Sustained Viremia Research Articles

324. Outcomes of Immunomodulatory and Biologic Therapy in People Living with HIV: A Report from Two Academic Hospitals

BackgroundThe use of immunomodulatory drugs (IMDs) is increasingly common. However, data on outcomes of IMD use in people living with HIV (PLWH) are limited and may be biased due to selective reporting of certain outcomes. Institution-level data reflecting patient-time at risk have not been described.MethodsWe systematically identified all PLWH prescribed non-steroidal IMDs from 2012 to 2019 at two centers. We defined a treatment episode (TE) as an uninterrupted period on a particular IMD regimen. Patients contributed multiple TEs if interrupting or switching therapy. We excluded those with lymphoproliferative disorders or transplants. We quantified infections and blips, defined as a detectable viral load following an undetectable result.Results35 patients contributed 55 TEs comprising 24,020 patient-days at risk. 29/35 (83%) were male, median age was 53 (IQR 39–59), median CD4 nadir was 197 (IQR 100–314), and 12/35 (34%) had a prior opportunistic infection. TEs utilized TNF inhibitors (19/55, 35%), PD-1 inhibitors (11/55, 20%), antimetabolites (7/55, 13%), interleukin inhibitors (7/55, 13%), and other agents (7/55, 13%). 4/55 (7%) involved in dual therapy. 32/35 (94%) patients were on antiretroviral therapy (ART) at IMD initiation; one was off therapy, one already on IMDs-acquired HIV, and one was an elite controller. Median CD4 count was 472 (IQR 337–807); CD4 was < 500 in 28/55 TEs (51%). Preceding plasma HIV RNA was undetectable in 36/55 (65%) TEs. Of these, 18 (50%) were associated with a viral blip within 1 year; one blip was >200 copies and none resulted in sustained viremia. Compared with other agents, PD-1 inhibitors were associated with a higher blip rate (incidence rate ratio 4.3, 1.3–12.3). 17/55 (32%) TEs were initiated with detectable plasma HIV RNA, which declined on ART in 13/15 (87%) TEs with follow-up testing; one patient stopped ART and one later suppressed. 9/55 (16%) TEs involved an infectious complication (7 soft-tissue infections, 2 pneumonias), although none was clearly attributed to IMDs. 36/55 (65%) TEs had good therapeutic response.ConclusionIMDs can be used without major complications in PLWH on ART, including those not yet suppressed or with CD4 counts < 500. PD-1 inhibitors may be associated with a higher rate of viral blips, although the clinical significance is unclear.Disclosures All authors: No reported disclosures.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS TRIGGERED BY ADENOVIRUS PNEUMONIA: A RARE COMPLICATION OF A COMMON DISEASE

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Adenovirus (ADV) pneumonia is a common disease with many extrapulmonary complications. We report a case of a 71-year old lady with history of follicular lymphoma who developed ADV pneumonia triggering hemophagocytic lymphohistiocytosis (HLH) CASE PRESENTATION: A 71-year-old female presented to our hospital with fever and cough. Chest X-ray revealed pneumonia. Additional labs upon admission showed pancytopenia. Six months prior to presentation, she was diagnosed with follicular lymphoma and she completed six cycles of R-CHOP (last cycle being four weeks prior to presentation). A PET-CT scan performed five days prior to admission revealed complete metabolic response, and a complete blood count was normal. Empiric antibiotics did not result in improvement prompting a CT scan of the chest that showed dense consolidation in the left lower lobe, ground glass opacities in upper lobes and trace pleural effusions. Bronchoscopy was performed. Bronchial wash cultures grew ADV. Other bacterial, fungal and viral serology/cultures were all negative. ADV was also isolated from serum. Patient remained febrile and had progressive pancytopenia with counts reaching a nadir of 0.0K/uL neutrophils, 5.8 g/dL hemoglobin and 34K/uL platelets. Further labs showed elevated ferritin at >40,000ng/ml , elevated soluble IL-2 receptor alpha and transaminitis. HLH was suspected and steroids were started empirically. Bone Marrow biopsy confirmed HLH without evidence of lymphoma or metastatic carcinoma. Patient continued to decline, she developed rectus sheath hematoma, hypotension, acute kidney injury and delirium. Family decided to withdraw all active treatments and take the route of comfort care which eventually lead to her unfortunate demise on day nine of admission. DISCUSSION: ADV pneumonia can occur in both immunocompetent and immunocompromised hosts(1). Both outbreaks and sporadic cases have been described. ADV-pneumonia can be fatal with poor prognostic factors including: viremia, multilobar infiltrates and parapneumonic effusions(2, 3). CT commonly shows dens consolidation with surrounding ground glass opacities. ADV infection induced HLH has been well described in children. This phenomenon is rare in adults with only a few reported cases, mostly described in hematopoietic stem cell transplant recipients. Older age, markedly elevated ferritin and underlying lymphoma are considered poor prognostic factors in HLH. Our patient’s history of follicular lymphoma had probably put her at higher risk for developing this immunological catastrophe. She had all of the aforementioned poor prognostic of both ADV-pneumonia and HLH. CONCLUSIONS: Our case signifies that HLH should be suspected in the setting of ADV infection and pancytopenia. Early diagnosis and treatment might be associated with better outcomes in this rare-life threatening- hematological complication. Reference #1: Shen CF, Wang SM, Ho TS, Liu CC. Clinical features of community acquired adenovirus pneumonia during the 2011 community outbreak in Southern Taiwan: role of host immune response. BMC infectious diseases. 2017;17(1):196. Reference #2: Gu L, Qu J, Sun B, Yu X, Li H, Cao B. Sustained Viremia and High Viral Load in Respiratory Tract Secretions Are Predictors for Death in Immunocompetent Adults with Adenovirus Pneumonia. PloS one. 2016;11(8):e0160777. Reference #3: Yoon H, Jhun BW, Kim SJ, Kim K. Clinical characteristics and factors predicting respiratory failure in adenovirus pneumonia. Respirology (Carlton, Vic). 2016;21(7):1243-50. DISCLOSURES: No relevant relationships by Muhammad Hamza, source=Web Response No relevant relationships by Khalid Mohamed Ahmed, source=Web Response No relevant relationships by Mahum Shahid, source=Web Response No relevant relationships by Qazi Ahmed Waqas, source=Web Response

710P - Systemic administration of the hyaluronidase-expressing oncolytic adenovirus VCN-01 in patients with advanced or metastatic pancreatic cancer: First-in-human clinical trial

710P - Systemic administration of the hyaluronidase-expressing oncolytic adenovirus VCN-01 in patients with advanced or metastatic pancreatic cancer: First-in-human clinical trial

Reactivation of BK virus after double umbilical cord blood transplantation in adults correlates with impaired reconstitution of CD4+ and CD8+ T effector memory cells and increase of T regulatory cells

BK virus (BKV), a human polyomavirus that remains latent in renal epithelial cells, can be reactivated after hematopoietic stem cell transplantation (HSCT) leading to hemorrhagic cystitis. The incidence of BK viremia is higher after Umbilical cord blood transplantation (UCBT) than HSCT from adult donors. Data regarding the role of immune recovery after UCBT in BKV reactivation is lacking. We examined the correlation between the development of BK viremia and immune reconstitution in 27 adult recipients of UCBT. The incidence of BK viremia was 52% and developed most frequently within the first 8 weeks after the transplantation, but persisted in seven patients at 6 months, and three patients at 1-year post UCBT. Detection of BK viremia 1 year after transplant was negatively associated with the number of CD8+ cells (p = 0.03) and CD8+CD45RO+ cells (p = 0.05) at 6 months, and the number of CD4+ (p = 0.03) and CD4+CD45RO+ cells (p = 0.03) at 12 months after UCBT. Conversely, BK viremia at 6 and 12 months was positively correlated with the number of T regulatory (Treg) cells at 1 month (p = 0.005 and p = 0.016, respectively). Because UCB Treg have highly potent immunosuppressive function, our findings indicate that sustained BK viremia in UCBT recipients might be associated with the increase of Treg cells early after transplantation, which mediate impaired and delayed reconstitution of CD4+ and CD8+ T effector cells.

Incidence, risk factors, and outcome of BK polyomavirus infection after kidney transplantation.

BACKGROUNDPolyomavirus-associated nephropathy is a leading cause of kidney allograft failure. Therapeutic options are limited and prompt reduction of the net state of immunosuppression represents the mainstay of treatment. More recent application of aggressive screening and management protocols for BK-virus infection after renal transplantation has shown encouraging results. Nevertheless, long-term outcome for patients with BK-viremia and nephropathy remains obscure. Risk factors for BK-virus infection are also unclear.AIMTo investigate incidence, risk factors, and outcome of BK-virus infection after kidney transplantation.METHODSThis single-centre observational study with a median follow up of 57 (31-80) mo comprises 629 consecutive adult patients who underwent kidney transplantation between 2007 and 2013. Data were prospectively recorded and annually reviewed until 2016. Recipients were periodically screened for BK-virus by plasma quantitative polymerized chain reaction. Patients with BK viral load ≥ 1000 copies/mL were diagnosed BK-viremia and underwent histological assessment to rule out nephropathy. In case of BK-viremia, immunosuppression was minimized according to a prespecified protocol. The following outcomes were evaluated: patient survival, overall graft survival, graft failure considering death as a competing risk, 30-d-event-censored graft failure, response to treatment, rejection, renal function, urologic complications, opportunistic infections, new-onset diabetes after transplantation, and malignancies. We used a multivariable model to analyse risk factors for BK-viremia and nephropathy.RESULTSBK-viremia was detected in 9.5% recipients. Initial viral load was high (≥ 10000 copies/mL) in 66.7% and low (< 10000 copies/mL) in 33.3% of these patients. Polyomavirus-associated nephropathy was diagnosed in 6.5% of the study population. Patients with high initial viral load were more likely to experience sustained viremia (95% vs 25%, P < 0.00001), nephropathy (92.5% vs 15%, P < 0.00001), and polyomavirus-related graft loss (27.5% vs 0%, P = 0.0108) than recipients with low initial viral load. Comparison between recipients with or without BK-viremia showed that the proportion of patients with Afro-Caribbean ethnicity (33.3% vs 16.5%, P = 0.0024), panel-reactive antibody ≥ 50% (30% vs 14.6%, P = 0.0047), human leukocyte antigen (HLA) mismatching > 4 (26.7% vs 13.4%, P = 0.0110), and rejection within thirty days of transplant (21.7% vs 9.5%; P = 0.0073) was higher in the viremic group. Five-year patient and overall graft survival rates for patients with or without BK-viremia were similar. However, viremic recipients showed higher 5-year crude cumulative (22.5% vs 12.2%, P = 0.0270) and 30-d-event-censored (22.5% vs 7.1%, P = 0.001) incidences of graft failure than control. In the viremic group we also observed higher proportions of recipients with 5-year estimated glomerular filtration rate < 30 mL/min than the group without viremia: 45% vs 27% (P = 0.0064). Urologic complications were comparable between the two groups. Response to treatment was complete in 55%, partial in 26.7%, and absent in 18.3% patients. The nephropathy group showed higher 5-year crude cumulative and 30-d-event-censored incidences of graft failure than control: 29.1% vs 12.1% (P = 0.008) and 29.1% vs 7.2% (P < 0.001), respectively. Our multivariable model demonstrated that Afro-Caribbean ethnicity, panel-reactive antibody > 50%, HLA mismatching > 4, and rejection were independent risk factors for BK-virus viremia whereas cytomegalovirus prophylaxis was protective.CONCLUSIONCurrent treatment of BK-virus infection offers sub-optimal results. Initial viremia is a valuable parameter to detect patients at increased risk of nephropathy. Panel-reactive antibody > 50% and Afro-Caribbean ethnicity are independent predictors of BK-virus infection whereas cytomegalovirus prophylaxis has a protective effect.

HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation

ObjectiveDeveloping a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to...

No clinical benefit of rapid versus gradual tapering of immunosuppression to treat sustained BK virus viremia after kidney transplantation: a single-center experience.

Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T0 ) were similar among patient groups. However, following onset, the dose of MPA at 1month (P=0.002) and 3months (P=0.005) and Tac T0 at 1month (P=0.030) and 3months (P=0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P<0.001) and resulted in a better protection of graft function in patients with confirmed BKV-associated nephropathy (P=0.033) without impacting 5-year graft survival. Survival without rejection was similar (P=0.571), but the RT group had increased the development of de novo donor-specific antibodies (dnDSAs; P<0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin® induction [hazard ratio (HR), 3.090; P=0.001] and the RT strategy (HR, 6.021; P=0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium-term clinical outcome but increases the risk of developing dnDSAs.

Conversion From Mycophenolates to Mizoribine Is Associated With Lower BK Virus Load in Kidney Transplant Recipients: A Prospective Study

BackgroundBK virus allograft nephropathy (BKVAN) is a graft-threatening complication after kidney transplantation. Current consensus regarding the prevention of BKVAN is to screen for BK viremia and to treat sustained BK viremia through reducing immunosuppression. This study assessed the effect of conversion from mycophenolates to mizoribine (MZR) on the prevention of BK viremia in kidney transplant recipients. MethodsDe novo kidney transplant recipients were screened for BK viruria. Sustained high levels of BK viruria (>107 copies/mL) were treated by switching from mycophenolates to MZR. The reduction and clearance of BK viruria and viremia were evaluated. ResultsFifty kidney transplant recipients with high levels BK viruria were enrolled, including 11 recipients with BK viremia. After 6 months of MZR therapy, only 3 recipients still had high levels of BK viruria. The clearance rate of BK viremia was 100%. One episode of acute rejection occurred (2.0%) and was reversed by steroid administration. The serum uric acid level of the recipients was similar before and after switching to MZR, but the proportion of recipients receiving uric acid–reducing drugs increased significantly after 3 months of MZR therapy (19/50 vs 31/50; P = .02). No new cases of BK viremia were observed after conversion to MZR. ConclusionConversion from mycophenolates to MZR in kidney transplant recipients with sustained high levels of BK viruria was associated with reduction of BK viruria and clearance of BK viremia. This may be an effective approach to prevent BK viremia and BKVAN.

Reducing calcineurin inhibitor first for treating BK polyomavirus replication after kidney transplantation: long-term outcomes.

Reducing immunosuppression is the mainstay of treating BK polyomavirus (BKPyV) viraemia after kidney transplantation, but the best approach, efficacy and impact are undefined. We established a standard operating procedure (SOP) treating BKPyV viraemia based on first reducing calcineurin inhibitor ('CNI first'). The aim of this study was to investigate long-term outcomes in 644 consecutive transplantations using this SOP. Patients were monitored for active BKPyV infection by urinary decoy cells and, if positive, by BKPyV viraemia. In case of sustained BKPyV viraemia >1000 copies/mL, immunosuppression was reduced stepwise according to the SOP. Patients were classified as 'no decoy cells' [n = 432 (66%)], 'decoy cells/no viraemia' [n = 107 (17%)] and 'viraemia' [n = 105 (17%)]. At 6-years post-transplant, graft survival was ∼84%, the clinical rejection rate was ∼25% and they were not different among the three groups (P = 0.14; P = 0.91). The median estimated glomerular filtration rate at the last follow-up was similar (range 49-53 mL/min, P = 0.08). Of 105 viraemic patients, 101 (96%) cleared BKPyV viraemia. In 39% of patients, viraemia clearance followed a tacrolimus reduction. A reduction of mycophenolic acid was required in 43% and discontinuation in 3%. No short-term graft loss was directly attributable to BKPyV-associated nephropathy. After a median follow-up of 5 years after clearance of BKPyV viraemia, 11/101 patients (11%) developed clinical rejection: 7 (7%) T-cell-mediated rejection and 4 (4%) antibody-mediated rejection (ABMR). Immunosuppression reduction based on 'CNI first' leads to similar long-term outcomes in patients with/without BKPyV viraemia and is associated with a low risk for ABMR after clearance of BKPyV viraemia. Randomized trials are needed to compare the risks and benefits of immunosuppression reduction strategies in kidney transplant patients with BKPyV viraemia.

Evidence of natural Zika virus infection in neotropical non-human primates in Brazil

In Africa, Old World Primates are involved in the maintenance of sylvatic circulation of ZIKV. However, in Brazil, the hosts for the sylvatic cycle remain unknown. We hypothesized that free-living NHPs might play a role in urban/periurban ZIKV dynamics, thus we undertook an NHP ZIKV investigation in two cities in Brazil. We identified ZIKV-positive NHPs and sequences obtained were phylogenetically related to the American lineage of ZIKV. Additionally, we inoculated four C. penicillata with ZIKV and our results demonstrated that marmosets had a sustained viremia. The natural and experimental infection of NHPs with ZIKV, support the hypothesis that NHPs may be a vertebrate host in the maintainance of ZIKV transmission/circulation in urban tropical settings. Further studies are needed to understand the role they may play in maintaining the urban cycle of the ZIKV and how they may be a conduit in establishing an enzootic transmission cycle in tropical Latin America.

Determination of viremia cut-off for risk to develop BKPyV-associated nephropathy among kidney transplant recipients.

BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is a consequence of BKPyV replication in the urinary tract in kidney transplant recipients (KTR). The objectives were to determine the prevalence of BKPyV replication and BKPyVAN, risk factors associated to sustained viremia and BKPyVAN, and viremia cut-off that best predict the occurrence of sustained viremia and nephropathy in KTR of a single University Hospital Kidney Transplant Center. All KTR undergoing transplantation from August 2010 to December 2011 were enrolled and monitored up to 2years posttransplantation for BKPyV viruria by decoy cells shedding or polymerase chain reaction (PCR) and viremia by PCR. Kidney biopsy was indicated if sustained viremia (two or more viremia above 10000copies/mL) to confirm BKPyVAN diagnosis. In this study, 326 transplants were performed and 246 patients were included. Prevalence of viruria was 36.9%, viremia 22.3% and nephropathy 3.2%. Male gender was the only risk factor associated to sustained viremia or nephropathy. Cut-off value of viremia that best discriminates the progression to sustained viremia and to BKPyVAN was 37488 and 44956copies/mL, respectively. Prevalence of viruria, viremia, and nephropathy were similar to those reported in literature but the cut-off value of viremia that best discriminates the risk of progression to nephropathy was greater than the value usually reported, which is 10000copies/mL.

2216 Characterizing physician trust and healthcare-based discrimination among long-term HIV viral trajectory groups in Washington, DC

OBJECTIVES/SPECIFIC AIMS: Discrimination within the healthcare system and physician distrust have been associated with adverse clinical outcomes for people living with HIV; however, many studies do not link these variables to biological data. We hypothesize that perceived healthcare discrimination and physician distrust associates with higher longitudinal viremia among HIV-positive women. METHODS/STUDY POPULATION: A 2006 cross-sectional survey assessed healthcare-based discrimination and physician trust in 92 HIV-positive and 46 high-risk HIV-negative women from the Washington DC Women’s Interagency HIV Study (DC-WIHS). In addition, we identified HIV viral load trajectories and demographics from the HIV-positive women who contributed≥4 semi-annual visits from 1994 to 2015. Viral suppression was defined by assay detection limits (&lt;80 to &lt;20 copies/mL). Group-based probability trajectory analyses grouped women based on longitudinal viral load patterns, and identified 3 groups: sustained viremia (n=32) with low-viral suppression over time, intermittent viremia (n=27) with varying suppression over time, and non-viremia (n=33) with high-longitudinal viral suppression. Ordinal logistic regression models assessed trajectory group and discrimination variables, controlling for demographics, using stepwise selection with significance level of α=0.05. RESULTS/ANTICIPATED RESULTS: Most women were African American (60%), insured at the time of visit (89%) and nonsmokers (56%). While physician trust did not differ by HIV viral trajectory group, trust was lower among HIV-negative women compared with HIV-positive women (p=0.03). Over 1 in 5 HIV-positive women reported discrimination in the healthcare system based on HIV status (21.3%). Report of discrimination based on drug/alcohol use was higher among HIV-negative participants (19.2% vs. 6.5%, p=0.01). Among women with longitudinal sustained viremia, report of discrimination based on race ethnicity (29%, p=0.004) and sexual orientation (15.6%, p=0.008) were higher than within the nonviremic and intermittent trajectory groups. DISCUSSION/SIGNIFICANCE OF IMPACT: Physician trust did not associate with increased longitudinal viral suppression among HIV-positive women in Washington, DC. Lack of physician trust among high-risk HIV-negative women could have implications for uptake of prevention methods. Reports of discrimination vary between HIV-positive and HIV-negative women in the Washington, DC area. The findings of healthcare system distrust among HIV-negative women has implications outside the realm of HIV, as this lack of trust may impact risk for other disease states among similar populations of women.

Species-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity

HIV-1 causes chronic inflammation and AIDS in humans, whereas related simian immunodeficiency viruses (SIVs) replicate efficiently in their natural hosts without causing disease. It is currently unknown to what extent virus-specific properties are responsible for these different clinical outcomes. Here, we incorporate two putative HIV-1 virulence determinants, i.e., a Vpu protein that antagonizes tetherin and blocks NF-κB activation and a Nef protein that fails to suppress T cell activation via downmodulation of CD3, into a non-pathogenic SIVagm strain and test their impact on viral replication and pathogenicity in African green monkeys. Despite sustained high-level viremia over more than 4 years, moderately increased immune activation and transcriptional signatures of inflammation, the HIV-1-like SIVagm does not cause immunodeficiency or any other disease. These data indicate that species-specific host factors rather than intrinsic viral virulence factors determine the pathogenicity of primate lentiviruses.

Lymphocyte-Dominant Encephalitis and Meningitis in Simian Immunodeficiency Virus–Infected Macaques Receiving Antiretroviral Therapy

A retrospective neuropathologic review of 30 SIV-infected pigtailed macaques receiving combination antiretroviral therapy (cART) was conducted. Seventeen animals with lymphocyte-dominant inflammation in the brain and/or meninges that clearly was morphologically distinct from prototypic SIV encephalitis and human immunodeficiency virus encephalitis were identified. Central nervous system (CNS) infiltrates in cART-treated macaques primarily comprised CD20+ B cells and CD3+ T cells with fewer CD68+ macrophages. Inflammation was associated with low levels of SIV RNA in the brain as shown by in situ hybridization, and generally was observed in animals with episodes of cerebrospinal fluid (CSF) viral rebound or sustained plasma and CSF viremia during treatment. Although the lymphocytic CNS inflammation in these macaques shared morphologic characteristics with uncommon immune-mediated neurologic disorders reported in treated HIV patients, including CNS immune reconstitution inflammatory syndrome and neurosymptomatic CSF escape, the high prevalence of CNS lesions in macaques suggests that persistent adaptive immune responses in the CNS also may develop in neuroasymptomatic or mildly impaired HIV patients yet remain unrecognized given the lack of access to CNS tissue for histopathologic evaluation. Continued investigation into the mechanisms and outcomes of CNS inflammation in cART-treated, SIV-infected macaques will advance our understanding of the consequences of residual CNS HIV replication in patients on cART, including the possible contribution of adaptive immune responses to HIV-associated neurocognitive disorders.

Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively. Clinical manifestations of both forms are frequently preceded by a viral infection, predominantly with herpesviruses. The exact role of the viral infection in the development of the hemophagocytic syndrome remains to be further elucidated.MethodsWe utilized a recently developed murine model of cytomegalovirus-associated secondary HLH and dissected the respective contributions of lytic viral replication and immunopathology in its pathogenesis.ResultsHLH-like disease only developed in cytomegalovirus-susceptible mouse strains unable to clear the virus, but the severity of symptoms was not correlated to the infectious viral titer. Lytic viral replication and sustained viremia played an essential part in the pathogenesis since abortive viral infection was insufficient to induce a full-blown HLH-like syndrome. Nonetheless, a limited set of symptoms, in particular anemia, thrombocytopenia and elevated levels of soluble CD25, appeared less dependent of the viral replication but rather mediated by the host’s immune response, as corroborated by immunosuppressive treatment of infected mice with dexamethasone.ConclusionBoth virus-mediated pathology and immunopathology cooperate in the pathogenesis of full-blown virus-associated secondary HLH and are closely entangled. A certain level of viremia appears necessary to elicit the characteristic HLH-like symptoms in the model.

BK polyomavirus infection after renal transplantation: Surveillance in a resource-challenged setting.

There is a paucity of data available about BK polyomavirus (BKPyV) infection after renal transplantation (RTX) in resource-limited countries with a predominantly living-donor, ABO-compatible RTX program. We aimed to assess BKPyV infection in such patients in a public hospital in India. We prospectively evaluated plasma BKPyV replication in 62 patients at 1, 3, 6, 9, and 12months after RTX. Sustained significant BK viremia (SSBKV) was defined as significant viremia (≥10000 copies/mL) detected ≥2 times, and BKPyV-associated nephropathy (BKVAN) as histologic changes of BKVAN with BK viremia with/without graft dysfunction. All patients underwent RTX without requiring desensitization. Incidence of BK viremia was: 17.7%, 41.9%, 16.1%, 25.8%, and 17.7% at 1, 3, 6, 9, and 12months, respectively. Of 62 patients, 64.5% had BKPyV viremia during the study, 32.2% had significant viremia, all except one detected in the first 6months. Nine (14.5%) patients had SSBKV. There was no biopsy-proven BKVAN. At the end of 1year, mean serum creatinine was higher and graft dysfunction was significantly more common in patients with SSBKV compared to those without SSBKV. Transient BK viremia is common in low/intermediate immunologic risk RTX recipients in India, with a peak occurring at 3-6months. Most clear their viremia by 12months. Graft dysfunction seems to be more frequent in patients with SSBKV, although BKVAN is uncommon on biopsy in these patients.

A DNA vaccine delivered by dermal electroporation fully protects cynomolgus macaques against Lassa fever

ABSTRACTLassa virus (LASV) is an ambisense RNA virus in the Arenaviridae family and is the etiological agent of Lassa fever, a severe hemorrhagic disease endemic to West and Central Africa.1,2 There are no US Food and Drug Administration (FDA)-licensed vaccines available to prevent Lassa fever.1,2 in our previous studies, we developed a gene-optimized DNA vaccine that encodes the glycoprotein precursor gene of LASV (Josiah strain) and demonstrated that 3 vaccinations accompanied by dermal electroporation protected guinea pigs from LASV-associated illness and death. Here, we describe an initial efficacy experiment in cynomolgus macaque nonhuman primates (NHPs) in which we followed an identical 3-dose vaccine schedule that was successful in guinea pigs, and a follow-on experiment in which we used an accelerated vaccination strategy consisting of 2 administrations, spaced 4 weeks apart. In both studies, all of the LASV DNA-vaccinated NHPs survived challenge and none of them had measureable, sustained viremia or displayed weight loss or other disease signs post-exposure. Three of 10 mock-vaccinates survived exposure to LASV, but all of them became acutely ill post-exposure and remained chronically ill to the study end point (45 d post-exposure). Two of the 3 survivors experienced sensorineural hearing loss (described elsewhere). These results clearly demonstrate that the LASV DNA vaccine combined with dermal electroporation is a highly effective candidate for eventual use in humans.

Evaluation of HIV-DNA and inflammatory markers in HIV-infected individuals with different viral load patterns

BackgroundPersistent residual viremia (RV) and low grade inflammation and immune activation have been associated with non-AIDS defining events. The impact of persistent RV and HIV-DNA load on immune activation/inflammation remains unclear. The purpose of this study was to gain new insights into the relation between viremia, markers of inflammation and HIV-DNA levels.MethodsThree hundred and twenty-one HIV-infected patients were studied. A retrospective analysis of viremia values, prospectively collected for 48 months, was performed. Patients were separated into three groups: 113 TND (Target Not Detected, patients with sustained undetectable viremia); 113 RV (Residual Viremia, patients who had at least three detectable viral load (VL) values <37 copies/ml); 95 LLV (Low Level Viremia, patients with at least two VL values >37 but <200 copies/ml). HIV-DNA, TNF-α, IL-6 and sCD14 were analyzed.ResultsHIV-DNA, sCD14 and TNF-α were significantly lower in the TND group than in the RV and LLV groups. In addition, RV patients showed lower levels of HIV-DNA and sCD14 than LLV individuals. HIV-DNA load was not related to markers of inflammation. The ordinal logistic analysis showed that two independent variables were significantly associated with VL pattern: sCD14, HIV-DNA. In addition NRTIs plus NNRTIs and NRTIs plus PIs were negatively associated to VL pattern compared to INI-containing regimen.ConclusionsPersistent undetectable viremia was associated with lower levels of inflammatory markers and HIV-DNA. However, the lack of normalization of these biomarkers in the TND group and the fact that HIV-DNA load was not associated with inflammation strongly suggest that other mechanisms play a major role in maintaining inflammation over time.

Early antibody therapy can induce long-lasting immunity to SHIV.

Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have been used to prevent and treat lentivirus infections in humanized mice, macaques, and humans. In immunotherapy experiments, administration of bNAbs to chronically infected animals transiently suppresses virus replication, which invariably returns to pre-treatment levels and results in progression to clinical disease. Here we show that early administration of bNAbs in a macaque simian/human immunodeficiency virus (SHIV) model is associated with very low levels of persistent viraemia, which leads to the establishment of T-cell immunity and resultant long-term infection control. Animals challenged with SHIVAD8-EO by mucosal or intravenous routes received a single 2-week course of two potent passively transferred bNAbs (3BNC117 and 10-1074 (refs 13, 14)). Viraemia remained undetectable for 56-177 days, depending on bNAb half-life in vivo. Moreover, in the 13 treated monkeys, plasma virus loads subsequently declined to undetectable levels in 6 controller macaques. Four additional animals maintained their counts of T cells carrying the CD4 antigen (CD4+) and very low levels of viraemia persisted for over 2 years. The frequency of cells carrying replication-competent virus was less than 1 per 106 circulating CD4+ T cells in the six controller macaques. Infusion of a T-cell-depleting anti-CD8β monoclonal antibody to the controller animals led to a specific decline in levels of CD8+ T cells and the rapid reappearance of plasma viraemia. In contrast, macaques treated for 15 weeks with combination anti-retroviral therapy, beginning on day 3 after infection, experienced sustained rebound plasma viraemia when treatment was interrupted. Our results show that passive immunotherapy during acute SHIV infection differs from combination anti-retroviral therapy in that it facilitates the emergence of potent CD8+ T-cell immunity able to durably suppress virus replication.

When patients fail UNAIDS' last 90 - the "failure cascade" beyond 90-90-90 in rural Lesotho, Southern Africa: a prospective cohort study.

Introduction: HIV-infected individuals on first-line antiretroviral therapy (ART) in resource-limited settings who do not achieve the last “90” (viral suppression) enter a complex care cascade: enhanced adherence counselling (EAC), repetition of viral load (VL) and switch to second-line ART aiming to achieve resuppression. This study describes the “failure cascade” in patients in Lesotho.Methods: Patients aged ≥16 years on first-line ART at 10 facilities in rural Lesotho received a first-time VL in June 2014. Those with VL ≥80 copies/mL were included in a cohort. The care cascade was assessed at four points: attendance of EAC, result of follow-up VL after EAC, switch to second-line in case of sustained unsuppressed VL and outcome 18 months after the initial unsuppressed VL. Multivariate logistic regression was used to assess predictors of being retained in care with viral resuppression at follow-up.Results: Out of 1563 patients who underwent first-time VL, 138 (8.8%) had unsuppressed VL in June 2014. Out of these, 124 (90%) attended EAC and 116 (84%) had follow-up VL (4 died, 2 transferred out, 11 lost, 5 switched to second-line before follow-up VL). Among the 116 with follow-up VL, 36 (31%) achieved resuppression. Out of the 80 with sustained unsuppressed VL, 58 were switched to second-line, the remaining continued first line. At 18 months’ follow-up in December 2015, out of the initially 138 with unsuppressed VL, 56 (41%) were in care and virally suppressed, 37 (27%) were in care with unsuppressed VL and the remaining 45 (33%) were lost, dead, transferred to another clinic or without documented VL. Achieving viral resuppression after EAC (adjusted odds ratio (aOR): 5.02; 95% confidence interval: 1.14–22.09; p = 0.033) and being switched to second-line in case of sustained viremia after EAC (aOR: 7.17; 1.90–27.04; p = 0.004) were associated with being retained in care and virally suppressed at 18 months of follow-up. Age, gender, education, time on ART and level of VL were not associated.Conclusions: In this study in rural Lesotho, outcomes along the “failure cascade” were poor. To improve outcomes in this vulnerable patient group who fails the last “90”, programmes need to focus on timely EAC and switch to second line for cases with continuous viremia despite EAC.