Mechanisms and Cardiorenal Complications of Chronic Anemia in People with HIV.

Chronic anemia is more prevalent in people living with HIV (PLWH) compared to the general population. The mechanisms that drive chronic anemia in HIV are multifaceted and include functional impairment of hematopoietic stem cells, dysregulation of erythropoietin production, and persistent immune activation. Chronic inflammation from HIV infection adversely affects erythropoiesis, erythrocyte lifespan, and erythropoietin response, leading to a heightened risk of co-infections such as tuberculosis, persistent severe anemia, and increased mortality. Additionally, chronic anemia exacerbates the progression of HIV-associated nephrotoxicity and contributes to cardiovascular risk through immune activation and inflammation. This review highlights the cardinal role of chronic inflammation as a link connecting persistent anemia and cardiovascular complications in PLWH, emphasizing the need for a universal understanding of these interconnected pathways for targeted interventions.

Characterizing Epstein-Barr virus infection of the central nervous system in Zambian adults living with HIV.

The significance of Epstein-Barr virus (EBV) detection in the cerebrospinal spinal fluid (CSF) in people living with HIV (PLWH) is not entirely understood. The detection of EBV DNA may represent active central nervous system (CNS) infection, reactivation in the setting of another CNS pathogen or due to impaired immunity, or detection of quiescent virus. We screened 470 adult PLWH in Zambia with neurological symptoms for the presence of EBV DNA in the CSF. We performed quantitative EBV PCR on the CSF and blood. We then performed quantitative EBV DNA PCR on the blood of controls with documented HIV viral suppression without CNS symptoms. The prevalence of EBV DNA in the CSF of patients with CNS symptoms was 28.9% (136/470). EBV DNA positivity was associated with younger age, shorter duration of HIV diagnosis, lower CSF glucose levels, higher CSF protein and white blood cell levels, and a positive CSF Mycobacterium tuberculosis result. The median EBV DNA load was 8000 cps/mL in both the CSF and blood with a range of 2000-2,753,000 cps/mL in the CSF and 1000 to 1,871,000 cps/mL in the blood. Molecular screening of CSF for other possible causes of infection identified Mycobacterium tuberculosis in 30.1% and cytomegalovirus (CMV) in 10.5% of samples. EBV DNA load in the blood and CSF was not associated with mortality. Our results suggest that even though EBV DNA was commonly detected in the CSF of our population, it appears to have limited clinical significance regardless of EBV DNA load.

Epstein-Barr Virus Detection in the Central Nervous System of HIV-Infected Patients.

Simply detecting Epstein-Barr virus deoxyribonucleic acid (EBV-DNA) is insufficient to diagnose EBV-associated diseases. The current literature around EBV-DNA detection from cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV)-positive non-lymphoma patients was systematically reviewed and a meta-analysis reporting the estimated pooled prevalence in this population when PCR methods are employed, targeting different sequence segments within the EBV genome, was conducted. Using a combination of three key concepts-Epstein-Barr virus detection, central nervous system disease, and human cerebrospinal fluid-and their MeSH terms, the PubMed database was searched. A total of 273 papers reporting the detection of EBV in CNS were screened, of which 13 met the inclusion criteria. The meta-analysis revealed a pooled prevalence of EBV-DNA in CSF of 20% (CI: 12-31%). The highest pooled prevalence was from studies conducted on the African population at 39% (CI: 27-51%). The investigation of the presence of EBV-DNA in the CSF was also very varied, with several gene targets used. While most patients from the articles included in this review and meta-analysis were symptomatic of CNS disorders, the pathogenicity of EBV in non-lymphoma HIV patients when detected in CSF has still not been determined. The presence of EBV-DNA in the CNS remains a concern, and further research is warranted to understand its significance in causing CNS disorders.

Immune correlates of Mycobacterium Tuberculosis patients in Zambia stratified by HIV serostatus and level of immunity-a cross-sectional analytical laboratory based study.

BACKGROUND: People living with HIV (PLHIV) co-infected with tuberculosis (TB) have a distinct clinical presentation and poorer treatment outcomes compared to HIV-seronegative TB patients. Excluding low CD4 count, innate immune factors associated with TB are not fully elucidated. We, therefore, characterised and compared the expression of IL-6, TNF-α, IFN-γ, and IL-10 in whole blood of treatment naïve TB patients stimulated with heat-killed Mycobacterium tuberculosis stratified by HIV status and the level of CD4 count. RESULTS: We recruited 39 HIV seropositive and 31 HIV seronegative TB patients. Median (IQR) age was 35(28-42) years and 31(25-36) years respectively, and a majority had pulmonary tuberculosis i.e. 38(95%) and 30(97%), respectively. The two groups were significantly different in the distribution of CD4 count, 563 [465-702.5 cells/mm3] vs 345 [157-483 cell/mm3] in HIV negative vs HIV positive respectively p = <0.001. Post stimulation, the expression of IL-6 in HIV negative TB patients was significantly higher than in the HIV positive 16,757366 [8,827-23,686 pg/ml] vs. 9,508 [5,514-15,008 pg/ml], respectively; p = 0.0360. TNF-α and IFN-γ were highly expressed in HIV negative TB patients compared to the HIV positive though not statistically significant. We only observed higher expression of IL-6 in HIV negative patients in comparison to the HIV positive when stratified by level of CD4 counts as < 500 and ≥ 500 cell/mm3 for both cohorts. 21,953 [8,990-24,206 pg/ml] vs 9,505 [5,400-15,313 pg/ml], p value = 0.0585 in patients with CD4 count < 500 cell/mm3 and 13,168 [7,087-22,584 pg/ml] vs 10,413 [7,397-14,806 pg/ml], p value = 0.3744 for patients with CD4 count of ≥ 500 cell/mm3 respectively. We found a positive pairwise correlation between TNF-α -alpha and IL-6 in both HIV positive and HIV negative patients, r = 0.61 (95% CI 0.36-0.72; p < 0.0001) and r = 0.48 (95% CI 0.15-0.68; p = 0.005) respectively. The IFNγ/IL-10 ratio was higher in HIV negative when compared to HIV positive individuals, 0.052 [0.0-0.28] vs 0.007 [0-0.32] respectively; p = 0.05759. IL-6 independently reduced the probability of TB/HIV, Adjusted odds ratio 0.99, p value 0.007. CONCLUSIONS: This study suggests that HIV seronegative TB patients have a higher pro-inflammatory response to MTB than HIV seropositive TB patients. Further, it also shows that the level of CD4 influences immunomodulation. The findings suggest that the difference in cytokine expression may be responsible for the distinct patterns of TB presentation between HIV positive and HIV negative patient.

Spectrum of common Hodgkin lymphoma and non-Hodgkin lymphomas subtypes in Zambia: a 3-year records review.

BACKGROUND: Lymphomas usually present with different occurrence patterns across different geographical locations, but their epidemiology in Zambia is yet to be extensively explored. OBJECTIVES: To study the spectrum of lymphoma subtypes prevalent within the Zambian population. METHODS: Histopathological records with suspected lymphoma at the University Teaching Hospital (UTH) in Lusaka from the year 2014 to 2016, diagnosed based on the 2008 World Health Organization (WHO) criteria were reviewed. The analysis was done in terms of type, sex, age, and site of biopsy; and Fisher's exact test was used for significance testing. RESULTS: During the study period (2014-2016), there were more B cell neoplasms {222 (92.5%)} than T cell neoplasms {18 (7.5%)}. Non-Hodgkin's lymphoma (NHL) was seen in 191 (79.6%) whereas classic Hodgkin's lymphoma (CHL) was seen in 39 (16.3%). Burkitt's lymphoma (BL) and diffuse large B cell lymphoma (DLBCL) showed equal proportions {17.5% of all lymphoma cases (42/240) each}, as the most prevalent subtypes of NHL whereas marginal zone B cell lymphoma was the rarest subtype with 1.4% (4/240). For CHL, mixed cellularity and lymphocyte rich subtypes (4.6% of all lymphoma cases) were the most common subtypes. There was a statistically significant difference in the occurrences of lymphoma subtypes across different age categories (p = 0.002). CONCLUSION: Zambia has a diverse lymphoma subtypes population, affecting a relatively young population. The data from this study will serve as a baseline for improved health care provision and more robust future studies.

High ELF4 expression in human cancers is associated with worse disease outcomes and increased resistance to anticancer drugs.

The malignant phenotype of tumour cells is fuelled by changes in the expression of various transcription factors, including some of the well-studied proteins such as p53 and Myc. Despite significant progress made, little is known about several other transcription factors, including ELF4, and how they help shape the oncogenic processes in cancer cells. To this end, we performed a bioinformatics analysis to facilitate a detailed understanding of how the expression variations of ELF4 in human cancers are related to disease outcomes and the cancer cell drug responses. Here, using ELF4 mRNA expression data of 9,350 samples from the Cancer Genome Atlas pan-cancer project, we identify two groups of patient's tumours: those that expressed high ELF4 transcripts and those that expressed low ELF4 transcripts across 32 different human cancers. We uncover that patients segregated into these two groups are associated with different clinical outcomes. Further, we find that tumours that express high ELF4 mRNA levels tend to be of a higher-grade, afflict a significantly older patient population and have a significantly higher mutation burden. By analysing dose-response profiles to 397 anti-cancer drugs of 612 well-characterised human cancer cell lines, we discover that cell lines that expressed high ELF4 mRNA transcript are significantly less responsive to 129 anti-cancer drugs, and only significantly more response to three drugs: dasatinib, WH-4-023, and Ponatinib, all of which remarkably target the proto-oncogene tyrosine-protein kinase SRC and tyrosine-protein kinase ABL1. Collectively our analyses have shown that, across the 32 different human cancers, the patients afflicted with tumours that overexpress ELF4 tended to have a more aggressive disease that is also is more likely more refractory to most anti-cancer drugs, a finding upon which we could devise novel categorisation of patient tumours, treatment, and prognostic strategies.

Antiretroviral Therapy for HIV-Associated Cutaneous Kaposi's Sarcoma: Clinical, HIV-Related, and Sociodemographic Predictors of Outcome.

Kaposi's sarcoma (KS) is an AIDS-defining malignancy that can improve or worsen with antiretroviral therapy (ART). We aimed at identifying clinical, HIV-related, and sociodemographic factors associated with either progression or nonprogression (regression or stable disease) of ART-treated HIV-associated KS in patients with limited cutaneous disease. We conducted a prospective cohort study of ART-treated HIV-associated KS cases. Clinical, HIV-related, and sociodemographic variables were collected at baseline, and patients were followed up to determine treatment outcomes. Cox regression, linear mixed effects model, and Spearman's rank correlation were used for analysis. Half (50%) of the study participants had KS regression or stable disease, whereas the other half (50%) had disease progression during the treatment and follow-up period. Among the data analyzed, presence of KS nodules at baseline (hazard ratio = 5.47; 95% confidence interval = 1.32-22.65; p = .02) was an independent predictor of poor treatment outcome. Progressors and nonprogressors were indistinguishable in the changes they experienced in the HIV plasma viral load and CD4 counts as a result of ART. Even when cutaneous presentation is limited, the presence of nodular morphotype KS lesions should be considered an indicator for combined ART plus chemotherapy. Temporal trends in CD4 counts and HIV viral loads did not correlate with treatment outcome in ART-treated HIV-associated KS.

Cells of the Innate and Adaptive Immune Systems in Kaposi's Sarcoma.

Kaposi's sarcoma (KS) is an angioproliferative malignancy whose associated etiologic agent is the Kaposi's sarcoma-associated herpesvirus (KSHV). KS is the most prevalent malignancy among HIV-infected individuals globally and is considered an AIDS-defining malignancy. The different forms of KS including HIV-associated KS, iatrogenic (immunosuppression-related) KS, and classical KS in elderly males suggest that immune cell dysregulation is among the key components in promoting KS development in KSHV-infected individuals. It is therefore expected that different cell types of the immune system likely play distinct roles in promoting or inhibiting KS development. This narrative review is focused on discussing cells of the innate and adaptive immune systems in KSHV infection and KS pathogenesis, including how these cells can be useful in the control of KSHV infection and treatment of KS.

Outcome markers of ART-treated HIV+ patients with early stage Kaposi's sarcoma.

HIV-associated/epidemic Kaposi's sarcoma (EpKS) is an AIDS-defining angio-proliferative malignancy. It can be treated with antiretroviral therapy (ART) alone or with ART plus cytotoxic chemotherapy. ART-treated EpKS can either respond or worsen upon treatment. This study aimed at identifying immunological markers of ART-treatment response. We compared responders (those with clinical EpKS tumor regression) versus poor responders (those with progressive or non-responsive EpKS). We measured plasma cytokine and chemokine levels using cytometric bead assays. Kaposi's sarcoma herpesvirus (KSHV) neutralizing antibody (nAb) responses were also quantified to test associations with treatment outcome. Interleukin (IL)-5 levels were significantly elevated in responders versus poor-responders at baseline (0.76pg/ml vs. 0.37pg/ml; p<0.01) and follow-up (0.56pg/ml vs. 0.37pg/ml; p<0.01); IL-6 was lower in responders than poor-responders at follow-up (600fg/ml vs. 4272fg/ml; p<0.05). IP-10/CxCL-10 was significantly lower at follow-up in responders versus poor-responders (187pg/ml vs. 528pg/ml; p<0.01). KSHV nAb were not significantly differential between responders and poor-responders. In conclusion, high plasma IL-5 at baseline could be a marker for ART-treated KS tumor regression, whereas increased pro-inflammatory cytokine IL-6, and the chemokine IP-10, associate with KS tumor progression.

Elevated Eosinophils as a Feature of Inflammation Associated With Hypertension in Virally Suppressed People Living With HIV.

Background People living with HIV (PLWH) are at increased risk of cardiovascular disease, including hypertension, which persists despite effective plasma viral suppression on antiretroviral therapy. HIV infection is characterized by long-term alterations in immune function, but the contribution of immune factors to hypertension in PLWH is not fully understood. Prior studies have found that both innate and adaptive immune cell activation contributes to hypertension. Methods and Results We hypothesized that chronic inflammation may contribute to hypertension in PLWH. To test this hypothesis, we enrolled a cohort of 70 PLWH (44% hypertensive) on a long-term single antiretroviral therapy regimen for broad phenotyping of inflammation biomarkers. We found that hypertensive PLWH had higher levels of inflammatory cytokines, including tumor necrosis factor-α receptor 1, interleukin-6, interleukin-17, interleukin-5, intercellular adhesion molecule 1 and macrophage inflammatory protein-1α. After adjustment for age, sex, and fat mass index, the circulating eosinophils remained significantly associated with hypertension. On the basis of these results, we assessed the relationship of eosinophils and hypertension in 2 cohorts of 50 and 81 039 similar HIV-negative people; although eosinophil count was associated with prevalent hypertension, this relationship was abrogated by body mass index. Conclusions These findings may represent a unique linkage between immune status and cardiovascular physiological characteristics in HIV infection, which should be evaluated further.