Uncommon histopathological features of cytomegalovirus encephalitis and measles inclusion body encephalitis on autopsy in two patients with primary immunodeficiency.

PURPOSE: To describe the neuropathological findings in two patients with primary immunodeficiency who had fatal viral encephalitis. MATERIALS AND METHODS: Severe combined immunodeficiency (SCID) was confirmed in case 1 by genetic testing, while case 2 had features suggestive of combined immunodeficiency; however, whole exome sequencing showed no pathogenic variants. Autopsies were performed in both cases after an informed consent. A detailed sampling of the brain including extracranial organs was conducted. Immunohistochemistry and electron microscopy was also performed to confirm the presence of viruses. RESULTS: Besides evidence of cystic encephalomalacia observed in both cases, the brain in case 1 revealed cytomegalovirus (CMV) ventriculoencephalitis accompanied by an exuberant gemistocytic response in the entire white matter. Nuclei of gemistocytes were loaded with several CMV nuclear inclusions, which was confirmed by immunohistochemistry. Case 2 demonstrated features of measles inclusion body encephalitis with several viral inclusions within neurons and astrocytes. Rare giant cells were also seen. Measles virus was confirmed on immunohistochemistry and electron microscopy. Plausibly, there was paucity of microglial nodules in both cases. Superadded bacterial pneumonia with diffuse alveolar damage was also seen in both cases. CONCLUSION: These cases add to the spectrum of unusual histological features of viral encephalitis seen in patients with underlying primary immunodeficiency diseases.

Molluscum contagiosum of the corneal limbus in an AIDS patient: a clinicopathological case report.

BACKGROUND: Molluscum contagiosum, a pox virus infection, is likely to occur in the eyelid skin; however, corneal involvements by molluscum lesions are extremely rare. We report a case of molluscum contagiosum arising in the corneal limbus in an untreated AIDS patient, together with anterior segment optical coherence tomography (OCT) findings and histopathology of the excised tumor. CASE PRESENTATION: A 46-year-old man with AIDS was referred to our department for the management of an ocular lesion. Blood tests revealed an extremely low CD4+ T-cell count of 11 cells/µL, being strongly positive for anti-HIV antibody (591.36 S/CO) with a high copy number of HIV RNA (8070.0 × 100 copy/mL). Slit-lamp examination of his right eye showed a white nodule at the lower limbus. Anterior segment OCT findings of the nodule revealed a highly reflective elevated lesion, which was considered to involve the Bowman layer. The nodular lesion was excised from the limbus including the superficial corneal stroma, and then processed for histologic examination. Histopathology of the excised lesion showed acanthotic corneal epithelium containing swollen cells with eosinophilic inclusions known as molluscum bodies. He was diagnosed with molluscum contagiosum. CONCLUSIONS: Anterior segment OCT findings provide useful information for morphological evaluations of and preoperative strategies against molluscum contagiosum.

Pharmaceutical care and evaluation of adherence to antiretroviral therapy in people living with HIV/AIDS

Abstract Highly Active Antiretroviral therapy (HAART) depends on optimal adherence to be effective. Pharmacotherapeutic follow-up can be used as a strategy for treatment fidelity. To provide pharmaceutical care for HAART patients, to assess adherence, to identify and resolve drug related problems (DRP). This is a prospective, interventional study aimed at people on HAART. Data was collected using the pharmacotherapeutic follow-up form and CEAT-VIH. There was a predominance of women (59%), older than 33 years (75%), mostly single (43%). Regarding adherence, 64% had insufficient adherence at the start of the study, while 36% had strict/adequate adherence. After the pharmacotherapeutic follow-up, 70% presented strict/adequate adherence. Regarding HAART, the relationship between adhesion versus time of HAART and adherence versus regimen used was significant, considering that less time of therapy and regimen containing protease inhibitors are predictors for insufficient adherence. Regarding the DRP identified (f=77), missed pills (32%), untreated disease, incorrect management frequency, and undue self-medication (12%) were the most frequent. Pharmaceutical interventions (f=137) were predominantly advising related to specific pharmacological treatment (32%), non-pharmacological measures (20%), and medication suspension (9%). Pharmaceutical care was shown to be animportant strategy, within the multi professional team, to improve adherence, besides identifying and resolving DRP.

The prevalence of thrombocytopenia and leucopenia among people living with HIV/AIDS in Ethiopia: A systematic review and meta-analysis.

INTRODUCTION: Thrombocytopenia and leucopenia are frequently encountered hematological disorders among people living with HIV/AIDS. This systematic review and meta-analysis were aimed to indicate the national prevalence of thrombocytopenia and leucopenia among HIV/AIDS patients. METHODS: This systematic review and meta-analysis was conducted following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. A systematic search was conducted from February 01, 2021 to April 02, 2021 using electronic databases Google Scholar, PubMed, Web of Sciences, Google, EMBASE, SCOPUS and ResearchGate. The quality of the included studies was assessed using Newcastle-Ottawa Quality Assessment Scale (NOS) adapted for cross-sectional studies. Data analysis was done using STATA version 14 using metan commands. Random effect meta-analysis was used to estimate the pooled prevalence of thrombocytopenia and leucopenia among people living with HIV/AIDS in Ethiopia. RESULT: Of the 349 initially searched articles, 90 were assessed for eligibility and only 13 articles published from 2014 to 2020 were included in the final meta-analysis. A total of 3854 participants were involved in the included studies. The pooled prevalence of thrombocytopenia was 9.69% (95%CI; 7.40-11.97%). Significant heterogeneity was observed with I2 value of 84.7%. Thrombocytopenia was 11.91% and 5.95% prevalent among HAART naive and HAART exposed HIV/AIDS patients, respectively. The pooled prevalence of leucopenia among HIV/AIDS patients was 17.31% (95%CI: 12.37-22.25%). CONCLUSION: This study showed a high prevalence of thrombocytopenia and leucopenia among people living with HIV/AIDS, indicating the necessity of regular screening of HIV seropositive patients for different hematological parameters and providing treatment.

Human umbilical cord mesenchymal stem cell transfusion in immune non-responders with AIDS: a multicenter randomized controlled trial.

We examined the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) infusion for immune non-responder (INR) patients with chronic HIV-1 infection, who represent an unmet medical need even in the era of efficient antiretroviral therapy (ART). Seventy-two INR patients with HIV were enrolled in this phase II randomized, double-blinded, multicenter, placebo-controlled, dose-determination trial (NCT01213186) from May 2013 to March 2016. They were assigned to receive high-dose (1.5 × 106/kg body weight) or low-dose (0.5 × 106/kg body weight) hUC-MSC, or placebo. Their clinical and immunological parameters were monitored during the 96-week follow-up study. We found that hUC-MSC treatment was safe and well-tolerated. Compared with baseline, there was a statistical increase in CD4+ T counts in the high-dose (P < 0.001) and low-dose (P < 0.001) groups after 48-week treatment, but no change was observed in the control group. Kaplan-Meier analysis revealed a higher cumulative probability of achieving an immunological response in the low-dose group compared with the control group (95.8% vs. 70.8%, P = 0.004). However, no significant changes in CD4/CD8+ T counts and CD4/CD8 ratios were observed among the three groups. In summary, hUC-MSC treatment is safe. However, the therapeutic efficacy of hUC-MSC treatment to improve the immune reconstitution in INR patients still needs to be further investigated in a large cohort study.

HLA-mismatched allogeneic adoptive immune therapy in severely immunosuppressed AIDS patients.

Severely immunosuppressed AIDS patients with recurrent opportunistic infections (OIs) represent an unmet medical need even in the era of antiretroviral therapy (ART). Here we report the development of a human leukocyte antigen (HLA)-mismatched allogeneic adaptive immune therapy (AAIT) for severely immunosuppressed AIDS patients. Twelve severely immunosuppressed AIDS patients with severe OIs were enrolled in this single-arm study. Qualified donors received subcutaneous recombinant granulocyte-colony-stimulating factor twice daily for 4-5 days to stimulate hematopoiesis. Peripheral blood mononuclear cells were collected from these donors via leukapheresis and transfused into the coupled patients. Clinical, immunological, and virological parameters were monitored during a 12-month follow-up period. We found AAIT combined with ART was safe and well-tolerated at the examined doses and transfusion regimen in all 12 patients. Improvements in clinical symptoms were evident throughout the study period. All patients exhibited a steady increase of peripheral CD4+ T cells from a median 10.5 to 207.5 cells/µl. Rapid increase in peripheral CD8+ T-cell count from a median 416.5 to 1206.5 cells/µl was found in the first 90 days since initiation of AAIT. In addition, their inflammatory cytokine levels and HIV RNA viral load decreased. A short-term microchimerism with donor cells was found. There were no adverse events associated with graft-versus-host disease throughout the study period. Overall, AAIT treatment was safe, and might help severely immunosuppressed AIDS patients to achieve a better immune restoration. A further clinical trial with control is necessary to confirm the efficacy of AAIT medication.

Let It Go: HIV-1 cis-Acting Repressive Sequences.

After human immunodeficiency virus type 1 (HIV-1) was identified in the early 1980s, intensive work began to understand the molecular basis of HIV-1 gene expression. Subgenomic HIV-1 RNA regions, spread throughout the viral genome, were described to have a negative impact on the nuclear export of some viral transcripts. Those studies revealed an intrinsic RNA code as a new form of nuclear export regulation. Since such regulatory regions were later also identified in other viruses, as well as in cellular genes, it can be assumed that, during evolution, viruses took advantage of them to achieve more sophisticated replication mechanisms. Here, we review HIV-1 cis-acting repressive sequences that have been identified, and we discuss their possible underlying mechanisms and importance. Additionally, we show how current bioinformatic tools might allow more predictive approaches to identify and investigate them.

Case Report: Interferon-γ Restores Monocytic Human Leukocyte Antigen Receptor (mHLA-DR) in Severe COVID-19 With Acquired Immunosuppression Syndrome.

Background: The major histocompatibility complex (MHC) class II characterized by monocytes CD14+ expression of human leukocyte antigen receptors (HLA-DR), is essential for the synapse between innate and adaptive immune response in infectious disease. Its reduced expression is associated with a high risk of secondary infections in septic patients and can be safely corrected by Interferon-y (IFNy) injection. Coronavirus disease (COVID-19) induces an alteration of Interferon (IFN) genes expression potentially responsible for the observed low HLA-DR expression in circulating monocytes (mHLA-DR). Methods: We report a case of one-time INFy injection (100 mcg s.c.) in a superinfected 61-year-old man with COVID-19-associated acute respiratory distress syndrome (ARDS), with monitoring of mHLA-DR expression and clinical tolerance. Observations: Low mHLA-DR pretreatment expression (26.7%) was observed. IFNy therapy leading to a rapid increase in mHLA-DR expression (83.1%). Conclusions: Severe ARDS in a COVID-19 patient has a deep reduction in mHLA-DR expression concomitantly with secondary infections. The unique IFNy injection was safe and led to a sharp increase in the expression of mHLA-DR. Based on immune and infection monitoring, more cases of severe COVID-19 patients with low mHLA-DR should be treated by IFNy to test the clinical effectiveness.

Natural Bioactives as Potential Therapeutic Modalities Against NeuroAIDS.

With the introduction of antiretroviral therapy, the worldwide AIDS-related deaths have decreased, and life expectancy has increased, including the prevalence of AIDS-related neurological disorders or neuroAIDS. HIV-associated neurocognitive disorders such as mild neurocognitive disorder and asymptomatic neurocognitive impairment have largely remained stable or increased among the HIV-infected individuals in the combination antiretroviral therapy era. The emerging evidence that antiretrovirals with high CNS penetration effectiveness score contribute to the neurotoxicity and HIV-associated neurocognitive disorders has ushered the search for natural, nontoxic bioactive constituents having pre-established neuroprotective, anti-inflammatory, and restorative neurocognitive activity. In this review, we have highlighted the probable mechanism of neuroAIDS infection, the problem with the existing antiretroviral therapy, along with various bioactive constituents with in vivo, in vitro, or ex vivo evidence of their neuroprotective activity that can be used as an adjuvant with the current combination antiretroviral therapy regimen or can even serve as an alternate to the antiretrovirals for treatment of HIV associated neurocognitive disorder.

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging.

According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.

Infections and Immunotherapy in Lung Cancer: A Bad Relationship?

Infectious diseases represent a relevant issue in lung cancer patients. Bacterial and viral infections might influence the patients' prognosis, both directly affecting the immune system and indirectly impairing the outcome of anticancer treatments, mainly immunotherapy. In this analysis, we aimed to review the current evidence in order to clarify the complex correlation between infections and lung cancer. In detail, we mainly explored the potential impact on immunotherapy outcome/safety of (1) bacterial infections, with a detailed focus on antibiotics; and (2) viral infections, discriminating among (a) human immune-deficiency virus (HIV), (b) hepatitis B/C virus (HBV-HCV), and (c) Sars-Cov-2. A series of studies suggested the prognostic impact of antibiotic therapy administration, timing, and exposure ratio in patients treated with immune checkpoint inhibitors, probably through an antibiotic-related microbiota dysbiosis. Although cancer patients with HIV, HBV, and HCV were usually excluded from clinical trials evaluating immunotherapy, some retrospective and prospective trials performed in these patient subgroups reported similar results compared to those described in not-infected patients, with a favorable safety profile. Moreover, patients with thoracic cancers are particularly at risk of COVID-19 severe outcomes and mortality. Few reports speculated about the prognostic implications of anticancer therapy, including immunotherapy, in lung cancer patients with concomitant Sars-Cov-2 infection, showing, to date, inconsistent results. The correlation between infectious diseases and immunotherapy remains to be further explored and clarified in the context of dedicated trials. In clinical practice, the accurate and prompt multidisciplinary management of lung cancer patients with infections should be encouraged in order to select the best treatment options for these patients, avoiding unexpected toxicities, while maintaining the anticancer effect.

DNA methylation changes in metabolic and immune-regulatory pathways in blood and lymph node CD4 + T cells in response to SIV infections.

The molecular mechanisms underlying HIV-induced inflammation, which persists even during effective long-term treatment, remain incompletely defined. Here, we studied pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections in macaques and African green monkeys, respectively. We longitudinally analyzed genome-wide DNA methylation changes in CD4 + T cells from lymph node and blood, using arrays. DNA methylation changes after SIV infection were more pronounced in lymph nodes than blood and already detected in primary infection. Differentially methylated genes in pathogenic SIV infection were enriched for Th1-signaling (e.g., RUNX3, STAT4, NFKB1) and metabolic pathways (e.g., PRKCZ). In contrast, nonpathogenic SIVagm infection induced DNA methylation in genes coding for regulatory proteins such as LAG-3, arginase-2, interleukin-21 and interleukin-31. Between 15 and 18% of genes with DNA methylation changes were differentially expressed in CD4 + T cells in vivo. Selected identified sites were validated using bisulfite pyrosequencing in an independent cohort of uninfected, viremic and SIV controller macaques. Altered DNA methylation was confirmed in blood and lymph node CD4 + T cells in viremic macaques but was notably absent from SIV controller macaques. Our study identified key genes differentially methylated already in primary infection and in tissues that could contribute to the persisting metabolic disorders and inflammation in HIV-infected individuals despite effective treatment.

A real-world, cross sectional study of oral lesions and their association with CD4 cell counts and HIV viral load in Yunnan, China.

Human immunodeficiency virus (HIV) supresses immune system, primarily cell-mediated immunity. Cluster of differentiation 4 (CD4) cell count, viral load, and oral lesions are the most important laboratory parameters to evaluate the evolution of acquired immunodeficiency syndrome. The present study aims to determine the incidence of HIV-related oral lesions with CD4 cell count and viral load in Yunnan, China.A cross-sectional study was conducted from December 2007 to December 2009, in 1812 HIV positive patients from Department of Infectious Diseases in Kunming Third People's Hospital. CD4, CD8, and viral load data were collected and analyzed statistically using SPSS 11.3.Out of 1812 HIV positive patients, 929 (51.27%) were associated with 1 or more oral lesions. The most common oral lesions observed were Candida Pseudomembranous (13.75%), Candida erythematous (10.93%), Oral hairy leukoplakia (7.95%), Aphthous ulcer (6.18%), Herpes simplex infection (5.58%). In most patients with oral lesions, the CD4 cell count was < 200/µL. The incidence of oral lesions was lower when CD4 count was > 200/µL and with undetectable (P < .01) HIV viral load. Almost no oral lesions was observed when CD4 count > 500/µL (P < .01). With highly active antiretroviral therapy, reduction in HIV-related oral lesions was observed especially in Candida erythematous, Candida Pseudomembranous, Oral hairy leukoplakia, and Aphthous ulcer.The higher incidence of oral lesions with lower CD4 count (<200/µL) in HIV-infected patients indicated importance of CD4 cell count in identifying disease progression.

Cognitive changes in patient living with HIV-AIDS and apolipoprotein-E polymorphism: is there an association?

Patients with HIV-AIDS treated with antiretroviral drugs still have high prevalence of cognitive disorders and many factors are likely to contribute for ongoing neurologic decline such as chronic low-level infection, coinfections with hepatitis B and C and genetic influences, both the virus and the host. Some evidences suggest that the genetic APOE polymorphism may be an associated risk factor. This study aimed to evaluate the association between APOE polymorphisms and cognitive disorders in patients with HIV-AIDS. This was a cross-sectional study comprising 133 patients aged 19-59 years old, with HIV-AIDS and were assisted at the infectious disease outpatient clinics at Hospital Universitário Oswaldo Cruz, in Recife, Brazil. For cognitive evaluation, Mini-Mental State Examination test (MMSE) and Montreal Cognitive Assessment test (MoCA) were used. The determination of APOE gene polymorphism was performed by using the PCR-RFLP technique. Sociodemographic and clinical characteristics were not significantly associated to APOE ε4 polymorphism, except for the high results of CD4 rate (p < 0.015). There was an absence associated between APOE ε4 polymorphism and neurocognitive tests. This study found no association between cognitive alterations and APOE polymorphism in patients with HIV-AIDS in the Northeast of Brazil. The imbalance of APOE allelic frequency distribution, according to Hardy-Weinberg law, there could be an adjustment phase of its equilibrium suffered by the HIV virus, however, the mechanism is still unknown.

Coronavirus disease 2019 (COVID-19) outcomes in HIV/AIDS patients: a systematic review.

OBJECTIVES: The aim of the study was to systematically review current studies reporting on clinical outcomes in people living with HIV (PLHIV) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A comprehensive literature search was conducted in Global Health, SCOPUS, Medline and EMBASE using pertinent key words and Medical Subject Headings (MeSH) terms relating to coronavirus disease 2019 (COVID-19) and HIV. A narrative synthesis was undertaken. Articles are summarized in relevant sections. RESULTS: Two hundred and eighty-five articles were identified after duplicates had been removed. After screening, eight studies were analysed, totalling 70 HIV-infected patients (57 without AIDS and 13 with AIDS). Three themes were identified: (1) controlled HIV infection does not appear to result in poorer COVID-19 outcomes, (2) more data are needed to determine COVID-19 outcomes in patients with AIDS and (3) HIV-infected patients presenting with COVID-19 symptoms should be investigated for superinfections. CONCLUSIONS: Our findings suggest that PLHIV with well-controlled disease are not at risk of poorer COVID-19 disease outcomes than the general population. It is not clear whether those with poorly controlled HIV disease and AIDS have poorer outcomes. Superimposed bacterial pneumonia may be a risk factor for more severe COVID-19 but further research is urgently needed to elucidate whether PLHIV are more at risk than the general population.

Phenotype variability of autoinflammatory disorders in the pediatric patient: A pictorial overview.

Disruption of innate immunity leading to systemic inflammation and multi-organ dysfunction is the basilar footprint of autoinflammatory disorders (AIDs), ranging from rare hereditary monogenic diseases to a large number of common chronic inflammatory conditions in which there is a simultaneous participation of multiple genetic components and environmental factors, sometimes combined with autoimmune phenomena and immunodeficiency. Whatever their molecular mechanism, hereditary AIDs are caused by mutations in regulatory molecules or sensors proteins leading to dysregulated production of proinflammatory cytokines or cytokine-inducing transcription factors, fever, elevation of acute phase reactants, and a portfolio of manifold inflammatory signs which might occur in a stereotyped manner, mostly with overactivity or misactivation of different inflammasomes. Symptoms might overlap in the pediatric patient, obscuring the final diagnosis of AIDs and delaying the most appropriate treatment. Actually, the fast-paced evolution of scientific knowledge has led to recognize or reclassify an overgrowing number of multifactorial diseases, which share the basic pathogenetic mechanisms with AIDs. The wide framework of classic hereditary periodic fevers, AIDs with prominent skin involvement, disorders of the ubiquitin-proteasome system, defects of actin cytoskeleton dynamics, and also idiopathic nonhereditary febrile syndromes occurring in children is herein presented. Interleukin-1 dependence of these diseases or involvement of other predominating molecules is also discussed.

Ocular pathology in NeuroAIDS - An autopsy study.

The central nervous system (CNS) and the eye are involved in Human immunodeficiency virus related disease. Although, optic nerve is considered an extension of the CNS, it has not been systematically evaluated to determine if infections of brain can extend into the eye or vice versa. The brain and posterior compartment of eyeball retrieved at autopsy of patients succumbing to NeuroAIDS, were evaluated with Hematoxylin & Eosin, special stains and immunohistochemistry for infective pathogens. Multiplex PCR was performed in vitreous, CSF and serum for simultaneous detection of bacterial, viral, and protozoal opportunistic infections. Ocular involvement in NeuroAIDS was seen in 93.7% (15/16) with opportunistic infection being the most common 62.5% (10/16); with toxoplasma optic neuropathy in 5 (50%), Cryptococcal optic neuritis in 3 (30%), and Cytomegalovirus chorioretinitis in 2 (20%). Concordance between ocular and CNS pathology was seen in 50% of cases. CSF PCR was more sensitive than PCR in vitreous for detecting ocular infections in posterior compartment of eye.