The effects of HIV and oncogenic human papillomavirus on the tumor immune microenvironment of penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (⍴ = 0.69; p = 0.0001), PD1 and TIM3 (⍴ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (⍴ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.

Antimicrobial resistance and heterogeneity of Neisseria gonorrhoeae isolated from patients attending sexually transmitted infection clinics in Lusaka, Zambia.

BACKGROUND: Antimicrobial resistance (AMR) of Neisseria gonorrhoeae is a threat to public health as strains have developed resistance to antimicrobials available for the treatment of gonorrhea. Whole genome sequencing (WGS) can detect and predict antimicrobial resistance to enhance the control and prevention of gonorrhea. Data on the molecular epidemiology of N. gonorrhoeae is sparse in Zambia. This study aimed to determine the genetic diversity of N. gonorrhoeae isolated from patients attending sexually transmitted infection (STI) clinics in Lusaka, Zambia. METHODS: A cross-sectional study that sequenced 38 N. gonorrhoeae isolated from 122 patients with gonorrhea from 2019 to 2020 was conducted. The AMR profiles were determined by the E-test, and the DNA was extracted using the NucliSens easyMaG magnetic device. Whole genome sequencing was performed on the Illumina NextSeq550 platform. The Bacterial analysis pipeline (BAP) that is readily available at: https://cge.cbs.dtu.dk/services/CGEpipeline-1.1 was used for the identification of the species, assembling the genome, multi-locus sequence typing (MLST), detection of plasmids and AMR genes. Phylogeny by single nucleotide polymorphisms (SNPs) was determined with the CCphylo dataset. RESULTS: The most frequent STs with 18.4% of isolates each were ST7363, ST1921 and ST1582, followed by ST1583 (13%), novel ST17026 (7.9%), ST1588 (7.9%), ST1596 (5.3%), ST11181 (5.3%), ST11750 (2.6/%) and ST11241 (2.6%) among the 38 genotyped isolates. The blaTeM-1B and tetM (55%) was the most prevalent combination of AMR genes, followed by blaTeM-1B (18.4%), tetM (15.8%), and the combination of blaTeM-1B, ermT, and tetL was 2.6% of the isolates. The AMR phenotypes were predicted in ciprofloxacin, penicillin, tetracycline, azithromycin, and cefixime. The combination of mutations 23.7% was gryA (S91F), parC (E91G), ponA (L421) and rpsJ (V57M), followed by 18.4% in gyrA (S91F), ponA (L421P), rpsJ (V57M), and 18.4% in gyrA (D95G, S91F), ponA (L421P), and rpsJ (V57M). The combinations in gyrA (D95G, S91F) and rpsJ (V57M), and gyrA (D95G, S91F), parC (E91F), ponA (L421P) and rpsJ (V57M) were 13.2% each of the isolates. Plasmid TEM-1 (84.2%), tetM (15.8%), and gonococcal genetic island (GGI) was detected in all isolates. CONCLUSION: This study revealed remarkable heterogeneity of N. gonorrhoeae with blaTEM-1, tetM, ponA, gyrA, and parC genes associated with high resistance to penicillin, tetracycline, and ciprofloxacin demanding revision of the standard treatment guidelines and improved antimicrobial stewardship in Zambia.

Viral Epitope Scanning Reveals Correlation between Seasonal HCoVs and SARS-CoV-2 Antibody Responses among Cancer and Non-Cancer Patients.

Seasonal coronaviruses (HCoVs) are known to contribute to cross-reactive antibody (Ab) responses against SARS-CoV-2. While these responses are predictable due to the high homology between SARS-CoV-2 and other CoVs, the impact of these responses on susceptibility to SARS-CoV-2 infection in cancer patients is unclear. To investigate the influence of prior HCoV infection on anti-SARS-CoV-2 Ab responses among COVID-19 asymptomatic individuals with cancer and controls without cancers, we utilized the VirScan technology in which phage immunoprecipitation and sequencing (PhIP-seq) of longitudinal plasma samples was performed to investigate high-resolution (i.e., epitope level) humoral CoV responses. Despite testing positive for anti-SARS-CoV-2 Ab in the plasma, a majority of the participants were asymptomatic for COVID-19 with no prior history of COVID-19 diagnosis. Although the magnitudes of the anti-SARS-CoV-2 Ab responses were lower in individuals with Kaposi sarcoma (KS) compared to non-KS cancer individuals and those without cancer, the HCoV Ab repertoire was similar between individuals with and without cancer independent of age, sex, HIV status, and chemotherapy. The magnitudes of the anti-spike HCoV responses showed a strong positive association with those of the anti-SARS-CoV-2 spike in cancer patients, and only a weak association in non-cancer patients, suggesting that prior infection with HCoVs might play a role in limiting SARS-CoV-2 infection and COVID-19 disease severity.

Antibody profiling and predictive modeling discriminate between Kaposi sarcoma and asymptomatic KSHV infection.

Protein-level immunodominance patterns against Kaposi sarcoma-associated herpesvirus (KSHV), the aetiologic agent of Kaposi sarcoma (KS), have been revealed from serological probing of whole protein arrays, however, the epitopes that underlie these patterns have not been defined. We recently demonstrated the utility of phage display in high-resolution linear epitope mapping of the KSHV latency-associated nuclear antigen (LANA/ORF73). Here, a VirScan phage immunoprecipitation and sequencing approach, employing a library of 1,988 KSHV proteome-derived peptides, was used to quantify the breadth and magnitude of responses of 59 sub-Saharan African KS patients and 22 KSHV-infected asymptomatic individuals (ASY), and ultimately to support an application of machine-learning-based predictive modeling using the peptide-level responses. Comparing anti-KSHV antibody repertoire revealed that magnitude, not breadth, increased in KS. The most targeted epitopes in both KS and ASY were in the immunodominant proteins, notably, K8.129-56 and ORF65140-168, in addition to LANA. Finally, using unbiased machine-learning-based predictive models, reactivity to a subset of 25 discriminative peptides was demonstrated to successfully classify KS patients from asymptomatic individuals. Our study provides the highest resolution mapping of antigenicity across the entire KSHV proteome to date, which is vital to discern mechanisms of viral pathogenesis, to define prognostic biomarkers, and to design effective vaccine and therapeutic strategies. Future studies will investigate the diagnostic, prognostic, and therapeutic potential of the 25 discriminative peptides.

Co-infection and co-localization of Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus in HIV-associated Kaposi sarcoma: a case report.

Kaposi sarcoma (KS), a multifocal vascular neoplasm frequently observed in HIV-positive individuals, primarily affects the skin, mucous membranes, visceral organs, and lymph nodes. KS is associated primarily with Kaposi sarcoma-associated herpesvirus (KSHV) infection. In this case report, we present a rare occurrence of co-infection and co-localization of KSHV and Epstein-Barr virus (EBV) in KS arising from the conjunctiva, which, to our knowledge, has not been reported previously. Immunohistochemistry (IHC), DNA polymerase chain reaction (PCR), and EBV-encoded RNA in situ hybridization (EBER-ISH) were utilized to demonstrate the presence of KSHV and EBV infection in the ocular KS lesion. Nearly all KSHV-positive cells displayed co-infection with EBV. In addition, the KS lesion revealed co-localization of KSHV Latency-Associated Nuclear Antigen (LANA) and EBV Epstein Barr virus Nuclear Antigen-1 (EBNA1) by multi-colored immunofluorescence staining with different anti-EBNA1 antibodies, indicating the possibility of interactions between these two gamma herpesviruses within the same lesion. Additional study is needed to determine whether EBV co-infection in KS is a common or an opportunistic event that might contribute to KS development and progression.

Comparative polar and lipid plasma metabolomics differentiate KSHV infection and disease states.

BACKGROUND: Kaposi sarcoma (KS) is a neoplastic disease etiologically associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV). KS manifests primarily as cutaneous lesions in individuals due to either age (classical KS), HIV infection (epidemic KS), or tissue rejection preventatives in transplantation (iatrogenic KS) but can also occur in individuals, predominantly in sub-Saharan Africa (SSA), lacking any obvious immune suppression (endemic KS). The high endemicity of KSHV and human immunodeficiency virus-1 (HIV) co-infection in Africa results in KS being one of the top 5 cancers there. As with most viral cancers, infection with KSHV alone is insufficient to induce tumorigenesis. Indeed, KSHV infection of primary human endothelial cell cultures, even at high levels, is rarely associated with long-term culture, transformation, or growth deregulation, yet infection in vivo is sustained for life. Investigations of immune mediators that distinguish KSHV infection, KSHV/HIV co-infection, and symptomatic KS disease have yet to reveal consistent correlates of protection against or progression to KS. In addition to viral infection, it is plausible that pathogenesis also requires an immunological and metabolic environment permissive to the abnormal endothelial cell growth evident in KS tumors. In this study, we explored whether plasma metabolomes could differentiate asymptomatic KSHV-infected individuals with or without HIV co-infection and symptomatic KS from each other. METHODS: To investigate how metabolic changes may correlate with co-infections and tumorigenesis, plasma samples derived from KSHV seropositive sub-Saharan African subjects in three groups, (A) asymptomatic (lacking neoplastic disease) with KSHV infection only, (B) asymptomatic co-infected with KSHV and HIV, and (C) symptomatic with clinically diagnosed KS, were subjected to analysis of lipid and polar metabolite profiles RESULTS: Polar and nonpolar plasma metabolic differentials were evident in both comparisons. Integration of the metabolic findings with our previously reported KS transcriptomics data suggests dysregulation of amino acid/urea cycle and purine metabolic pathways, in concert with viral infection in KS disease progression. CONCLUSIONS: This study is, to our knowledge, the first to report human plasma metabolic differentials between in vivo KSHV infection and co-infection with HIV, as well as differentials between co-infection and epidemic KS.

HIV and inflammatory markers are associated with persistent COVID-19 symptoms.

BACKGROUND: A proportion of COVID19 survivors may present with long-COVID, which is persistent symptoms lasting four or more weeks post SARS-CoV-2 infection. These symptoms may be mild to severe, and may affect different organ-systems of the body. AIMS: The main objective of this study was to determine the demographic, clinical and immunological factors associated with long COVID. MATERIALS & METHODS: We conducted a nested case control study, with a total of 94 study participants initially included, and 64 participants matched for age and sex for biomarker analyses. RESULTS: 32/94 (34.1%) of all the participants had long COVID. Respiratory symptoms were the most common (59.5%) followed by the musculoskeletal symptoms (28.1%). HIV was an independent predictor of long COVID (adjusted odds ratio = 2.7; p = .037). In all the 64 matched cases and controls, IFN-ß was significantly higher among controls than cases. After stratifying by HIV, IL6 was significantly higher among cases than controls in the HIV- group (2.06 vs. 0.81 pg/mL; p = .02). On the other hand, IFN-ß was significantly higher among controls than cases in the HIV+ group (251 vs. 0 pg/mL; p = .01). CONCLUSION: HIV infection is a risk factor for long COVID, and inflammatory markers associated with long COVID may be slightly different for HIV- and HIV+ individuals.

Upregulation of Cell Surface Glycoproteins in Correlation with KSHV LANA in the Kaposi Sarcoma Tumor Microenvironment.

HIV-associated epidemic Kaposi sarcoma (EpKS) remains one of the most prevalent cancers in sub-Saharan Africa despite the widespread uptake of anti-retroviral therapy and HIV-1 suppression. In an effort to define potential therapeutic targets against KS tumors, we analyzed previously published KS bulk tumor transcriptomics to identify cell surface biomarkers. In addition to upregulated gene expression (>6-fold) in the EpKS tumor microenvironment, biomarkers were selected for correlation with KSHV latency-associated nuclear antigen (LANA) expression. The cell surface glycoprotein genes identified were KDR, FLT4, ADAM12, UNC5A, ZP2, and OX40, as well as the endothelial lineage determinants Prox-1 and CD34. Each protein was evaluated for its expression and co-localization with KSHV LANA using multi-color immunofluorescence in KS tissues, KSHV-infected L1T2 cells, uninfected TIVE cells, and murine L1T2 tumor xenografts. Five surface glycoproteins (KDR, FLT4, UNC5A, ADAM12, and CD34) were associated with LANA-positive cells but were also detected in uninfected cells in the KS microenvironment. In vitro L1T2 cultures showed evidence of only FLT4, KDR, and UNC5A, whereas mouse L1T2 xenografts recapitulated human KS cell surface expression profiles, with the exception of CD34 and Prox-1. In KS tumors, most LANA-positive cells co-expressed markers of vascular as well as lymphatic endothelial lineages, suggesting KS-associated dedifferentiation to a more mesenchymal/progenitor phenotype.

Elevated iNOS and 3'-nitrotyrosine in Kaposi's Sarcoma tumors and mouse model.

Kaposi's Sarcoma (KS) is a heterogenous, multifocal vascular malignancy caused by the human herpesvirus 8 (HHV8), also known as Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Here, we show that KS lesions express iNOS/NOS2 broadly throughout KS lesions, with enrichment in LANA positive spindle cells. The iNOS byproduct 3-nitrotyrosine is also enriched in LANA positive tumor cells and colocalizes with a fraction of LANA-nuclear bodies. We show that iNOS is highly expressed in the L1T3/mSLK tumor model of KS. iNOS expression correlated with KSHV lytic cycle gene expression, which was elevated in late-stage tumors (>4 weeks) but to a lesser degree in early stage (1 week) xenografts. Further, we show that L1T3/mSLK tumor growth is sensitive to an inhibitor of nitric oxide, L-NMMA. L-NMMA treatment reduced KSHV gene expression and perturbed cellular gene pathways relating to oxidative phosphorylation and mitochondrial dysfunction. These finding suggest that iNOS is expressed in KSHV infected endothelial-transformed tumor cells in KS, that iNOS expression depends on tumor microenvironment stress conditions, and that iNOS enzymatic activity contributes to KS tumor growth.

SARS-CoV-2-specific T cell and humoral immunity in individuals with and without HIV in an African population: a prospective cohort study.

OBJECTIVES: To longitudinally compare SARS-CoV-2-specific T cell and humoral immune responses between convalescent individuals who are HIV-positive (HIV+) and HIV-negative (HIV-). METHODS: We conducted enzyme-linked immunospots to determine the SARS-CoV-2-specific T cell responses to spike and nucleocapsid, membrane protein, and other open reading frame proteins (NMO), whereas an immunofluorescence assay was used to determine the humoral responses. Participants were sampled at baseline and after 8 weeks of follow-up. RESULTS: Individuals who are HIV- had significantly more T cell responses to NMO and spike than individuals who are HIV+ at baseline, P-value = 0.026 and P-value = 0.029, respectively. At follow-up, T cell responses to NMO and spike in individuals who are HIV+ increased to levels comparable with individuals who are HIV-. T cell responses in the HIV- group significantly decreased from baseline levels at the time of follow-up (spike [P-value = 0.011] and NMO [P-value = 0.014]). A significantly higher number of individuals in the HIV+ group had an increase in T cell responses to spike (P-value = 0.01) and NMO (P-value = 0.026) during the follow-up period than the HIV- group. Antispike and antinucleocapsid antibody titers were high (1: 1280) and not significantly different between individuals who were HIV- and HIV+ at baseline. A significant decrease in antinucleocapsid titer was observed in the HIV- (P-value = 0.0001) and the HIV+ (P-value = 0.001) groups at follow-up. SARS-CoV-2 vaccination was more effective in boosting the T cell than antibody responses shortly after infection. CONCLUSION: There is an impairment of SARS-CoV-2-specific T cell immunity in individuals who are HIV+ with advanced immunosuppression. SARS-CoV-2-specific T cell immune responses may be delayed in individuals who are HIV+, even in those on antiretroviral therapy. There is no difference in SARS-CoV-2-specific humoral immunity between individuals who are HIV- and HIV+.

Antibody epitope profiling of the KSHV LANA protein using VirScan.

The humoral antibody response against Kaposi sarcoma-associated herpesvirus (KSHV) in infected individuals has been characterized demonstrating the latency-associated nuclear antigen (LANA) as the most antigenic KSHV protein. Despite the antigenicity of the protein, specific LANA epitopes have not been systematically characterized. Here, we utilized a bacteriophage T7 library, which displays 56-amino acid KSHV LANA peptides with 28-amino acid overlap (VirScan), to define those epitopes in LANA targeted by antibodies from a cohort of 62 sub-Saharan African Kaposi sarcoma (KS) patients and 22 KSHV-infected asymptomatic controls. Intra- and inter-patient breadth and magnitude of the anti-LANA responses were quantified at the peptide and amino acid levels. From these data, we derived a detailed epitope annotation of the entire LANA protein, with a high-resolution focus on the N- and C-termini. Overall, the central repeat region was highly antigenic, but the responses to this region could not be confidently mapped due to its high variability. The highly conserved N-terminus was targeted with low breadth and magnitude. In a minority of individuals, antibodies specific to the nuclear localization sequence and a portion of the proline-rich regions of the N-terminus were evident. In contrast, the first half of the conserved C-terminal domain was consistently targeted with high magnitude. Unfortunately, this region was not included in LANA partial C-terminal crystal structures, however, it was predicted to adopt predominantly random-coil structure. Coupled with functional and secondary structure domain predictions, VirScan revealed fine resolution epitope mapping of the N- and C-terminal domains of LANA that is consistent with previous antigenicity studies and may prove useful to correlate KSHV humoral immunity with pathogenesis.

Lower SARS-CoV-2 Seroprevalence among Cancer Patients in Sub-Saharan Africa.

BACKGROUND: Despite the high COVID-19 morbidity and mortality rates across the world, the reported rates in sub-Saharan Africa (SSA), which has a higher burden of other infectious diseases and overwhelmed healthcare systems, remain relatively low. This study aims to better understand the potential factors that contribute to this phenomenon, especially among cancer patients who are considered as a high-risk group for developing severe COVID-19. METHODS: Plasma samples collected during the COVID-19 pandemic from SARS-CoV-2 unvaccinated cancer and potential blood donor populations were analyzed for SARS-CoV-2 (spike and nucleocapsid proteins) antibodies by an immunofluorescence assay. The relationships between SARS-CoV-2 seroprevalences and study variables were determined using a logistic regression analysis. RESULTS: High seroprevalence against the SARS-CoV-2 spike and nucleocapsid proteins were found among the SARS-CoV-2 unvaccinated COVID-19 pandemic populations in SSA. However, the cancer patients demonstrated a lower seroprevalence compared to potential blood donors. There was also an association between mild COVID-19 symptoms with prior tuberculosis vaccination among cancer patients. CONCLUSION: Cancer patients in SSA tend to have a relatively lower SARS-CoV-2 seroprevalence compared to potential blood donors recruited from the same geographic locations during the COVID-19 pandemic. More study is required to determine its cause and potential impact on SARS-CoV-2 vaccination among cancer patients.

Antimicrobial resistance of Neisseria gonorrhoeae isolated from patients attending sexually transmitted infection clinics in Urban Hospitals, Lusaka, Zambia.

BACKGROUND: Neisseria gonorrhoeae, the causative agent for sexually transmitted infection (STI) gonorrhoea, has emerged with a significant public health impact on acquiring resistance to antimicrobials available for treatment. The resistance of N. gonorrhoeae limit treatment options and contributed to high morbidity associated with gonorrhoea. Data on antimicrobial resistance (AMR) profiles in N. gonorrhoeae is scares in Zambia. This study aimed to determine the antibiotic susceptibilities in N. gonorrhoeae isolates from Lusaka, Zambia. METHODS: A prospective cross-sectional study was conducted on 630 STI patients who presented with urethral or vaginal discharge from 2019 to 2020. Urethral and endocervical secretions were cultured on Modified Thayer Martin agar and incubated at 36 °C ± 1 °C in 5% CO2 for 24 h. Identification of N. gonorrhoeae isolates was achieved by Gram stain, oxidase, nitrocefin disk, BactiCard Neisseria, and Viteck® Compact. The AMR profiles were determined using E-test. Statistical significant was determined by Pearson's Chi-square test, Mann-Whitney U test, or logistic regression with p-values of < 0.05 indicating significance. RESULTS: A total of 630 patients were recruited of which 46% (290/630) with the median of 29 years and interquartile range (IQR) of 19-39 years were male. The median of the females was 26 years and IQR of 15-37 years. Neisseria gonorrhoeae was isolated from 19.4% (122/630) patients of which 72.9% (89/122) were male, with highest prevalence of isolation in the age category of 25-34 years. The prevalence of resistance was high to penicillin (85.2%), tetracycline (68.9%) and ciprofloxacin (59.8%) with MIC90 of 32 µg/mL, 8 µg/mL, and 8 µg/mL respectively. The isolates had reduced susceptibility to cefixime (1.6%), spectinomycin (4.9%) and (4.9%) for azithromycin. All isolates were susceptible to ceftriaxone. Risk factors associated with AMR were douching in females (AOR 6.69, 95% CI; 1.11-40.31, p = 0.039), female gender (AOR 7.64, 95% CI; 1.11-52.33, p = 0.048), HIV-positivity (AOR 26.59, 95% CI; 3.67-192.7, p = 0.005), no condom use or unprotected sex (AOR 5.48, 95% CI; 1.17-22.75 p = 0.026), sex trading (AOR 4.19, 95% CI; 1.55-11.33, p = 0.010), and over-counter treatment of ciprofloxacin (AOR 3.44, 95% CI; 1.17-22.75, p = 0.023). CONCLUSION: The N. gonorrhoeae resistance to penicillin, tetracycline and ciprofloxacin was high necessitating revision of the treatment guidelines. However, no resistance to ceftriaxone was detected. Therefore, monitoring of antibiotic resistance remains critical in Zambia.

SARS-CoV-2-Specific T Cell Immunity in HIV-Associated Kaposi Sarcoma Patients in Zambia.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus is the cause of coronavirus disease 2019 (COVID-19). It has caused millions of infections and deaths globally over a 2-year period. Some populations including those living with HIV and/or cancer are reported to be at a higher risk of infection and severe disease. HIV infection leads to a depletion of CD4+ T cells which impairs cell-mediated immunity and increases the risk of malignancies such as Kaposi sarcoma (KS) and viral infections such as SARS-CoV-2. However, several other factors including level of immunosuppression and chemotherapy may also affect the immune response against SARS-CoV-2. In this study, we investigated factors affecting SARS-CoV-2-specific T cell immunity towards the spike, nucleoprotein, membrane protein, and other open reading frame proteins in individuals with HIV-associated KS. The KS patients were SARS-CoV-2 seropositive with detectable T cell responses, but had no history of symptomatic SARS-CoV-2 infection. We observed that the T cell responses increase from baseline levels during follow-up, with responses towards the NMO peptide pool being statistically significant. Low CD4 counts below 200 cells/µl were associated with lower SARS-CoV-2-specific T cell responses. Cancer chemotherapy and KS T staging did not have a significant effect on the T cell responses.

Vaccines to prevent COVID-19: A living systematic review with Trial Sequential Analysis and network meta-analysis of randomized clinical trials.

BACKGROUND: COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. METHODS AND FINDINGS: Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. CONCLUSIONS: The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

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.

Viral and immunological markers of HIV-associated Kaposi sarcoma recurrence.

Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy highly prevalent in Sub-Saharan Africa. The main objective of this study was to determine the factors associated with recurrence of HIV-associated KS. We recruited a cohort of individuals on antiretroviral therapy who were in remission for HIV-associated KS after undergoing cytotoxic cancer chemotherapy. Collected variables included sociodemographic and clinical parameters, cytokines and chemokines, HIV viral loads, and CD4 counts. Compared to individuals who had KS recurrence, IL-5 was significantly higher at time of follow-up in individuals who had sustained remission (22.7pg/ml vs. 2.4pg/ml; p = 0.02); IL-6 was significantly higher at baseline and time of follow-up in individuals who had sustained remission, (18.4pg/ml vs. 0pg/ml; p = 0.01) and (18.0pg/ml vs. 0.18pg/ml; p = 0.03) respectively; IP-10 was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (534pg/ml vs. 920pg/ml; p = 0.04) and (446pg/ml vs.1098pg/ml; p = 0.01) respectively; while HIV viral load was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (0copies/ml vs. 113copies/ml; p = 0.004) and (0copies/ml vs. 152copies/ml; p = 0.025) respectively. Plasma levels of IL-5, IL-6, and IP-10 are associated with recurrence of HIV-associated KS, while persistently detectable HIV viral loads increase the risk of KS recurrence.

Acquired Acrodermatitis Enteropathica in a 28-Year-Old Male with Type 1 Diabetes.

Acrodermatitis enteropathica (AE) is a rare disorder arising from inherited or acquired zinc deficiency. It is mainly characterized by acral dermatitis, periorificial dermatitis, alopecia, and gastrointestinal symptoms in the form of diarrhea. There are many complications of AE including local and systemic infections that may develop as a result of untreated AE. In addition, due to the role of zinc in glucose metabolism, chronic zinc deficiency may pose a challenge in the control of blood glucose levels in diabetics. We report the case of a 28-year-old male with type 1 diabetes who presented with signs and symptoms of AE.

Expression of CD40L on CD4+T cells distinguishes active versus inactive HIV-associated Kaposi's Sarcoma.

Kaposi's sarcoma (KS) is a malignancy of vascular origin. It is caused by the Kaposi's sarcoma-associated herpes virus (KSHV). Immune dysregulation is a key feature in the development and progression of KS. The main aim of this study was to determine and compare circulating CD4+ and CD8+T cell subsets including their expression of CD40 ligand (CD40L) and programmed cell death protein 1 (PD1), natural killer (NK) cells, and NK T cells between individuals with active HIV-associated KS versus those in remission. We found that the proportion of CD4+T cells was significantly higher in individuals in remission compared to those with active KS (26.3% vs 13.9%; p = 0.01). We also observed that the proportion of CD4+T cells and central memory CD4+T cells expressing CD40L was significantly higher in individuals with active KS versus those in remission, (10.6% vs 5.4%; p = 0.03) and (14.8% vs 5.9%; p = 0.01) respectively. There was no significant difference in proportion of CD4+ and CD8+ naïve, central memory, effector memory, and terminal effector cells between the two groups. In addition, there was no difference in expression of PD1 on the T cell subsets between the two groups. Furthermore, the proportion of NK cells and NK T cells were not differential between individuals with active disease versus those in remission. CD40L expression is higher in individuals with active HIV-associated KS compared to those in remission. The proportion of CD4+T cells is higher in individuals in remission compared to those with active HIV-associated KS.

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.