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Chikungunya virus (CHIKV) is characterized by disabling joint pain that can cause persistent arthritis in approximately one-fourth of patients. Currently, no standard treatments are available for chronic CHIKV arthritis. Our preliminary data suggest that decreases in interleukin-2 (IL2) levels and regulatory T cell (Treg) function may play a role in CHIKV arthritis pathogenesis. Low-dose IL2-based therapies for autoimmune diseases have been shown to up-regulate Tregs, and complexing IL2 with anti-IL2 antibodies can prolong the half-life of IL2. A mouse model for post-CHIKV arthritis was used to test the effects of IL-2, an anti-IL2 monoclonal antibody (mAb), and the complex on tarsal joint inflammation, peripheral IL2 levels, Tregs, effector (Teff) T cells, and histological disease scoring. The complex treatment resulted in the highest levels of IL2 and Tregs, but also increased Teffs, and therefore did not significantly reduce inflammation or disease scores. However, the antibody group, which had moderately increased levels of IL2 and activated Tregs, resulted in a decreased average disease score. These results suggest the IL2/anti-IL2 complex stimulates both Tregs and Teffs in post-CHIKV arthritis, while the anti-IL2 mAb increases IL2 availability enough to shift the immune environment towards a tolerogenic one.

Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) are described after chikungunya virus infection. We aimed to compare the relevance of joint counts and symptoms to clinical outcomes in RA and chronic chikungunya disease. Forty patients with chronic chikungunya arthralgia and 40 patients with RA were enrolled in a cross-sectional study. The association of tenderness and swelling, clinically assessed in 28 joints, and patient evaluations of pain and musculoskeletal stiffness with modified Health Assessment Questionnaire (HAQ) and quality of life (QoL) assessments were investigated. Tender and swollen joint counts, pain and stiffness scores were all associated with the HAQ disability index in RA (all r > 0.55, p ≤ 0.0002), but only stiffness was significantly associated with disability in chikungunya (r = 0.38, p = 0.02). Joint counts, pain and stiffness were also associated with most QoL domains in RA patients. In contrast, in chikungunya disease, tender joint counts were associated only with one QoL domain and swollen joints for none, while pain and stiffness were associated with several domains. Our results confirm the relevance of joint counts in RA, but suggest that in chronic chikungunya disease, joint counts have more limited value. Stiffness and pain score may be more important to quantify chikungunya arthritis impact.

Although anti-retroviral therapy (ART) is successful in suppressing HIV-1 replication, HIV latently infected reservoirs are not eliminated, representing a major hurdle in efforts to eradicate the virus. Current strategies to eradicate HIV involve two steps: (1) the reactivation of latently infected cells with latency reversing agents (LRAs) to expose persisting HIV, and (2) the elimination of these cells with immune effectors while continuing ART to prevent reinfection. HIV-specific T cells (HSTs) can kill reactivated HIV-infected cells and are currently being evaluated in early-stage immunotherapy trials. HIV can mutate sequences in T cell epitopes and evade T cell-mediated killing of HIV-infected cells. However, by directing T cells to target multiple conserved, non-escaped HIV epitopes, the opportunity for viral escape can be reduced. Using a good manufacturing practice (GMP)-compliant platform, we manufactured HSTs against non-escape epitope targets (HST-NEETs) from HIV+ and HIV-seronegative donors. HST-NEETs expanded to clinically relevant numbers, lysed autologous antigen-pulsed targets, and showed a polyfunctional pro-inflammatory cytokine response. Notably, HST-NEETs recognized multiple conserved, non-escaped HIV epitopes and their common variants. We propose that HST-NEETs could be used to eliminate reactivated virus from latently infected cells in HIV+ individuals following LRA treatment. Additionally, HST-NEETs derived from HIV-negative individuals could be used post-transplant for HIV+ individuals with hematologic malignancies to augment anti-viral immunity and destroy residual infected cells. Keywords: HIV-specific T cells, immunotherapy, latent reservoir, viral escape, conserved epitopes

Despite reductions in mortality from the use of highly active antiretroviral therapy (HAART), the presence of latent or transcriptionally silent proviruses prevents HIV cure/eradication. We have previously reported that DNA-dependent protein kinase (DNA-PK) facilitates HIV transcription by interacting with the RNA polymerase II (RNAP II) complex recruited at HIV LTR. In this study, using different cell lines and peripheral blood mononuclear cells (PBMCs) of HIV-infected patients, we found that DNA-PK stimulates HIV transcription at several stages, including initiation, pause-release and elongation. We are reporting for the first time that DNA-PK increases phosphorylation of RNAP II C-terminal domain (CTD) at serine 5 (Ser5) and serine 2 (Ser2) by directly catalyzing phosphorylation and by augmenting the recruitment of the positive transcription elongation factor (P-TEFb) at HIV LTR. Our findings suggest that DNA-PK expedites the establishment of euchromatin structure at HIV LTR. DNA-PK inhibition/knockdown leads to the severe impairment of HIV replication and reactivation of latent HIV provirus. DNA-PK promotes the recruitment of Tripartite motif-containing 28 (TRIM28) at LTR and assists the release of paused RNAP II through TRIM28 phosphorylation. These results provide the mechanisms through which DNA-PK controls the HIV gene expression and, likely, can be extended to cellular gene expression, including during cell malignancy, where the role of DNA-PK has been well-established.

Chikungunya virus (CHIKV) was introduced to the Americas in 2013, causing two million infections across over thirty countries. CHIKV causes a chronic debilitating arthritis in one fourth of infected individuals and currently evidence-based targeted therapies for the treatment of CHIKV arthritis are lacking. Multiple mouse models of chikungunya have been developed to study acute CHIKV infection. In humans, post-CHIKV arthritis may persist for months to years after viremia from a CHIKV infection has resolved. Therefore, the development of a mouse model of post-acute arthritis of chikungunya may facilitate the study of potential novel therapeutics for this arthritis. In this article we describe the development of a wild-type immunocompetent C57BL/6 mouse model for post-acute arthritis of chikungunya, including a histologic inflammation scoring system, as well as suggestions for how this mouse model may be used to examine the efficacy of novel therapies for CHIKV arthritis.

Objective.To determine the frequency of chronic joint pain and stiffness 3 years after infection with chikungunya virus (CHIKV) in a Latin American cohort.Methods.A cross-sectional followup of 120 patients from an initial cohort of 500 patients who reported joint pain 2 years after infection from the Atlántico Department, Colombia. Patients were clinically diagnosed as having CHIKV during the 2014–2015 epidemic, and baseline and followup symptoms at 40 months were evaluated in serologically confirmed cases.Results.Of the initial 500 patients enrolled in the study, 482 had serologically confirmed chikungunya infection. From this group, 123 patients reported joint pain 20 months after infection, and 54% of those patients reported continued joint pain 40 months after infection. Therefore, 1 out of every 8 people who tested serologically positive for CHIKV infection had persistent joint pain 3 years after infection. Participants who followed up in person were predominantly adult (mean ± SD age 51 ± 14 yrs) and female (86%). The most common type of pain reported in these patients at 40 months post-infection was pain with periods of relief and subsequent reoccurrence, and over 75% reported stiffness after immobility, with 39% experiencing morning stiffness.Conclusion.To our knowledge, this is the first report to describe persistent joint pain and stiffness 40 months after viral infection. The high frequency of chronic disease highlights the need to develop prevention and treatment methods. Further studies should be conducted to understand the similarities between post-chikungunya joint pain and rheumatoid arthritis.

Objective The primary objective of this research was to explore the link between sleep and flare pain associated with chikungunya virus (CHIKV) infection. The secondary objective was to investigate if cytokines and T regulatory (Treg) cells have an influence on this relationship. Methods A cross-sectional study was performed using data collected in Barranquilla, Colombia, which enrolled patients with and without chronic arthritis with a history of chikungunya infection. Flare severity was measured by a version of the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) flare questionnaire adapted for CHIKV arthritis, including metrics for pain, difficulty with physical activity, fatigue, stiffness and difficulty maintaining social activities due to arthritis that contribute to flare severity. In addition, four sleep disturbance items, five inflammatory cytokine levels, four anti-inflammatory cytokine levels, and six Treg levels were measured. Then, multivariable linear regression models were used to test the direct and indirect effects of flare-pain on sleep disturbance, and to determine whether this relationship was mediated by cytokines or Tregs. Finally, the SAS CALIS procedure was used to test path models showing possible causal effects with mediators and confounds. Results The analysis showed that sleep disturbance is positively correlated with CHIKV arthritis flare pain, and that it is a significant predictor of flare severity after adjusting for demographic variables, cytokine, and T cell levels. Further, neither T cells nor cytokines mediate the pain/sleep relationship in CHIKV arthritis. Conclusion There is a strong association between sleep disturbance and arthritis flare pain and severity; however, this relationship is not mediated by cytokines or T cells. Since this study is unable to determine causation, further research is needed to determine the mechanism underlying the relationship between sleep disturbances and CHIKV arthritis flares.

PROBLEM HIV/AIDS and sexual violence act synergistically and compromise women's health. Yet, immuno-biological mechanisms linking sexual violence and increased HIV susceptibility are poorly understood. METHODS We conducted a cross-sectional pilot study of HIV-uninfected women, comparing 13 women exposed to forced vaginal penetration within the past 12 weeks (Exposed) with 25 Non-Exposed women. ELISA assays were conducted for 49 biomarkers associated with HIV pathogenesis in plasma and cervicovaginal lavage (CVL). Differences between Exposed and Non-Exposed were analyzed by linear and logistic regression, using propensity score weighting to control for age, race, socioeconomic status, menstrual cycle, and contraceptive use. RESULTS In CVL, Exposed women had significantly reduced chemokines MIP-3α (p

Purpose of Review Persistent joint pain is a common manifestation of arthropod-borne viral infections and can cause long-term disability. We review the epidemiology, pathophysiology, diagnosis, and management of arthritogenic alphavirus infection. Recent findings The global re-emergence of alphaviral outbreaks has led to an increase in virus-induced arthralgia and arthritis. Alphaviruses, including Chikungunya, O’nyong’nyong, Sindbis, Barmah Forest, Ross River, and Mayaro viruses, are associated with acute and/or chronic rheumatic symptoms. Identification of Mxra8 as a viral entry receptor in the alphaviral replication pathway creates opportunities for treatment and prevention. Recent evidence suggesting virus does not persist in synovial fluid during chronic chikungunya infection indicates that immunomodulators may be given safely. Summary The etiology of persistent joint pain after alphavirus infection is still poorly understood. New diagnostic tools along and evidence-based treatment could significantly improve morbidity and long-term disability.

Malaria acquired in endemic areas poses a substantial risk to travelers arriving in or returning to the United States. Timely diagnosis and recognition of severe illness are crucial; however, many U.S.-based clinicians lack familiarity with this disease. We conducted a retrospective review of 100 cases of malaria in adults seen at a single urban university hospital during 2000–2017. Descriptive and analytical statistics were calculated, including logistic regression modeling case severity. Most of the patients presented with Plasmodium falciparum (76%), most commonly after travel from sub-Saharan Africa (94%). Prior malaria experience was common (50%), but adherence to a prophylactic regimen was exceedingly rare (4%). Twenty-one patients had severe malaria, including 10 with cerebral malaria. Severity was predicted by high parasitemia, bandemia, hypoglycemia, and hypotension at the time of presentation. In 24 patients, the initial treatment regimen was changed, usually because of the appearance of clinical deterioration or drug toxicity. One patient required intravenous artesunate. All patients survived, although one suffered fetal loss. Among 30 patients initially evaluated at other institutions, 43% had been treated for an alternative diagnosis. The most common reasons for transfer of patients to our hospital were inadequate facilities and lack of expertise with malaria. There needs to be increased awareness among U.S.-based travelers and clinicians regarding malaria as a potentially lethal condition, emphasizing the use of appropriate prophylaxis. Our simple model of disease severity could serve frontline physicians when deciding which patients should be admitted to the intensive care unit or transferred for higher level care.

Objective To determine if chikungunya virus persists in synovial fluid after infection, potentially acting as a causative mechanism of persistent arthritis. Methods We conducted a cross-sectional study of 38 Colombian participants with clinical chikungunya virus infection during the 2014-2015 epidemic who reported chronic arthritis and 10 location-matched controls without chikungunya virus or arthritis. Prior chikungunya virus infection status was serologically confirmed, and the presence of synovial fluid chikungunya virus, viral RNA, and viral proteins was determined by viral culture, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and mass spectrometry, respectively. Biomarkers were assessed by multiplex analysis. Results Patients with serologically confirmed chikungunya arthritis (33 of 38 [87%]) were predominantly female (82%) and African Colombian (55%) or white Colombian (33%), with moderate disease activity (mean ± SD Disease Activity Score in 28 joints 4.52 ± 0.77) a median of 22 months after infection (interquartile range 21-23 months). Initial symptoms of chikungunya virus infection included joint pain (97%), swelling (97%), stiffness (91%), and fever (91%). The most commonly affected joints were the knees (87%), elbows (76%), wrists (75%), ankles (56%), fingers (56%), and toes (56%). Synovial fluid samples from all patients with chikungunya arthritis were negative for chikungunya virus on qRT-PCR, showed no viral proteins on mass spectrometry, and cultures were negative. Case and control plasma cytokine and chemokine concentrations did not differ significantly. Conclusion This is one of the largest observational studies involving analysis of the synovial fluid of chikungunya arthritis patients. Synovial fluid analysis revealed no detectable chikungunya virus. This finding suggests that chikungunya virus may cause arthritis through induction of potential host autoimmunity, suggesting a role for immunomodulating agents in the treatment of chikungunya arthritis, or that low-level viral persistence exists in synovial tissue only and is undetectable in synovial fluid.

The Amazon region of Brazil experienced a large epidemic of East Central South African (ECSA) chikungunya virus (CHIKV) in 2017 and continuous transmission of CHIKV persists. The impact of chronic arthritis caused by ECSA CHIKV is unknown.The study aim was to describe the duration, severity, and characteristics of CHIKV arthritis in Roraima, Brazil, in comparison with local controls to further understand the long-term rheumatologic impact of ECSA CHIKV infection.We performed a cross-sectional analysis comparing clinical arthritis outcomes among 40 cases with chronic ( 3 months) arthritis attributed to their CHIKV disease (n = 40) with control participants who were exposed to CHIKV but did not develop chronic arthritis (n = 40), rheumatoid arthritis controls (n = 40), and healthy controls lacking CHIKV exposure and arthritis (n = 40).Our primary finding is that over 2 years post-infection, patients report moderate arthritis disease severity comparable with rheumatoid arthritis with the most significant impact on decreased quality of life from pain.These findings suggest that chronic arthritis caused by ECSA CHIKV infection has had a moderate impact in the Americas. Key Points • Chikungunya infection is responsible for moderate arthritis disease severity. • The East Central South African (ECSA) strain of CHIKV is a cause of persistent arthritis in Roraima, Brazil.

With one vaccine on the market and others in clinical trials, policy makers in dengue endemic regions face the decision of whether to introduce a dengue vaccine in their communities. The World Health Organization (WHO) recommends that individualized assessments be conducted before any vaccine introduction to evaluate disease burden and the strength of current vaccination programs. This study seeks to aid in that decision-making process by examining the acceptability and feasibility of dengue vaccine introduction in Barranquilla, Colombia, and Merida, Venezuela. Surveys were administered February&ndash, June of 2018 for three groups: patients (n = 351), health professionals (n = 197), and government officials (n = 26). In Barranquilla, most respondents reported dengue to be a moderate-severe problem, that a dengue vaccine would be useful in their communities, and that their current vaccination programs could handle the addition of a new vaccine. In Venezuela, respondents were less likely to view dengue as a major concern and listed multiple barriers to not just dengue vaccine introduction, but to providing current vaccines as well. Further work is needed in Colombia to more objectively assess the country&rsquo, s readiness as a whole for a future dengue vaccine. As political and social unrest continues in Venezuela, however, future initiatives should focus on trust and capacity building. This study can serve as a framework for future assessments of the acceptability and feasibility of a dengue vaccine in both targeted areas and on larger scales.

The role of neutralizing antibodies in Zika-induced Guillain-Barré syndrome (GBS) has not yet been investigated. We conducted a case-control study using sera from the 2016 Zika epidemic in Colombia to determine the neutralizing antibody activity against Zika virus (ZIKV) and dengue virus serotype 2 (DENV2). We observed increased neutralizing antibody titers against DENV2 in ZIKV-infected individuals compared with uninfected controls and higher titers to both ZIKV and DENV2 in ZIKV-infected patients diagnosed with GBS compared with non-GBS ZIKV-infected controls. These data suggest that high neutralizing antibody titers to DENV and to ZIKV are associated with GBS during ZIKV infection., We conducted a case-control study using sera from the 2016 Zika epidemic in Colombia and found that high neutralizing antibody titers to dengue virus and Zika virus (ZIKV) were associated with Guillain-Barré syndrome during ZIKV infection.

HIV infection is known to be associated with cardiometabolic abnormalities; here we investigated the progression and causes of these abnormalities. Three groups of participants were recruited: HIV-negative subjects and two groups of treatment-naive HIV-positive subjects, one group initiating antiretroviral treatment, the other remaining untreated. Intima-media thickness (cIMT) increased in HIV-positive untreated group compared to HIV-negative group, but treatment mitigated the difference. We found no increase in diabetes-related metabolic markers or in the level of inflammation in any of the groups. Total cholesterol, low density lipoprotein cholesterol and apoB levels were lower in HIV-positive groups, while triglyceride and Lp(a) levels did not differ between the groups. We found a statistically significant negative association between viral load and plasma levels of total cholesterol, LDL cholesterol, HDL cholesterol, apoA-I and apoB. HIV-positive patients had hypoalphalipoproteinemia at baseline, and we found a redistribution of sub-populations of high density lipoprotein (HDL) particles with increased proportion of smaller HDL in HIV-positive untreated patients, which may result from increased levels of plasma cholesteryl ester transfer protein in this group. HDL functionality declined in the HIV-negative and HIV-positive untreated groups, but not in HIV-positive treated group. We also found differences between HIV-positive and negative groups in plasma abundance of several microRNAs involved in lipid metabolism. Our data support a hypothesis that cardiometabolic abnormalities in HIV infection are caused by HIV and that antiretroviral treatment itself does not influence key cardiometabolic parameters, but mitigates those affected by HIV.

We report a case of septic polyarthritis caused by Ureaplasma urealyticum in a woman with neuromyelitis optica who was receiving rituximab. Her case exemplifies some of the unique characteristics of invasive Ureaplasma infections that can lead to delayed diagnosis as well as treatment challenges including recurrence following antibiotic discontinuation.

Human immunodeficiency virus (HIV)–associated neurocognitive disorder (HAND) is found in 30%–50% of individuals with HIV infection. To date, no HIV+ individual has been reported to have a positive amyloid PET scan. We report a 71‐year‐old HIV+ individual with HAND. Clinical and neuropsychologic evaluations confirmed a progressive mild dementia. A routine brain MRI was normal for age. [18F]Fluorodeoxyglucose–PET revealed mild hypermetabolism in bilateral basal ganglia and hypometabolism of bilateral parietal cortex including the posterior cingulate/precuneus. Resting state functional MRI revealed altered connectivity as found with individuals with mild AD. CSF examination revealed a low Aβ42/tau index but a low phospho‐tau. An amyloid PET/CT with [18F]florbetaben revealed pronounced cortical radiotracer deposition. This case report suggests that progressive dementia in older HIV+ individuals may be due to HAND, AD, or both. HIV infection does not preclude CNS Aβ/amyloid deposition. Amyloid PET imaging may be of value in distinguishing HAND from AD pathologies.

The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the human immunodeficiency virus (HIV)-1 LTR promoter. Here, we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. Chromatin immunoprecipitation (ChIP) assays using latently infected primary T cells and Jurkat T-cell lines demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting polycomb group (PcG/PRC) corepressor complexes or polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes enhancing the recruitment of RNA polymerase II (RNAP II) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 also led to the reactivation of latent proviruses. Similarly, the treatment of latently infected primary CD4+ T cells with the PRC2/EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation.

Background:Chronic rheumatological manifestations similar to those of rheumatoid arthritis (RA) have been described after chikungunya virus infection. However, the clinical significance of the symptoms and disease severity in the two conditions has not been directly compared.Objectives:To compare, using identical measures of disease severity and patient outcomes, the impact of disease severity measures and symptoms on outcomes in RA and chronic chikungunya disease.Methods:Forty patients with chronic chikungunya arthralgia two years post-infection and 40 matched patients with RA were enrolled in Roraima, Brazil. Twenty-eight joints were assessed for tenderness and swelling, a pain intensity visual analogue scale, musculoskeletal stiffness questionnaire, modified Health Assessment Questionnaire and the EuroQol EQ5D-5L quality of life assessment were completed. The importance of the various measures of disease severity were analysed using Spearman’s rank correlation and regression analysis.Results:Tender and swollen joint counts, pain and stiffness were all predictive of the HAQ disability index in RA, but only stiffness was significantly associated with disability in chikungunya patients (Table 1). Tender and swollen joint counts, pain and stiffness were predictive for all EQ5D quality of life domains (except anxiety/depression) in RA patients. In contrast, in chikungunya disease, tender joint counts were predictive only of usual daily activities; pain was predictive of impaired mobility, self-care and discomfort, while stiffness was predictive for the mobility and anxiety/depression domains (Figure 1). Swollen joint counts were not associated with any of the patient outcomes in chikungunya disease. Linear regression analysis confirmed (p=0.003) that the effect of swollen joint count on the HAQ disability index depends on the underlying disease.Table 1.Association of disease severity with HAQ disability index in rheumatoid and CHIKV+ arthritisSeverity measureRheumatoid arthritisCHIKV+ arthritisr (p)r (p)Tender joint count0.56 (0.0002)0.24 (0.14)Swollen joint count0.60 (0.002 (0.99)Joint pain (VAS)0.55 (0.0002)0.29 (0.07)Stiffness severity0.57 (0.0001)0.38 (0.02)Figure 1.Association of disease severity with quality of life domains in rheumatoid and CHIKV+ arthritisConclusion:The value of all the disease severity measures tested in RA were confirmed, but tender joint counts may have more limited value in the assessment of chronic chikungunya disease. Joint swelling appears to have little impact for chikungunya patients, while stiffness appears to be an important metric to quantify chikungunya arthritis disease severity.Disclosure of Interests:Hugh Watson Shareholder of: Sanofi, Employee of: Sanofi, Ramão Luciano Nogueira-Hayd: None declared, Maony Rodrigues-Moreno: None declared, Felipe Naveca: None declared, Giulia Calusi: None declared, Richard Amdur: None declared, Karol Suchowiecki: None declared, Gary S. Firestein: None declared, Gary Simon: None declared, Aileen Chang: None declared

The cytokine profile during acute chikungunya infection that predicts future chronic arthritis has not yet been investigated. We conducted a nested case-control study comparing serum cytokine concentrations during acute chikungunya infection in cases (n = 121) that reported the presence of chronic joint pain versus age- and gender-matched controls (n = 121) who reported recovery at 20 months post infection. We observed that a robust cytokine response during acute infection was correlated with a decreased incidence of chronic joint pain and that low TNF&alpha, IL-13, IL-2, and IL-4 during acute infection was predictive of chronic joint pain. These data suggest that a robust cytokine response is necessary for viral clearance and cytokines that are related to immune tolerance during acute infection may be protective for chronic arthritis pathogenesis.

Zika virus infection has been associated with the development of a spectrum of neurologic disease including Guillain–Barre syndrome (GBS)1. GBS is an autoimmune disorder of the peripheral nervous s...

Objective To estimate the frequency of chronic joint pain after infection with chikungunya virus in a Latin American cohort. Methods A cross-sectional follow-up of a prospective cohort of 500 patients from the Atlantico Department, Colombia who were clinically diagnosed as having chikungunya virus during the 2014-2015 epidemic was conducted. Baseline symptoms and follow-up symptoms at 20 months were evaluated in serologically confirmed cases. Results Among the 500 patients enrolled, 485 had serologically confirmed chikungunya virus and reported joint pain status. Patients were predominantly adults (mean ± SD age 49 ± 16 years) and female, had an education level of high school or less, and were of Mestizo ethnicity. The most commonly affected joints were the small joints, including the wrists, ankles, and fingers. The initial virus symptoms lasted a median of 4 days (interquartile range [IQR] 3-8 days). Sixteen percent of the participants reported missing school or work (median 4 days [IQR 2-7 days]). After 20 months, one-fourth of the participants had persistent joint pain. A multivariable analysis indicated that significant predictors of persistent joint pain included college graduate status, initial symptoms of headache or knee pain, missed work, normal activities affected, ≥4 days of initial symptoms, and ≥4 weeks of initial joint pain. Conclusion This is the first report to describe the frequency of chikungunya virus-related arthritis in the Americas after a 20-month follow-up. The high frequency of chronic disease highlights the need for the development of prevention and treatment methods.

Background Temperature ≥104°F (T ≥ 104) is uncommon in adults. The diagnoses and clinical characteristics were reviewed for patients with T ≥ 104. Methods Infectious disease physicians reviewed charts of patients with T ≥ 104 seen at the Washington DC Veterans Affairs Medical Center from 2009 to 2018. The following was collected: demographics, past medical history, medications, WBC, maximum temperature, time to defervescence, etiology of T ≥ 104, and death. Results Less than 0.01% of all patient encounters were associated with T ≥ 104. Of the 60 most recent patients with T ≥ 104 (from 2014 to 2018), the median age was 63.5 years (range 23–97), 65% were African American, 88% were male. 82% of those with T ≥ 104 were hospitalized; 76% of those had the T ≥ 104 on or within 72 hours of admission. 25% of the 60 patients had underlying cancer, 10% HIV, 30% DM, 13% CKD, and 13% were on steroids/immunosuppressants/biologics. The median peak temperature was 104.3°F (interquartile range 104.0 – 104.7); maximum was 106.8°F. 82% had T ≥ 104 for only 1 day and the median time to defervescence was 2 days. There were 55 diagnoses amongst 48 patients; 12 had no identifiable etiology of T ≥ 104. Of the identifiable diagnoses, there were 45 (81.8%) infections, 4 (7.3%) metastatic malignancies (1 Hodgkin’s lymphoma, 1 small cell carcinoma, 1 squamous cell carcinoma, 1 unknown primary), 2 (3.6%) intracranial bleeds, 2 (3.6%) GI bleeds, 1 (1.8%) mixed collagen vascular disease, and 1 (1.8%) neuroleptic malignant syndrome. The most common infections were 15 cases of pneumonia including 2 Legionella, 8 complicated UTI/pyelonephritis, 3 primary bacteremia, 2 West Nile virus, 2 influenza, and 2 cholangitis with bacteremia. The median WBC of infectious diagnoses (9.8) was significantly higher than noninfectious diagnoses (5.8, P = 0.006, T-test). Of the 60 patients, 20% died within 30 days of T ≥ 104 including 2 patients who died of sepsis. 67% of those who died were receiving hospice care. Conclusion T ≥ 104 is rare in adults and is usually associated with bacterial infections such as pneumonia (including Legionella), complicated UTIs/pyelonephritis, and primary bacteremia but may also be seen with viral infections such as West Nile virus and influenza. Mortality is high. Disclosures All authors: No reported disclosures.

Illicit drug users are a high-risk population for infection with the human immunodeficiency virus (HIV). A strong correlation exists between prohibited drug use and an increased rate of HIV transmission. Cocaine stands out as one of the most frequently abused illicit drugs, and its use is correlated with HIV infection and disease progression. The central nervous system (CNS) is a common target for both drugs of abuse and HIV, and cocaine intake further accelerates neuronal injury in HIV patients. Although the high incidence of HIV infection in illicit drug abusers is primarily due to high-risk activities such as needle sharing and unprotected sex, several studies have demonstrated that cocaine enhances the rate of HIV gene expression and replication by activating various signal transduction pathways and downstream transcription factors. In order to generate mature HIV genomic transcript, HIV gene expression has to pass through both the initiation and elongation phases of transcription, which requires discrete transcription factors. In this review, we will provide a detailed analysis of the molecular mechanisms that regulate HIV transcription and discuss how cocaine modulates those mechanisms to upregulate HIV transcription and eventually HIV replication.

Coronary artery disease is a growing clinical problem in HIV-infected subjects. The increased risk of coronary events in this population has been linked to low levels of HDL, but the effects of HIV infection and anti-retroviral treatment (ART) on HDL structure and function remain unknown. Here, we aimed to determine the composition and function of HDL particles isolated from ART-naive and ART-positive HIV-infected patients.Proteomic profiling revealed decreased levels of paraoxonase (PON) 1 and PON 3 in HDL from HIV patients relative to HDL from uninfected controls (p0.0001), and PON activity of HDL from control group (0.13 ± 0.01 U/μl) was significantly higher than PON activity of HDL from HIV-infected untreated subjects (0.12 ± 0.01 U/μl, p = 0.0035), subjects treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy (0.11 ± 0.01 U/μl, p0.0001), subjects treated with protease inhibitor (PI)-based therapy with detectable viral load (0.11 ± 0.01 U/μl, p0.0001), and PI-treated patients with undetectable viral load (0.12 ± 0.01 U/μl, p = 0.0164). Lipidomic profiling uncovered a negative correlation between CD4 T cell counts and particle sphingomyelin, lyso-phosphatidylcholine and ether-linked phosphatidylserine content in the ART-naive (R(2) = 0.2611, p0.05; R(2) = 0.2722, p0.05; and R(2) = 0.3977, p0.05, respectively) but not treated HIV-infected subjects. Functional analysis demonstrated a negative correlation between cholesterol efflux capacity of HDL and viral load in the ART-naive HIV-infected group (R(2) = 0.26, p = 0.026).Taken together, these results indicate that HIV infection associates with a number of both protein and lipid compositional changes in HDL particles. Moreover, HIV infection affects cholesterol efflux function of HDL, thus contributing to an increased risk of atherosclerosis in this patient population.

The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the HIV-1 LTR promoter. Here we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. Chromatin immunoprecipitation (ChIP) assays using latently infected primary T cells and Jurkat T-cell lines demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting Polycomb Group (PcG/PRC) corepressor complexes or Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes enhancing the recruitment of RNA polymerase II (RNAP II) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 also led to the reactivation of latent proviruses. Similarly, treatment of latently infected primary CD4+ T cells with the EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation.

Despite the use of highly effective antiretroviral therapy (HAART), the presence of latent or transcriptionally silent proviruses prevents cure and eradication of HIV infection. These transcriptionally silent proviruses are well protected from both the immune system and HAART regimens. Thus, in order to tackle the problem of latent HIV reservoirs, it is a prerequisite to define all the pathways that regulate HIV transcription. We have previously reported that DNA-PK facilitates HIV transcription by interacting with the RNA polymerase II (RNAP II) complex recruited at HIV LTR. To extend those studies further, here we demonstrate that DNA-PK promotes HIV transcription by supporting it at several stages, including initiation, pause-release and elongation. We discovered that DNA-PK increases phosphorylation of RNAP II C-terminal domain (CTD) at serine 5 (Ser5) and serine 2 (Ser2) by both directly catalyzing and by augmenting the recruitment of P-TEFb at HIV LTR. We found that DNA-PK facilitates the establishment of euchromatin structure at HIV LTR, which further supports HIV gene expression. DNA-PK inhibition or knockdown leads to the severe impairment of HIV gene expression and conversion of euchromatin to heterochromatin at HIV LTR. It also profoundly restricts HIV replication and reactivation of latent provirus. DNA-PK promotes the recruitment of TRIM28 at LTR and facilitates the release of paused RNAP II through TRIM28 phosphorylation. The results were reproduced in cell lines belonging to both lymphoid and myeloid lineages and were confirmed in primary CD4+T cells and peripheral blood mononuclear cells (PBMCs) from HIV-infected patients.IMPORTANCE:Our results reveal the important role of DNA-PK in supporting HIV transcription, replication and latent proviral reactivation. Intriguingly, this study sheds light on an important pathway that affects HIV gene expression. These findings provide strong rationale for developing and using transcriptional inhibitors, such as DNA-PK inhibitors, as supplement to HAART regimens in order to further enhance their effectiveness and to suppress toxicity due to HIV proteins.

Studies have implicated sexual violence as a strong correlate of HIV acquisition in women. Characterizing how such violence affects the female immune system may provide insight into the biological mechanisms of HIV transmission and ultimately improve global HIV prevention strategies. Little research has been carried out in this domain, and the obstacles to investigation can be daunting. Here, we describe methodological challenges encountered and solutions explored while implementing a study of dysregulation of immune biomarkers potentially indicative of increased HIV susceptibility in women following sexual assault. Challenges included accessing sexual assault survivors and defining sexual assault, promoting study participant well-being during research engagement, reducing selection and information bias, collecting and processing biological samples, and adjusting for confounders such as reproductive tract infections and emotional and physical abuse. We found that many survivors of sexual assault welcomed the attention from study staff and felt empowered by the opportunity to help other women at risk for violence. Well-trained research staff and well-articulated community and medical partnerships were key methods to overcoming challenges while promoting the safety and welfare of vulnerable study participants.

Objective. Our team created a knowledge, attitudes, and practice (KAP) survey in order to assess changes over time in healthcare provider and community member awareness of Zika virus symptoms, transmission, treatment, and current and future concerns. Study Design. The cross-sectional survey was issued at an academic medical center in Washington, DC, and via an online link to healthcare providers and community members between June and August 2016. Survey distribution was then repeated the following year, from March to April 2017. Outcomes were compared by survey year and healthcare provider versus community member status using SAS Program Version 9.4. Results. Significant differences in knowledge, attitudes, and practices existed between 2016 and 2017 survey time points. By 2017, more respondents had knowledge of various Zika virus infection characteristics; however healthcare provider knowledge also waned in certain areas. Attitudes towards Zika virus infection displayed an overall decreased concern by 2017. Practice trends by 2017 demonstrated fewer travel restrictions to Zika-endemic areas and increased mosquito protective measures within the US. Conclusions. Our results provide novel insight into the transformation of knowledge, attitudes, and practice of community members and healthcare providers regarding Zika virus since its declaration as a public health emergency of international concern in 2016.

Background As the number of older people living with HIV (PLWH) in the US rises, there is a need to identify factors that lead to poorer clinical outcomes. This study aimed to identify age-based disparities in virologic, immunologic, and clinical disease control. Methods We analyzed data from the DC cohort, a longitudinal observational cohort of patients receiving HIV care at 15 clinics in 2011–2016 in Washington, DC. We compared 608 patients aged ≥60 years with 832 patients aged 18–35 years. t-Test and Wilcoxon rank-sum test were conducted for continuous variables, and chi-square or Fisher’s exact tests for categorical variables. Results Older patients reported less MSM-related (25% vs. 60%, P < 0.0001) and more IDU-related (18% vs. 0.5%, P < 0.0001) HIV acquisition than younger patients. The proportion of older patients with CD4 >500 cells/μL was higher at enrollment (56% vs. 53%, P = 0.0067), but lower at CD4 nadir (18% vs. 21%, P < 0.0001) and at most recent recording (60% vs. 69%, P = 0.0003). Younger patients were more likely to have HIV VL >200 copies/mL at enrollment (35% vs. 11%, P < 0.0001), recently (18% vs. 6%, P < 0.0001), and peak VL >100,000 copies/mL during the study period (15% vs. 4%, P < 0.0001). Viral re-emergence after initial suppression was less common in older PLWH overall (27% vs. 39%, P < 0.0001), but more common in older patients infected for ≥10 years (29% vs. 22%, P = 0.0607). There was a shift toward novel ART regimens (TAF and INSTI) during the study period, with more older patients on an INSTI by its end (59% vs. 50%, P = 0.0007). Among older patients, 23% had chronic kidney disease (CKD), and 24% had a serum creatinine rise of ≥150% during the study period. Of patients with CKD, 16% remained on TDF. The incidence of malignancies during the study period was 3.5% among younger and 14.3% among older patients). These were mainly (92.2%) non-AIDS-defining cancers. Conclusion Older PLWH in DC have a high burden of complications related to renal dysfunction, lower CD4 counts, and non-AIDS-defining malignancies; those with longer duration of infection also had more viral re-emergence. Opportunities to improve care include closer monitoring for resistant virus and new cancers, and consideration of ART regimens with high efficacy and better renal safety profiles. Disclosures All authors: No reported disclosures.

To address the organizational complexities associated with a highly virulent infectious disease (HVID) hazard, such as Ebola Virus Disease (EVD), an acute care facility should institute an emergency management program rooted in the fundamentals of mitigation, preparedness, response, and recovery. This program must address all known facets of the care of a patient with HVID, from unannounced arrival to discharge. The implementation of such a program not only serves to mitigate the risks from an unrecognized exposure but also serves to prepare the organization and its staff to provide for a safe response, and ensure a full recovery. Much of this program is based on education, training, and infection control measures along with resourcing for appropriate personal protective equipment which is instrumental in ensuring an organized and safe response of the acute care facility in the service to the community. This emergency management program approach can serve as a model in the care of not only current HVIDs such as EVD but also future presentations in our healthcare setting.

Background Due to increasing global travel and evolving epidemiologic factors, the number of incident cases of malaria imported into the United States has been growing in recent years. Methods We conducted a retrospective review of 90 cases of malaria seen at a single urban university hospital during 2000–2016. Results Of the 90 cases, 77% were Plasmodium falciparum, 14% were either P. ovale or P. vivax, 1% was P. malariae, and the rest were mixed or unknown. Eighty-one patients had traveled to Africa, four to Asia, four to more than one continent, and one to Haiti. Mean age was 41, and 59% were male. The main presenting symptoms were fever (92%), chills (78%), and headache (66%); 10% presented with cerebral malaria. Thirteen cases were managed as outpatients, 59 on a medical ward, and 18 in the ICU. Fourteen (16%) had severe malaria; these were more likely to present with hypotension, non-segmented neutrophilia, hyponatremia, metabolic acidosis, and acute kidney injury (all P < 0.01). Thrombocytopenia was more severe in patients with severe malaria (54,000 vs. 113,000, P < 0.01). Treatment included quinine-based therapy (38%), atovaquone/proguanil (31%), artemether/lumefantrine (19%), and chloroquine/primaquine (11%). Twenty (22%) required change of treatment regimen due to inadequate clinical response or adverse effects. The most common in-hospital complications were ARDS (8%), QT prolongation (7%), and nosocomial infection (4%). Two patients were pregnant at the time of presentation; one suffered severe malaria and fetal loss. Only 3% of patients reported being prescribed a prophylactic regimen and completing it; 20% reported taking an incomplete course, and the majority took no prophylaxis at all. Of 27 patients who had presented to another United States-based medical provider prior to hospitalization, 11 were initially misdiagnosed and treated for conditions other than malaria, including two who underwent extensive hematologic investigations. Inadequate experience and resources in treating malaria were the primary reasons cited for transfer to the tertiary hospital from community-based providers. Conclusion Malaria poses a substantial health risk to US travelers, particularly in light of under-utilization of prophylaxis, lack of familiarity with the disease by local providers, and delays to diagnosis. Disclosures All authors: No reported disclosures.

Background: There is a strong correlation between the use and abuse of illicit drugs and the spread of Human Immunodeficiency Virus (HIV). It is well established that illicit drugs users are a high risk population for infection with HIV with an increased rate of HIV transmission and replication. Cocaine, amphetamine, methamphetamine, heroin and morphine stand out as the most frequently abused illicit drugs and their use correlates well with HIV infection and AIDS progression. Notably, the high incidence of HIV infection in illicit drug abusers is primarily due to high risk activities such as needle sharing and unprotected sex. Several studies have also demonstrated that drugs of abuse increase viral RNA concentrations by enhancing HIV replication, in particular in the central nervous system (CNS). The CNS is a common target for both drugs of abuse and HIV, and their synergistic action accelerates neuronal injury and cognitive impairment. In order to generate complete genomic transcripts, HIV gene expression has to progress through both the initiation and elongation phases of transcription, which requires coordinated action of different transcription factors. Conclusion: In this review, we will provide the latest updates of the molecular mechanisms that regulate HIV transcription and discuss how drugs of abuse, such as cocaine, amphetamine, methamphetamine, heroin and morphine, modulate those mechanisms to upregulate HIV transcription and eventually HIV replication.