensity or a significant decrease (p<0.001) in T1 relaxation, measured as %T1 change. In vitro assessment of the anti-DMPO probe indicated a significant decrease (p<0.0001) in T1 relaxation in GL261 cells that were oxidatively stressed with hydrogen peroxide, compared to controls. The biotin moiety of the anti-DMPO probe was targeted with fluorescently-labeled streptavidin to locate the anti-DMPO probe in excised brain tissues. As a negative control a non-specific IgG antibody covalently bound to the albumin-Gd-DTPA-biotin construct was used. DMPO adducts were also confirmed in tumor tissue from animals administered DMPO, compared to non-tumor brain tissue. GL261 gliomas were found to have significantly increased malondialdehyde (MDA) protein adducts (p<0.001) and 3-nitrotyrosine (3-NT) (p<0.05) compared to normal mouse brain tissue, indicating increased oxidized lipids and proteins, respectively. Co-localization of the anti-DMPO probe with either 3-NT or 4-hydroxynonenal was also observed. This is the first report regarding the detection of in vivo levels of free radicals from a glioma model.

High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted Gag-derived epitopes associated with relative HIV control.

Virus-specific cytotoxic T lymphocytes (CTL) with high levels of functional avidity have been associated with viral clearance in hepatitis C virus infection and with enhanced antiviral protective immunity in animal models. However, the role of functional avidity as a determinant of HIV-specific CTL efficacy remains to be assessed. Here we measured the functional avidities of HIV-specific CTL responses targeting 20 different, optimally defined CTL epitopes restricted by 13 different HLA class I alleles in a cohort comprising 44 HIV controllers and 68 HIV noncontrollers. Responses restricted by HLA-B alleles and responses targeting epitopes located in HIV Gag exhibited significantly higher functional avidities than responses restricted by HLA-A or HLA-C molecules (P = 0.0003) or responses targeting epitopes outside Gag (P < 0.0001). The functional avidities of Gag-specific and HLA-B-restricted responses were higher in HIV controllers than in noncontrollers (P = 0.014 and P = 0.018) and were not restored in HIV noncontrollers initiating antiretroviral therapy. T-cell receptor (TCR) analyses revealed narrower TCR repertoires in higher-avidity CTL populations, which were dominated by public TCR sequences in HIV controllers. Together, these data link the presence of high-avidity Gag-specific and HLA-B-restricted CTL responses with viral suppression in vivo and provide new insights into the immune parameters that mediate spontaneous control of HIV infection.

Assessment of physical fitness aspects and their relationship to firefighters' job abilities.

The purpose of this study was to identify the relationships between various fitness parameters and firefighting performance on an "Ability Test" (AT) that included a set of 6 simulated firefighting tasks. The relationships between each fitness parameter and each task of the AT were determined. Ninety firefighters participated in this study (age 33 ± 7 years). The AT completion time was associated with abdominal strength (r = -0.53, p < 0.01), relative power (r = -0.44, p < 0.01), upper-body muscular endurance (push-ups, r = -0.27, p < 0.05) (sit-ups, r = -0.41, p < 0.01), and upper-body strength (1 repetition maximum bench press, r = -0.41, p < 0.01). In addition, poor performance on the AT was associated with high resting heart rate (r = 0.36, p < 0.01), high body mass index (r = 0.34, p < 0.01), high body fat (BF)% (r = 0.57, p < 0.01), increasing age (r = 0.42, p < 0.01), and large waist size (r = 0.67, p < 0.01). Multiple regression analyses indicated that a significant (F[5, 53] = 14.02, p < 0.01) proportion (60%) of the variation observed in the AT was explained by the variation of the fitness parameters used in the model. This study demonstrated that fitness variables, such as abdominal strength, power (step test), push-ups, resting Hr, and BF%, contributed significantly to the predictive power of firefighters' AT performance. The findings of this study may be useful to fire department instructors and trainers in the design and implementation of training programs that are more specifically tailored to improving both individual firefighting skills and general fire suppression performance.

A genetic mosaic approach for neural circuit mapping in Drosophila.

Transgenic manipulation of subsets of brain cells is increasingly used for studying behaviors and their underlying neural circuits. In Drosophila, the GAL4-upstream activating sequence (UAS) binary system is powerful for gene manipulation, but GAL4 expression is often too broad for fine mapping of neural circuits. Here, we describe the development of unique molecular genetic tools to restrict GAL4 expression patterns. Building on the GAL4-UAS system, our method adds two components: a collection of enhancer-trap recombinase, Flippase (ET-FLP), transgenic lines that provide inheritable, reproducible, and tissue-specific FLP and an FRT-dependent GAL80 "flip-in" construct that converts FLP expression into tissue-specific repression of GAL4 by GAL80. By including a UAS-encoded fluorescent protein, circuit morphology can be simultaneously marked while the circuit function is assessed using another UAS transgene. In a proof-of-principle analysis, we applied this ET-FLP-induced intersectional GAL80/GAL4 repression (FINGR) method to map the neural circuitry underlying fly wing inflation. The FINGR system is versatile and powerful in combination with the vast collection of GAL4 lines for neural circuit mapping as well as for clonal analysis based on the infusion of the yeast-derived FRT/FLP system of mitotic recombination into Drosophila. The strategies and tactics underlying our FINGR system are also applicable to other genetically amenable organisms in which transgenes including the GAL4, UAS, GAL80, and FLP factors can be applied.

Viral adaptation to immune selection pressure by HLA class I-restricted CTL responses targeting epitopes in HIV frameshift sequences.

CD8+ cytotoxic T lymphocyte (CTL)-mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q<0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03-restricted +2 frame-encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level.

Cellular immune responses and disease control in acute AIDS-associated Kaposi's sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) specific T cell responses and KSHV viremia were analyzed in seven HIV-infected patients with active Kaposi's sarcoma lesions who initiated highly active antiretroviral therapy, and were compared between patients with improved Kaposi's sarcoma and those with progressive Kaposi's sarcoma requiring further systemic chemotherapy. Patients with controlled Kaposi's sarcoma disease demonstrated undetectable Kaposi's sarcoma viremia together with KSHV-specific CD8 T cells secreting interferon-gamma and tumor necrosis factor-alpha, whereas progressors showed increasing viremia with weak or no T-cell responses. These data point toward a potential role of KSHV-specific immunity in the control of AIDS-associated Kaposi's sarcoma.

Extensive HLA class I allele promiscuity among viral CTL epitopes.

Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I-restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals' HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I-restricted antigen presentation and vaccine development.

Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic in South Africa and the clinical manifestation of AIDS-associated Kaposi's sarcoma (KS) represents a significant clinical problem. Whereas the positive effects of HAART on the regression of KS have been well established, less is known about the role of herpesvirus-specific cellular immunity in disease improvement. DESIGN: Thirty-three treatment-naive HIV clade C-infected individuals with KS were randomly assigned into two treatment arms (HAART plus systemic chemotherapy versus HAART alone). KSHV-specific cellular immune responses, viral loads and clinical outcome were evaluated. METHODS: KSHV, Epstein-Barr virus and HIV-specific cellular immunity was measured using an IFN-gamma enzyme-linked immunospot assay in samples obtained at baseline and up to 11 months after treatment initiation. Cell-associated KSHV viremia was determined by real-time polymerase chain reaction. RESULTS: Robust increases in CD4 cell counts and suppressed HIV viral loads were seen in parallel with significant increases in the KSHV-specific cellular immune responses over time. Although slowly increasing after 5 months, KSHV-specific T-cell responses were significantly elevated only after 11 months, with both lytic and latent antigens being more frequently targeted. A trend towards better clinical outcome with HAART plus chemotherapy treatment was observed compared with HAART alone, and was accompanied by a significant reduction in cellular KSHV viral load in the HAART plus chemotherapy-treated subjects but not those treated with HAART alone after 11 months of treatment. CONCLUSION: The data show a temporal association between the clinical improvement of KS and the re-appearance of KSHV-specific cellular immunity, and demonstrate an effective suppression of KSHV viral replication using combination therapy.

Lytic and latent antigens of the human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus induce T-cell responses with similar functional properties and memory phenotypes.

The cellular immunity against Kaposi's sarcoma-associated herpesvirus (KSHV) is poorly characterized and has not been compared to T-cell responses against other human herpesviruses. Here, novel and dominant targets of KSHV-specific cellular immunity are identified and compared to T cells specific for lytic and latent antigens in a second human gammaherpesvirus, Epstein-Barr virus. The data identify a novel HLA-B57- and HLA-B58-restricted epitope in the Orf57 protein and show consistently close parallels in immune phenotypes and functional response patterns between cells targeting lytic or latent KSHV- and EBV-encoded antigens, suggesting common mechanisms in the induction of these responses.

Impact of HLA-B alleles, epitope binding affinity, functional avidity, and viral coinfection on the immunodominance of virus-specific CTL responses.

Immunodominance is variably used to describe either the most frequently detectable response among tested individuals or the strongest response within a single individual, yet factors determining either inter- or intraindividual immunodominance are still poorly understood. More than 90 individuals were tested against 184 HIV- and 92 EBV-derived, previously defined CTL epitopes. The data show that HLA-B-restricted epitopes were significantly more frequently recognized than HLA-A- or HLA-C-restricted epitopes. HLA-B-restricted epitopes also induced responses of higher magnitude than did either HLA-A- or HLA-C-restricted epitopes, although this comparison only reached statistical significance for EBV epitopes. For both viruses, the magnitude and frequency of recognition were correlated with each other, but not with the epitope binding affinity to the restricting HLA allele. The presence or absence of HIV coinfection did not impact EBV epitope immunodominance patterns significantly. Peptide titration studies showed that the magnitude of responses was associated with high functional avidity, requiring low concentration of cognate peptide to respond in in vitro assays. The data support the important role of HLA-B alleles in antiviral immunity and afford a better understanding of the factors contributing to inter- and intraindividual immunodominance.

Differential targeting and shifts in the immunodominance of Epstein-Barr virus--specific CD8 and CD4 T cell responses during acute and persistent infection.

The evolution of Epstein-Barr virus (EBV)-specific T cell responses that occurs during the acute and persistent stages of infection remains poorly characterized despite its importance for developing immune interventions for EBV-associated disorders. This study assessed T cell responses to 113 EBV-derived epitopes in 40 subjects with acute or persistent EBV infection. Although no significant differences were seen in the breadth of CD8 and CD4 T cell responses, their magnitude differed significantly over time; acutely infected subjects generated especially strong responses to lytic viral antigens. The cross-sectional shift in immunodominance was also confirmed in subjects followed longitudinally from acute to persistent infection. In addition, human leukocyte antigen-matched siblings with discordant histories of symptomatic EBV infection showed no significant differences in their response patterns, suggesting that symptomatic EBV infection does not lead to unique persistent-stage responses. These data provide an assessment of immunodominance patterns and guidance for developing immunotherapeutic interventions for EBV-associated disorders.