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.

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.

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.

Encephalitis is mediated by ROP18 of Toxoplasma gondii, a severe pathogen in AIDS patients.

The neurotropic parasite Toxoplasma gondii is a globally distributed parasitic protozoan among mammalian hosts, including humans. During the course of infection, the CNS is the most commonly damaged organ among invaded tissues. The polymorphic rhoptry protein 18 (ROP18) is a key serine (Ser)/threonine (Thr) kinase that phosphorylates host proteins to modulate acute virulence. However, the basis of neurotropism and the specific substrates through which ROP18 exerts neuropathogenesis remain unknown. Using mass spectrometry, we performed proteomic analysis of proteins that selectively bind to active ROP18 and identified RTN1-C, an endoplasmic reticulum (ER) protein that is preferentially expressed in the CNS. We demonstrated that ROP18 is associated with the N-terminal portion of RTN1-C and specifically phosphorylates RTN1-C at Ser7/134 and Thr4/8/118. ROP18 phosphorylation of RTN1-C triggers ER stress-mediated apoptosis in neural cells. Remarkably, ROP18 phosphorylation of RTN1-C enhances glucose-regulated protein 78 (GRP78) acetylation by attenuating the activity of histone deacetylase (HDAC), and this event is associated with an increase of neural apoptosis. These results clearly demonstrate that both RTN1-C and HDACs are involved in T. gondii ROP18-mediated pathogenesis of encephalitis during Toxoplasma infection.

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.

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.

Methods of competing risks flexible parametric modeling for estimation of the risk of the first disease among HIV infected men.

BACKGROUND: Patients infected with the Human Immunodeficiency Virus (HIV) are susceptible to many diseases. In these patients, the occurrence of one disease alters the chance of contracting another. Under such circumstances, methods for competing risks are required. Recently, competing risks analyses in the scope of flexible parametric models have risen to address this requirement. These lesser-known analyses have considerable advantages over conventional methods. METHODS: Using data from Multi Centre AIDS Cohort Study (MACS), this paper reviews and applies methods of competing risks flexible parametric models to analyze the risk of the first disease (AIDS or non-AIDS) among HIV-infected patients. We compared two alternative subdistribution hazard flexible parametric models (SDHFPM1 and SDHFPM2) with the Fine & Gray model. To make a complete inference, we performed cause-specific hazard flexible parametric models for each event separately as well. RESULTS: Both SDHFPM1 and SDHFPM2 provided consistent results regarding the magnitude of coefficients and risk estimations compared with estimations obtained from the Fine & Gray model, However, competing risks flexible parametric models provided more efficient and smoother estimations for the baseline risks of the first disease. We found that age at HIV diagnosis indirectly affected the risk of AIDS as the first event by increasing the number of patients who experience a non-AIDS disease prior to AIDS among > 40 years. Other significant covariates had direct effects on the risks of AIDS and non-AIDS. DISCUSSION: The choice of an appropriate model depends on the research goals and computational challenges. The SDHFPM1 models each event separately and requires calculating censoring weights which is time-consuming. In contrast, SDHFPM2 models all events simultaneously and is more appropriate for large datasets, however, when the focus is on one particular event SDHFPM1 is more preferable.

The factors associated with natural disease progression from HIV to AIDS in the absence of ART, a propensity score matching analysis.

This study aimed at comparing the factors associated with the natural progression between typical progressors (TPs) and rapid progressors (RPs) in HIV-infected individuals. A retrospective study was conducted on 2095 eligible HIV-infected individuals from 1995 to 2016 in a high-risk area of Henan Province, China. Propensity score matching was used to balance covariates, and the conditional logistic regression analyses were performed to explore the factors of natural disease progression among HIV infectors. A total of 379 pairs of RPs and TPs were matched. The standardised difference values of all covariates were less than 10%. HIV-infected individuals transmitted through sexual transmission (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.36-0.85) were more likely to progress to AIDS compared with those infected through contaminated blood. Older age at diagnosis of HIV-infected individuals (OR 0.72, 95% CI 0.58-0.89) exhibited a faster progression to AIDS. HIV-infected individuals identified through a unique survey (OR 7.01, 95% CI 2.99-16.44) were less likely to progress to AIDS compared with those identified through medical institutions. HIV-infected individuals who had higher baseline CD4+T cell counts (OR 3.37, 95% CI 2.59-4.38) had a slower progression to AIDS. These findings provide evidence for natural disease progression from HIV to AIDS between TPs and RPs.

Burden of fatigue among adults living with HIV/AIDS attending antiretroviral therapy in Ethiopia.

BACKGROUND: Fatigue is one of the most common and devastating Human Immuno-deficiency Virus (HIV) - related symptoms, with a varying prevalence in different study areas. In Ethiopia, there is a paucity of information on the magnitude and factors associated with fatigue among HIV/Acquired Immune Deficiency Syndrome (AIDS) patients. This may lead to under-diagnosis and eventually under-management of the symptom. METHODS: Institution based cross-sectional study design was conducted among 609 HIV/AIDS patients who were selected by using a systematic random sampling method. Data were collected by using interviewer administered structured questionnaire. Level of fatigue was measured by Fatigue Severity Scale. RESULTS: The prevalence of fatigue was found to be 51.7%. The factors associated with fatigue were: Parity [AOR = 2.01; 95% CI: 1.09-3.71], CD4 count 200-499 cells/mm3 [AOR = 2.81; 95% CI: 1.58-4.99], anemia [AOR = 4.90 95% CI: 2.40-9.97], co-morbidities [AOR = 3.65; 95% CI: 1.71-7.78], depression [AOR = 3.68 95% CI: 1.99-6.79], not being physically active [AOR = 3.20 95% CI: 1.50-6.81], clinical stage II or IV HIV [AOR = 3.11; 95% CI: 1.51-6.40] and [AOR = 4.08; 95% CI: 1.37-12.14], respectively. CONCLUSION: The finding of this study revealed that fatigue is a common health problem among adult People Living with HIV (PLHIV). Factors associated with fatigue included: Parity, CD4 count 200-499 cells/mm3, Clinical Stage II or IV HIV, anemia, co-morbidities, depression, and not being physically active. The health care service needs to address the predisposing factors by provision integrated care including timely detection and treatment of comorbidities, mental health problems, and promote physical activity to slow down disease progression and then reduce exposure to fatigue.

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.

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.

Circulating miRNA-375 as a potential novel biomarker for active Kaposi's sarcoma in AIDS patients.

The aim of this study was to identify circulating microRNAs (miRNAs) that could be used as biomarkers in patients at risk for or affected by AIDS-Kaposi's sarcoma (KS). Screening of 377 miRNAs was performed using low-density arrays in pooled plasma samples of 10 HIV/human herpesvirus 8 (HHV8)-infected asymptomatic and 10 AIDS-KS patients before and after successful combined antiretroviral therapy (cART). MiR-375 was identified as a potential marker of active KS, being the most down-regulated in AIDS-KS patients after cART and the most up-regulated in naïve AIDS-KS patients compared to naïve asymptomatic subjects. Validation on individual plasma samples confirmed that miR-375 levels were higher in AIDS-KS compared to asymptomatic patients, decreased after cART-induced remission in most AIDS-KS patients and increased in patients with active KS. In asymptomatic patients miR-375 was up-regulated after cART in both screening and validation. Statistical analyses revealed an association between miR-375 changes and CD4 cell counts, which could explain the discordant cases and the opposite trend between asymptomatic and AIDS-KS patients. These data suggest that circulating miR-375 might be a good indicator of active AIDS-KS. Moreover, changes in miR-375 levels may have a prognostic value in HIV/HHV8-infected patients undergoing treatment. Further large-scale validation is needed.

Hemophagocytic syndrome in patients living with HIV: a retrospective study.

Various infectious diseases can hyper-stimulate the immune system, causing hemophagocytic syndrome (HPS). Little is known regarding the accuracy of diagnostic criteria and epidemiological triggering factors in the acquired immunodeficiency syndrome (AIDS) setting. We investigated the major infectious disease triggers of HPS in patients living with human immunodeficiency virus (HIV)/AIDS and determined the accuracy of bone marrow aspiration (BMA). The inclusion criteria were (i) confirmed HIV diagnosis, (ii) bone marrow aspiration, and (iii) a minimum of four HPS criteria. Patients were further classified into those with four presumed HPS criteria, or ≥ 5 confirmed criteria. The disease triggers, accuracy of bone marrow aspiration, and prognosis markers were examined. Presumed HPS was observed in 15/36 patients (41%), and confirmed HPS in 58% (n = 21). The major etiological triggers were infection with Mycobacterium (34%), Cytomegalovirus (14%), Cryptococcus neoformans (11%), and hematological or tumoral disease (11%). BMA demonstrated 93% specificity on screening diagnosis (odds ratio [OR] 12.7, 95% confidence interval [CI] 1.4-115.1, P = 0.01). Ferritin > 5000 ng/mL correlated with probability of death in univariate analysis (OR 6.00, 95% CI 1.33-27.05, P = 0.02). Ferritin performance as test of death probability presented area under the curve as 0.74 (95% CI 0.56-0.91, P = 0.016). However, neither cluster of differentiation for lymphocyte count nor HIV viral load correlated with patient deaths. Mycobacterium spp. and Cytomegalovirus were the main factors triggering HPS, followed by Cryptococcus neoformans, and hematological and tumoral diseases. High ferritin levels were associated with increased death probability. High specificity was noted with BMA.

Successful implementation of intestinal endoscopy in non-human primates prompts the possibility of achieving AIDS longitudinal intestinal research.

HIV infection induces pathological changes in the intestinal mucosa. Here, a successful endoscopy was performed on the colon of a Chinese rhesus macaque by using Olympus CV170 gastroscope. The stability on postoperative recovery and the integrity of biopsy tissue implied a possibility of achieving AIDS longitudinal intestinal research on macaques.

A rare case of an HIV-seronegative AIDS patient with Pneumocystis jirovecii pneumonia.

BACKGROUND: As technology progresses, several highly sensitive human immunodeficiency virus (HIV) screening kits are being researched and developed to quickly and efficiently identify serum HIV antibodies within the non-window period. In individuals who are HIV-seronegative, HIV infections that are not within a window period are rare. In such cases, all antibody detection methods will fail, and misdiagnosing these patients will have catastrophic consequences. CASE PRESENTATION: A 22-year-old male Chinese patient with diffuse exudative lesions in both lungs and initial symptoms of cough and dyspnoea was diagnosed with Pneumocystis jirovecii pneumonia (PJP) by aetiological examination, and the patient's plasma CD4+ T-cell count was extremely low. In China, PJP is prevalent in HIV-infected individuals. Pneumocystis jirovecii (P. jirovecii) has a high colonisation rate in patients with HIV infections. This patient was naturally suspected of being an HIV patient; however, serum HIV antibody tests were negative using both an enzyme-linked immunosorbent assay (ELISA) and a latex agglutination assay, and HIV was not detected by western blotting. Subsequently, the plasma HIV viral load was found to be extremely high on two repeated plasma HIV RNA tests, thus confirming HIV-seronegative acquired immunodeficiency syndrome (AIDS) in this patient. With administration of effective anti-P. jirovecii treatment and highly active antiretroviral therapy (HAART) after diagnosis, the patient's disease condition was rapidly controlled. CONCLUSION: This is the second reported case in China of an HIV-seronegative AIDS patient. Such cases are also rare worldwide. Although HIV-seronegative HIV infections are rare, AIDS should be considered in immunodeficient patients with opportunistic infections, even if the test results are HIV-seronegative. Plasma HIV RNA testing is important for such patients.

Emotional and behavioral problems and associated factors among children and adolescents on highly active anti-retroviral therapy in public hospitals of West Gojjam zone, Amhara regional state of Ethiopia, 2018: a cross-sectional study.

BACKGROUND: Children and adolescents with HIV/AIDS are more likely to have emotional and behavioral problems than the general population. This can result in a continuing negative influence on the quality of life, school performance, immunity and co-morbidity of children and adolescents with HIV/AIDS. OBJECTIVE: To assess the prevalence and associated factors of Emotional and Behavioral Problems among children and adolescents on Highly Active Anti-Retroviral Therapy in the public hospitals of West Gojjam Zone, Amhara regional state of Ethiopia. METHODS: An institutional based cross sectional study was conducted by screening 411 children and adolescents for emotional and behavioral problems using Pediatric Symptomatology Check List (PSCL). Systematic random sampling technique was used to select the study participants. Data analysis was done using SPSS version 23. Bivariable and multivariable logistic regression analysis were fitted to identify factors associated with Emotional and Behavioral Problems. Odds ratio (OR) with 95% confidence interval (CI) was computed to determine the level of significance. RESULT: Out of the total 411 participants, 43.6% were screened positive for Emotional and Behavioral Problems. Lower age (AOR = 5.33, 95%CI: 2.56-11.04), having non-kin care giver (AOR = 4.64, 95%CI: 1.20-17.90), parental loss (AOR = 2.15, 95%CI: 1.03-4.49), non self -disclosure of HIV sero status (AOR = 1.99, 95% CI: 1.16-3.41) and having distressed care giver (AOR = 1.64, 95%CI: 1.04-2.57) had statistically significant association with EBPs. CONCLUSION: The prevalence of Emotional and Behavioral Problems is high among children and adolescents on HAART. Lower age, care giver's mental distress, non-self disclosure status, having non-kin care giver and parental loss were variables significantly associated with EBPs. This demonstrates a need for the integration of Mental Health and Psycho Social Support (MHPSS) service with HIV/AIDS care.

Cancer survival in people with AIDS: A population-based study from São Paulo, Brazil.

Cancer survival among people with AIDS (PWA) has been described in developed countries, but there is lack of data from developing countries. The aim of this study was to evaluate survival after cancer diagnosis in PWA and compare it with people without AIDS (non-PWA) in São Paulo, Brazil. A probabilistic record linkage was carried out between the databases of the Population-based Cancer Registry of São Paulo (PBCR-SP) and the AIDS registry of SP (SINAN) to identify PWA who developed cancer. For comparison, non-PWA were frequency matched from the PBCR-SP by cancer site/type, sex, age, and period. Hazard ratio (HR) stratified by matching variables was estimated using a Cox proportional hazards model. A total of 1,294 PWA (20 patients with two primary site tumors) were included in the site/type-specific analyses. AIDS-defining cancers (ADC) comprised 51.9% of cases assessed. The all-cancer 5-year overall survival in PWA was 49.4% versus 72.7% in non-PWA (HR = 2.64; 95%CI = 2.39-2.91). Survival was impaired in PWA for both ADC (HR = 2.93; 95%CI = 2.49-3.45) and non-ADC (HR = 2.51; 95%CI = 2.21-2.84), including bladder (HR = 8.11; 95% CI = 2.09-31.52), lung (HR = 2.93; 95%CI = 1.97-4.36) and anal cancer (HR = 2.53; 95%CI = 1.63-3.94). These disparities were seen mainly in the first year after cancer diagnosis. The overall survival was significantly lower in PWA in comparison with non-PWA in São Paulo, as seen in high-income countries. Efforts to enhance early diagnosis and ensure proper cancer treatment in PWA should be emphasized.

Marked Enteropathy in an Accelerated Macaque Model of AIDS.

Enteropathy in HIV infection is not eliminated with combination antiretroviral therapy and is possibly linked to microbial translocation. We used a rapidly progressing SIV/pigtailed macaque model of HIV to examine enteropathy and microbial translocation. Histologic evidence of intestinal disease was observed in only half of infected macaques during late-stage infection (LSI). Combination antiretroviral therapy initiated during acute infection prevented intestinal disease. In the ileum and colon, enteropathy was associated with increased caspase-3 staining, decreased CD3+ T cells, and increased SIV-infected cells. CD3+ T cells were preserved in LSI animals without intestinal disease, and levels of CD3 staining in all LSI animals strongly correlated with the number of infected cells in the intestine and plasma viral load. Unexpectedly, there was little evidence of microbial translocation as measured by soluble CD14, soluble CD163, lipopolysaccharide binding protein, and microbial 16s ribosomal DNA. Loss of epithelial integrity indicated by loss of the tight junction protein claudin-3 was not observed during acute infection despite significantly fewer T cells. Claudin-3 was reduced in LSI animals with severe intestinal disease but did not correlate with increased microbial translocation. LSI animals that did not develop intestinal disease had increased T-cell intracytoplasmic antigen 1-positive cytotoxic T lymphocytes, suggesting a robust adaptive cytotoxic T-lymphocyte response may, in part, confer resilience to SIV-induced intestinal damage.

Multisystem multitasking by CXCL12 and its receptors CXCR4 and ACKR3.

Chemokines are named and best known for their chemotactic cytokine activity in the hematopoietic system; however, their importance extends far beyond leukocytes, cell movement and immunoregulation. CXCL12, the most protean of chemokines, regulates development in multiple systems, including the hematopoietic, cardiovascular and nervous systems, and regulates diverse cell functions, including differentiation, distribution, activation, immune synapse formation, effector function, proliferation and survival in the immune system alone. The broad importance of CXCL12 is revealed by the complex lethal developmental phenotypes in mice lacking either Cxcl12 or either one of its two known 7-transmembrane domain receptors Cxcr4 and Ackr3, as well as by gain-of-function mutations in human CXCR4, which cause WHIM syndrome, a multisystem and combined immunodeficiency disease and the only Mendelian condition caused by a chemokine system mutation. In addition, wild type CXCR4 is important in the pathogenesis of HIV/AIDS and cancer. Thus, CXCL12 and its receptors CXCR4 and ACKR3 provide extraordinary examples of multisystem multitasking in the chemokine system in both health and disease.