non-HIV Setting Research Articles

Extracellular vesicles released from macrophages modulates interleukin-1β in astrocytic and neuronal cells

We have recently demonstrated that long-term exposure of cigarette smoke condensate (CSC) to HIV-uninfected (U937) and -infected (U1) macrophages induce packaging of pro-inflammatory molecules, particularly IL-1β, in extracellular vesicles (EVs). Therefore, we hypothesize that exposure of EVs derived from CSC-treated macrophages to CNS cells can increase their IL-1β levels contributing to neuroinflammation. To test this hypothesis, we treated the U937 and U1 differentiated macrophages once daily with CSC (10 µg/ml) for 7 days. Then, we isolated EVs from these macrophages and treated these EVs with human astrocytic (SVGA) and neuronal (SH-SY5Y) cells in the absence and presence of CSC. We then examined the protein expression of IL-1β and oxidative stress related proteins, cytochrome P450 2A6 (CYP2A6), superoxide dismutase-1 (SOD1), catalase (CAT). We observed that the U937 cells have lower expression of IL-1β compared to their respective EVs, confirming that most of the produced IL-1β are packaged into EVs. Further, EVs isolated from HIV-infected and uninfected cells, both in the absence and presence of CSC, were treated to SVGA and SH-SY5Y cells. These treatments showed a significant increase in the levels of IL-1β in both SVGA and SH-SY5Y cells. However, under the same conditions, the levels of CYP2A6, SOD1, and catalase were only markedly altered. These findings suggest that the macrophages communicate with astrocytes and neuronal cells via EVs-containing IL-1β in both HIV and non-HIV setting and could contribute to neuroinflammation.

The use of optical coherence tomography in diagnosis of HIV-associated atherosclerosis: Case report

Background and Aims: Patients with human immunodeficiency virus (HIV) are at higher risk for coronary artery disease, due to accelerated atherosclerosis resulting from chronic inflammation, the prevalence of cardiovascular risk factors and the side effects of highly active antiretroviral therapy (HAART). The atherosclerosis associated with HIV differs in important ways from atherosclerosis in the non-HIV setting. The present article aimed to report an unusual case of atherosclerosis in HIV-infected young women without any traditional cardiovascular risk factors on OCT.

Hepatitis C virus or hepatitis B virus coinfection and lymphoma risk in people living with HIV.

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are associated with increased risks of lymphomas in the non-HIV setting. Their impacts on HIV-associated lymphomas deserved further studies in the modern combined antiretroviral therapy (cART) era. We evaluated the associations between HCV, HBV and HIV-related lymphomas in the Lymphovir-ANRS-CO16 cohort. Prevalence of HCV seropositivity and chronic HBV infections were compared with those observed in the French Hospital Database on HIV (FHDH-ANRS-CO4). Between 2008 and 2015, 179 patients with HIV-related lymphomas from 32 French hospitals were enrolled, 69 had Hodgkin's lymphoma (39%), and 110 non-Hodgkin's lymphoma (NHL) (61%). The prevalence of HCV infection was higher in patients with NHL than in the FHDH-ANRS-CO4 [26 versus 14%, odd ratio (OR): 2.15; 95% confidence interval (1.35-3.32)] whereas there was no association between Hodgkin's lymphoma and chronic HCV infection. Chronic HBV infection was not associated with NHL in our cohort with a prevalence of 5 versus 7% in FHDH-ANRS-CO4 but tended to be associated with Hodgkin's lymphoma [prevalence of 14%, OR: 2.16 (0.98-4.27)]. Chronic HCV infection tended to pejoratively impact 2-year overall survival in patients with NHL: 72% [57%, 91%] versus 82% [74%, 91%], hazard ratio: 2.14 [0.95-4.84]. In contrast, chronic HBV infection did not correlate with outcome. In the modern cART era, chronic HCV infection is associated with an increased risk of NHL in PLWHIV and tends to pejoratively impact overall survival. HBV infection is not associated with the risk of NHL but with a borderline increase of Hodgkin's lymphoma risk.

Mitochondria and ageing with HIV.

Some older people living with HIV (PLWH) exhibit features of unsuccessful ageing, such as frailty. Mitochondrial dysfunction is one of the best characterized ageing mechanisms. There has been recent interest in whether some people ageing with HIV may have an excess of mitochondrial dysfunction. This review aims to address this question through: analogy with ageing and chronic disease; discussion of the key unknowns; suggested ways that measures of mitochondrial dysfunction might be incorporated into HIV research studies. Recent data suggest that mitochondrial dysfunction in PLWH may not be wholly a legacy effect of historical nucleoside analog reverse transcriptase inhibitor exposures. Research in the non-HIV setting has altered our understanding of the important mediators of mitochondrial dysfunction in ageing. Mitochondrial dysfunction is a very plausible driver of adverse ageing phenotypes in some older PLWH. As such it may be a target for therapeutic interventions. Currently, however, there remain considerable uncertainties around the extent of this phenomenon, and its relative importance. Current studies are likely to clarify these questions over the next few years.

Bilateral extensive CMV retinitis in a sick child – Harbinger of severe combined immunodeficiency

Cytomegalovirus (CMV) retinitis is a marker of severe cellular immunodeficiency. Severe combined immunodeficiency (SCID) must be considered in infants presenting with CMV retinitis in a non-HIV setting. Severe combined immunodeficiency (SCID) is a life-threatening syndrome characterized by recurrent infections, diarrhoea, dermatitis, and failure to thrive. Clinically, most children present before the age of 3 months. Without intervention, SCID is universally fatal. SCID is considered a pediatric emergency because survival depends on expeditious hematopoietic stem cell transplantation. Cytomegalovirus (CMV) is the most common opportunistic ocular infection in children with SCID. We report a 4-month-old male infant, with extensive bilateral CMV retinitis secondary to SCID.

Surgical complications in 275 HIV-infected liver and/or kidney transplantation recipients

In this report, we examine the surgical safety and complications (SC) among 125 liver (L) and 150 kidney (K) HIV+ transplantation (TX) recipients in a prospective nonrandomized U.S. multicenter trial. Subjects were required to have CD4+ T-cell counts >200/100 cells/mm3 (K/L) and undetectable plasma HIV-1 RNA (Viral Load [VL]) (K) or expected posttransplantation suppression (L). Impact of SCs (N ≥ 7) was evaluated by use of the proportional hazards models. Baseline morbidity predictors for SCs (N ≥ 7) were assessed in univariate proportional hazards models. At median 2.7 (interquartile range 1.9-4.1) and 2.3 (1.0-3.7) years after TX, 3-month and 1-year graft survival were [K] 96% (95% CI 91%-98%) and 91% (95% CI 85%-94%) and [L] 91% (95% CI 85%-95%) and 77% (95% CI 69%-84%), respectively. A total of 14 K and 28 L graft losses occurred in the first year; 6 K and 11 L were in the first 3 months. A total of 26 (17%) K and 43 (34%) L experienced 29 and 62 SCs, respectively. In the liver multivariate model, re-exploration was marginally associated (hazard ratio [HR] 2.8; 95% CI 1.0-8.4; P = .06) with increased risk of graft loss, whereas a greater MELD score before transplantation (HR 1.07 per point increase; 95% CI: 1.01-1.14; P = .02), and detectable viral load before TX (HR 3.6; 95% CI 0.9-14.6; P = .07) was associated with an increased risk of wound infections/dehiscence. The rates and outcomes of surgical complications are similar to what has been observed in the non-HIV setting in carefully selected HIV-infected liver and kidney TX recipients.

The CD8+ HLA-DR+ T cells expanded in HIV-1 infection are qualitatively identical to those from healthy controls.

HIV-induced immune activation leads to expansion of a subset of human CD8(+) T cells expressing HLA-DR antigens. Expansion of CD8(+) HLA-DR(+) T cells can be also observed in non-HIV settings including several autoimmune diseases and aging. Although these cells are felt to represent "immune exhaustion" and/or to be anergic, their precise role in host defense has remained unclear. Here, we report that this subset of cells exhibits a restricted repertoire, shows evidence of multiple rounds of division, but lacks markers of recent TCR engagement. Detailed cell cycle analysis revealed that compared with their CD8(+) HLA-DR(-) counterpart, the CD8(+) HLA-DR(+) T-cell pool contained an increased fraction of cells in S-phase with elevated levels of the G2/M regulators: cyclin A2, CDC25C, Cdc2 (CDK1), indicating that these cells are not truly anergic but rather experiencing proliferation in vivo. Together, these data support a hypothesis that antigen stimulation leads to the initial expansion of a CD8(+) pool of cells in vivo that undergo further expansion independent of ongoing TCR engagement. No qualitative differences were noted between CD8(+) HLA-DR(+) cells from HIV(+) and HIV(-) donors, indicating that the generation of CD8(+) HLA-DR(+) T cells is a part of normal immune regulation that is exaggerated in the setting of HIV-1 infection.

JC Virus Infection of the Brain

Since its initial description, there have been significant changes in the epidemiology, pathogenesis, and clinical and imaging manifestations of JCV infection of brain. The most common clinical manifestation is PML. Other recently described CNS manifestations are JCE, JCVGCN, and JCM. Although AIDS is the most common predisposing factor for JCV reactivation, there is increasing incidence of brain manifestations of JCV reactivation in non-HIV settings, including different rheumatologic, hematologic, and oncologic conditions; monoclonal antibody therapy; transplant recipients; primary immunodeficiency syndromes; and even in patients without any recognizable immune deficiency. IRIS may develop secondary to restoration of immunity in HIV-positive patients with PML receiving antiretroviral therapy. This is of profound clinical significance and needs to be diagnosed promptly. Imaging plays a crucial role in the diagnosis of the disease, monitoring of treatment response, identifying disease progression, and predicting prognosis. In this article, current understanding of the epidemiology, pathogenesis, clinical presentations, and all aspects of imaging of JCV infection of the brain have been comprehensively reviewed.

Beware of 'normal' creatine kinase levels in HIV-associated polymyositis

Generalised weakness may be a common complaint of persons infected with HIV, but the development of significant proximal weakness requires specific attention. Polymyositis may occur in HIV infection and is readily treatable with prednisone. Elevated creatine kinase (CK) levels have been regarded as an important criterion for diagnosing polymyositis. A study of HIV-associated polymyositis reported similarly elevated CK levels to those observed in non-HIV settings. However, muscle inflammation can be associated with normal or near-normal CK levels. We report 4 cases of HIV-associated polymyositis in which the diagnosis was almost missed owing to the absence of raised CK levels.

FATAL DISSEMINATED MYCOBACTERIUM KANSASII INFECTION IN A RENAL TRANSPLANT PATIENT

INTRODUCTION: Disseminated infection due to Mycobacterium kansasii (M. kansasii) is uncommon in a non-HIV setting. Fatality from Non tuberculous Mycobacteria (NTM) is rare. Here we present a case with disseminated M. kansasii in a renal transplant patient that was fatal.

HIV-associated anaplastic large cell lymphoma

e19563 Background: Anaplastic large cell lymphoma (ALCL) is a CD30+ T-cell lymphoma that is generally unrelated to EBV in the non-HIV setting. Based upon anaplastic lymphoma kinase (ALK) expression, the new WHO classification provisionally distinguishes between ALK+ (favorable) and ALK- (unfavorable) ALCL. The characteristics of ALCL, such as ALK expression and EBV coinfection, in individuals with HIV infection have not been adequately evaluated. The aim of this study was to investigate these features in HIV-associated ALCL cases. Methods: A MEDLINE search for all cases of HIV-associated non-cutaneous ALCL was undertaken. Data regarding patient age, gender, HIV status (CD4 count, viral load, opportunistic infections), HAART, lymphoma features (B symptoms, stage, sites of involvement, immunophenotype, ALK expression, molecular studies), EBV coinfection, therapy and outcome (survival, cause of death) were extracted and analyzed. Results: A total of 23 cases were included. Patients were of median age 39 years with a male:female ratio of 7:1. Median CD4+ count was 76 cells/mm3 and HIV viral load 416,500 copies/ml. Most (67%) patients had an opportunistic infection, although only 3 (17%) were on HAART. ALCL was extranodal in 22 cases (96%) affecting most commonly lung, soft tissue and liver. Many (78%) patients had stage IV disease and B symptoms were reported in 9 cases (50%). T-cell receptor gene rearrangement was present in all cases, CD30 was positive in 22 (96%), and the vast majority (90%) were ALK-negative. EBV was identified in 8 (35%) cases. Therapy for ALCL was documented in 15 (67%) cases; 64% received CHOP. In 2 of the 3 patients who were on HAART, long-term survival was achieved. Many (68%) patients died, with a median survival of 9 months. Death was caused by either lymphoma progression (42%) or infection (58%). Conclusions: HIV-associated non-cutaneous ALCL appears to affect younger individuals and is associated with EBV infection in a subset of cases. Apart from marked immunosuppression, the poor prognosis of HIV-associated ALCL appears to be related to the absence of ALK expression, advanced stage at presentation with prominent extranodal disease, inadequate therapy including HAART, and poor response to CHOP. Further research is needed to better understand and treat this unique HIV-associated lymphoma. No significant financial relationships to disclose.

Factors associated with sexual dysfunction in men with HIV infection

Where men have had access to successful treatment for HIV (highly active antiretroviral therapy), expectations of both patients and physicians alike have changed significantly over the past decade. Such men, living with HIV, expect to lead fully functional lives including a normal sex life. Sexual dysfunction is well described among men with HIV. We retrospectively analysed details of 190 consecutive men attending a dedicated sexual dysfunction service in our HIV unit over an 18-month period. We took note of the specifics of their HIV disease, illnesses other than HIV, as well as other risk factors associated with sexual dysfunction. Men with sexual dysfunction all commonly reported recreational drug use, hepatitis B and C co-infection, anxiety and depressive illnesses, peripheral neuropathy and lipodystrophy. There was a significant relationship between men complaining of retarded ejaculation and peripheral neuropathy. Sexual dysfunction in non-HIV settings is known to lead to poor adherence to prescribed medications, e.g. antihypertensive agents. Iatrogenic sexual dysfunction in patients may similarly have a potential to lead to poor antiretroviral compliance if not addressed.

WITHDRAWN: Low CD4+ lymphocyte count in a non-HIV setting: A surrogate marker of sarcoidosis?

WITHDRAWN: Low CD4+ lymphocyte count in a non-HIV setting: A surrogate marker of sarcoidosis?

Multidrug resistance in AIDS-related lymphoma

AIDS-related lymphoma has a decreased response rate and poorer prognosis to standard chemotherapy when compared with lymphoma in the non-HIV population. In addition to the known HIV-related and lymphoma-related poor prognostic factors, this review discusses another factor, MDR-1 expression and its impact on response to therapy in patients with AIDS-related lymphoma. There is an increased incidence of de-novo MDR-1 expression in AIDS-related lymphoma compared with lymphoma in the non-HIV settings. MDR-1 expression in AIDS-related lymphoma is associated with poor response to conventional combination chemotherapy. Liposomal encapsulation of doxorubicin when substituted for doxorubicin in the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) seems to overcome P-glycoprotein-mediated drug resistance in AIDS-related lymphoma. The overexpression of MDR-1 gene product P-glycoprotein is an adverse prognostic factor in AIDS-related lymphoma. Treatment with liposomal encapsulated doxorubicin seems to overcome the P-glycoprotein-related drug resistance. This and other strategies to modulate MDR-1 should be further explored in order to improve success rates in the treatment of AIDS-related lymphoma.

Durable remissions with autologous stem cell transplantation for high-risk HIV-associated lymphomas

AbstractThe treatment of HIV-associated lymphoma has changed since the widespread use of highly active antiretroviral therapy. HIV-infected individuals can tolerate more intensive chemotherapy, as they have better hematologic reserves and fewer infections. This has led to higher response rates in patients with HIV-associated Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) treated with chemotherapy in conjunction with antiretroviral therapy. However, for patients with refractory or relapsed disease, salvage chemotherapy still offers little chance of long-term survival. In the non-HIV setting, patients with relapsed Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) have a better chance of long-term remission with high-dose chemotherapy with autologous stem cell rescue (ASCT) compared with conventional salvage chemotherapy. In a prior report we demonstrated that this approach is well tolerated in patients with underlying immunodeficiency from HIV infection. Furthermore, similar engraftment to the non-HIV setting and low infectious risks have been observed. Herein, we expand upon this early experience with the largest single institution series of 20 patients. With long-term follow-up we demonstrate that ASCT can lead to an 85% progression-free survival, which suggests that this approach may be potentially curative in select patients with relapsed HIV-associated HD or NHL.

Stem cell transplantation and gene therapy for HIV-related lymphomas.

The treatment of patients with HIV-related non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) is less successful than in the non-HIV setting, in part due to the aggressive character of these lymphomas but also due to the underlying HIV infection. High-dose therapy with stem cell transplantation has been used with success in the HIV-negative lymphoma setting for high-risk or relapsed disease. However, for patients with HIV-NHL and HIV-HD, ultimately the chance for long-term lymphoma-free survival also depends on successful control of the HIV infection. Gene therapy approaches may provide the opportunity for this long-term control. Herein, we describe the use of high-dose chemotherapy with stem cell rescue in conjunction with current and future gene therapy approaches for the treatment of HIV-associated lymphomas.

HIV-associated lymphoepithelial cysts and lesions: morphological and immunohistochemical study of the lymphoid cells.

To determine the morphology, immunophenotype and bcl-2 protein status of intraepithelial lymphocytes in HIV-positive lymphoepithelial lesions. Seventeen cases (from adults and children) of HIV-associated parotid and lung lymphoid lesions were examined. In addition, three lymphoepithelial cysts from HIV-negative patients were studied in parallel. Immunohistochemistry was performed on paraffin embedded tissue with the following antibodies: CD20, CD79a, CD3, CD4, CD8, bcl-2, CAM5.2, AE1/3, MIB1, kappa/lambda light chains and EBV-LMP-1. Heavy chain rearrangement was sought by polymerase chain reaction (PCR) in four of the cases. The lymphocytes participating in lymphoepithelial lesions of HIV-positive patients had the morphology of centrocyte-like cells with occasional cells resembling centroblasts. The majority of these cells were of B-cell lineage, but occasional intraepithelial T-cells (CD8 positive, CD4 negative) were also present. T-cells also formed a significant component of the infiltrative lymphoid cells outside the lymphoepithelial lesions. These were mainly CD8 positive, but very occasional CD4-positive T-cells were also noted. None of the cases showed light chain restriction and the four cases did not demonstrate heavy chain rearrangement by molecular biology. The interesting finding was the absence of bcl-2 expression by the intraepithelial lymphocytes. In contrast, the intraepithelial lymphocytes seen in the non-HIV setting were strongly bcl-2 positive. The majority of these were B-cells, and very occasional CD8 and CD4 positive T-cells formed the intraepithelial population. It is postulated that this finding is due to the HIV causing down-regulation of bcl-2 protein.