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Relationship among serum levels of IL-6, sIL-6R, s gp130 and CD126 on T-cell in HIV-1 infected and uninfected men participating in the Los Angeles Multi-Center AIDS Cohort Study
Interleukin 6 (IL-6) activates cells through its unique heterodimeric signaling complex of IL-6 receptor (IL6R) subunit and interleukin 6 signal transducer β-subunit glycoprotein 130 (gp130). The objective of this study was to investigate associations among serum levels of IL-6, sIL-6R, sgp130 and relative fluorescence intensity (RFI) of the α-subunit of the IL-6 receptor (CD126) on T-cells of HIV-1 infected and uninfected men.
Blood samples were obtained from 69 HIV-1-infected men on Highly Active Antiretroviral Therapy (HAART) with mean age of 49.1 and 52 HIV-1-uninfected with mean age of 54.3 years -. All men were participating in the Los Angeles Multi-Center AIDS Cohort Study (MACS). Serum levels of IL-6, sIL-6R, sgp130 were measured by enzyme-linked immunoassays and T-cell phenotypic analysis and RFI of CD126 on CD4+ and CD8+ by flow cytometry.
Mean serum levels of IL-6, sIL6R, sgp130 and of CD126 RFI on CD4+ were 4.34 pg/mL, 39.3 ng/mL, 349 ng/mL and 526 RFI respectively for HIV-1-infected men and 2.74 pg/mL, 41.9 ng/mL, 318 ng/mL and 561 RFI respectively for HIV-1-uninfected men. The mean serum concentrations of IL-6, sIL-6R in HIV-1-infected and uninfected men were not significantly different (p>0.05). There was a positive correlation between plasma HIV-1 RNA and the levels of IL-6 (p<0.001), sIL6R (p = 0.002) but no correlation with sgp130 (p = 0.339). In addition, there was a negative correlation between serum levels of IL-6 with RFI of CD126 on CD4+ (p = 0.037) and a positive correlation between serum levels of sgp130 (p = 0.021) and sIL-6R in HIV-1-infected men.
Knowledge of biological variation, differences in the blood levels of biomarkers among healthy individuals and individuals experiencing illness, are very important for selection of appropriate tests for stage and progression of disease. Our data suggest no correlation among IL-6, and sIL-R6, in the treated phase of HIV-1 infection. The action and blood level of IL-6 and its receptors may be different at each stage of a disease progression.
Journal Article
Evolution of China's response to HIV/AIDS
Four factors have driven China's response to the HIV/AIDS pandemic: (1) existing government structures and networks of relationships; (2) increasing scientific information; (3) external influences that underscored the potential consequences of an HIV/AIDS pandemic and thus accelerated strategic planning; and (4) increasing political commitment at the highest levels. China's response culminated in legislation to control HIV/AIDS—the AIDS Prevention and Control Regulations. Three major initiatives are being scaled up concurrently. First, the government has prioritised interventions to control the epidemic in injection drug users, sex workers, men who have sex with men, and plasma donors. Second, routine HIV testing is being implemented in populations at high risk of infection. Third, the government is providing treatment for infected individuals. These bold programmes have emerged from a process of gradual and prolonged dialogue and collaboration between officials at every level of government, researchers, service providers, policymakers, and politicians, and have led to decisive action.
Journal Article
Biological variation of immunological blood biomarkers in healthy individuals and quality goals for biomarker tests
Background
Cytokines, chemokines, adipocytokines, soluble cell receptors, and immune activation markers play an important role in immune responsiveness and can provide prognostic value since they reflect underlying conditions and disease states. This study was undertaken to investigate the components of biological variation for various laboratory tests of blood immunological biomarkers.
Results
Estimates of intra-individual coefficient of variation (CV
I
) and inter-individual coefficient of variation (CV
G
) were examined for blood immunological biomarkers. Biomarkers with CV
I
< 10% for both genders were CD3, CD4, and CD8 T-cells, serum levels of soluble cluster of differentiation 14 (sCD14), sCD163, and soluble glycoprotein 130 (sgp130). The CV
I
for serum levels of adiponectin, interleukin-1 receptor antagonist (IL-1Ra), macrophage inflammatory protein 1 beta (MIP-1β), soluble CD40 Ligand (sCD40L), soluble interleukin-2 receptor alpha (sIL-2Rα), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor II (sTNF-RII), and tumor necrosis factor alpha (TNF-α) were between 11 and 20%. Biomarkers with CV
G
< 20% were CD3 T-cell, and serum concentrations of sCD14, sCD40L, and sgp130. The biomarkers with CV
G
> 40% were adiponectin, IL-1ra, leptin, MIP-1β, sCD163, and sIL-2Rα.
Conclusion
The biological variations of biomarkers have important monitoring value for longitudinal investigation and are essential for quality specification of tests that are performed in the laboratory. The CV
I
was relatively small while CV
G
was comparatively large and mean values of each biomarker vary between subjects. The individuality of biomarkers significantly influences reference interval values. A majority of the biomarkers in this study had strong individuality and the result of each biomarker should be cautiously interpreted if using established reference interval values. Comparison of a patient’s test result with previous ones may be more useful than the usage of conventional reference values.
Journal Article
Spectrum of malignancies among the population of adults living with HIV infection in China: A nationwide follow-up study, 2008–2011
Although increasingly studied in high-income countries, there is a paucity of data from the Chinese population on the patterns of cancer among people living with HIV (PLHIV).
We conducted a nationwide follow-up study using routinely collected data for adult PLHIV diagnosed on or before 31 December 2011 and alive and in care as of 1 January 2008. Participants were observed from 1 January 2008 (study start) to 30 June 2012 (study end). Main outcome measures were gender-stratified age-standardized incidence rates for China (ASIRC) and standardized incidence ratios (SIR) for all malignancy types/sites observed.
Among 399,451 subjects, a majority was aged 30-44 years (49.3%), male (69.8%), and Han Chinese (67.9%). A total of 3,819 reports of cancer were identified. Overall, ASIRC was 776.4 per 100,000 for males and 486.5 per 100,000 for females. Malignancy sites/types with highest ASIRC among males were lung (226.0 per 100,000), liver (145.7 per 100,000), and lymphoma (63.1 per 100,000), and among females were lung (66.8 per 100,000), lymphoma (48.0 per 100,000), stomach (47.8 per 100,000), and cervix (47.6 per 100,000). Overall SIR for males was 3.4 and for females was 2.6. Highest SIR was observed for Kaposi sarcoma (2,639.8 for males, 1,593.5 for females) and lymphoma (13.9 for males, 16.0 for females).
These results provide evidence of substantial AIDS-defining and non-AIDS-defining cancer burden among adult Chinese PLHIV between 2008 and 2011. Although further study is warranted, China should take action to improve cancer screening, diagnosis, and treatment for this vulnerable population.
Journal Article
Characterization of unique B-cell populations in the circulation of people living with HIV prior to non-Hodgkin lymphoma diagnosis
People living with HIV (PLWH) are at higher risk of developing lymphoma. In this study, we performed cytometry by time-of-flight (CyTOF) on peripheral blood mononuclear cells of cART-naïve HIV+ individuals and cART-naïve HIV+ individuals prior to AIDS-associated non-Hodgkin lymphoma (pre-NHL) diagnosis. Participants were enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Uniform Manifold Approximation and Projection (UMAP) and unsupervised clustering analysis were performed to identify differences in the expression of B-cell activation markers and/or oncogenic markers associated with lymphomagenesis. CD10 + CD27 - B cells, CD20 + CD27 - B cells, and B-cell populations with aberrant features (CD20 + CD27 + CXCR4 + CD71 + B cells and CD20 + CXCR4 + cMYC + B cells) were significantly elevated in HIV+ cART-naïve compared to HIV-negative samples. CD20 + CD27 + CD24 + CXCR4 + CXCR5 + B cells, CD20 + CD27 + CD10 + CD24 + CXCR4 + cMYC + B cells, and a cluster of CD20 + CXCR4 hi CD27 - CD24 + CXCR5 + CD40 + CD4 + AICDA + B cells were significantly elevated in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. A potentially clonal cluster of CD20 + CXCR4 + CXCR5 + cMYC + AICDA + B cells and a cluster of germinal center B-cell-like cells (CD19 - CD20 + CXCR4 + Bcl-6 + PD-L1 + cMYC + ) were also found in the circulation of HIV+ pre-NHL (cART-naïve) samples. Moreover, significantly elevated clusters of CD19 + CD24 hi CD38 hi cMYC + AICDA + B regulatory cells were identified in HIV+ pre-NHL (cART-naïve) compared to HIV+ cART-naïve samples. The present study identifies unique B-cell subsets in PLWH with potential pre-malignant features that may contribute to the development of pre-tumor B cells in PLWH and that may play a role in lymphomagenesis.
Journal Article
The Incidence and Correlates of Symptomatic and Asymptomatic Chlamydia trachomatis and Neisseria gonorrhoeae Infections in Selected Populations in Five Countries
Background: Asymptomatic Chlamydia trachomatis (chlamydia) and Neisseria gonorrhoeae (gonorrhea) infections pose diagnostic and control problems in developing countries. Methods: Participants in China, India, Peru, Russia, and Zimbabwe were screened for C. trachomatis and N. gonorrhoeae infections and symptoms. Results: A total of 18,014 participants were evaluated at baseline, 15,054 at 12 months, and 14,243 at 24 months. The incidence of chlamydia in men was 2.0 per 100 person years both from baseline to 12 months and from 12 to 24 months, and in women, 4.6 from baseline to 12 months and 3.6 from 12 to 24 months; a range of 31.2% to 100% reported no symptoms across the 5 countries. The incidence of gonorrhea in men was 0.3 per 100 person years both from baseline to 12 months and from 12 to 24 months, and in women, 1.4 from baseline to 12 months and 1.1 from 12 to 24 months; a range of 66.7% to 100% reported no symptoms. Being female, aged 18 to 24 years, and having more than 1 partner were associated with both the infections. In addition, being divorced, separated, or widowed was associated with gonorrhea. Being male, having 6+ years of education, and reporting only 1 partner were associated with having no symptoms among those infected with chlamydia. No variables correlated with asymptomatic gonorrhea among those infected. Conclusion: A high prevalence and incidence of asymptomatic sexually transmitted infections was identified among men and women in a wide variety of settings. More effective programs are needed to identify and treat chlamydia and gonorrhea infections, especially among women, young adults, those with multiple partners, those repeatedly infected, and particularly those at risk without symptoms. The risk of transmission from persons with no symptoms requires further study.
Journal Article
Greater ambient air pollution exposure is associated with worse respiratory symptoms in men and women with HIV and chronic lung disease: a cohort study
Background
COPD and impairment in diffusing capacity for carbon monoxide (DLCO) are common comorbidities in people with HIV (PWH). HIV may increase susceptibility to inhaled toxins including air pollution. In PWH and people without HIV (PWoH), we investigated whether air pollution exposure was associated with within-group differences in lung function or respiratory symptoms, and whether these associations differed by HIV serostatus or the presence of underlying lung disease.
Methods
We analyzed cross-sectional data from the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS), including participants with pulmonary function tests and accompanying standardized respiratory questionnaires in 2017–2020. The participants were linked to fine particulate matter (PM
2.5
) and ozone exposure data. Associations between exposures and respiratory outcomes were quantified with regression models. Two subgroup analyses were conducted, restricting to individuals with COPD (FEV
1
/FVC ratio < 0.7) or impaired DLCO (< 80% predicted).
Results
338 MACS participants and 1073 WIHS participants were included. Overall, there were no significant associations between pollution exposures and either lung function or respiratory symptoms. In PWH with COPD, 1 µg/m
3
greater exposure to PM
2.5
was associated with worse St. George’s Respiratory Questionnaire (SGRQ) score (4.04 points; 95% CI 0.36–7.72) and worse modified Medical Research Council (mMRC) dyspnea score (0.28 points; 95% CI 0.02–0.53). In PWH with impaired DLCO, 1 µg/m
3
greater PM
2.5
exposure was associated with worse SGRQ (2.14 points, 95% CI 0.2–4.08) and mMRC (0.16 points, 95% CI 0.02–0.29). There were no significant associations between PM
2.5
and respiratory symptoms in PWoH with COPD or impaired DLCO. Ozone exposure was not associated with respiratory symptoms in PWH or PWoH.
Conclusions
PM
2.5
exposure may act synergistically with HIV infection to worsen respiratory symptoms in people with chronic lung disease. Further study is needed to determine if air pollution leads to decline in lung function in PWH.
Journal Article
Spatial distribution of tuberculosis incidence in Los Angeles County
Background
In Los Angeles County, the tuberculosis (TB) disease incidence rate is seven times higher among non-U.S.-born persons than U.S.-born persons and varies by country of birth. But translating these findings into public health action requires more granular information, especially considering that Los Angeles County is more than 4000 mile
2
. Local public health authorities may benefit from data on which areas of the county are most affected, yet these data remain largely unreported in part because of limitations of sparse data. We aimed to describe the spatial distribution of TB disease incidence in Los Angeles County while addressing challenges arising from sparse data and accounting for known cofactors.
Methods
Data on 5447 TB cases from Los Angeles County were combined with stratified population estimates available from the 2005–2011 Public Use Microdata Survey. TB disease incidence rates stratified by country of birth and Public Use Microdata Area were calculated and spatial smoothing was applied using a conditional autoregressive model. We used Bayesian Poisson models to investigate spatial patterns adjusting for age, sex, country of birth and years since initial arrival in the U.S.
Results
There were notable differences in the crude and spatially-smoothed maps of TB disease rates for high-risk subgroups, namely persons born in Mexico, Vietnam or the Philippines. Spatially-smoothed maps showed areas of high incidence in downtown Los Angeles and surrounding areas for persons born in the Philippines or Vietnam. Areas of high incidence were more dispersed for persons born in Mexico. Adjusted models suggested that the spatial distribution of TB disease could not be fully explained using age, sex, country of birth and years since initial arrival.
Conclusions
This study highlights areas of high TB incidence within Los Angeles County both for U.S.-born cases and for cases born in Mexico, Vietnam or the Philippines. It also highlights areas that had high incidence rates even when accounting for non-spatial error and country of birth, age, sex, and years since initial arrival in the U.S. Information on spatial distribution provided here complements other descriptions of local disease burden and may help focus ongoing efforts to scale up testing for TB infection and treatment among high-risk subgroups.
Journal Article
Extracellular vesicles as biomarkers for AIDS-associated non-Hodgkin lymphoma risk
Extracellular vesicles are membrane-bound structures secreted into the extracellular milieu by cells and can carry bioactive molecules. There is emerging evidence suggesting that EVs play a role in the diagnosis, treatment, and prognosis of certain cancers. In this study, we investigate the association of EVs bearing PD-L1 and molecules important in B-cell activation and differentiation with AIDS-NHL risk.
EVs were isolated from archived serum collected prior to the diagnosis of AIDS-NHL in cases (N = 51) and matched HIV+ controls (N = 52) who were men enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Serum specimens of AIDS-NHL cases were collected at a mean time of 1.25 years (range of 2 to 36 months) prior to an AIDS-NHL diagnosis. The expression of PD-L1 and other molecules on EVs (CD40, CD40L, TNF-RII, IL-6Rα, B7-H3, ICAM-1, and FasL) were quantified by Luminex multiplex assay.
We observed significantly higher levels of EVs bearing PD-L1, CD40, TNF-RII and/or IL-6Rα in AIDS-NHL cases compared with controls. Using multivariate conditional logistic regression models adjusted for age and CD4
T-cell count, we found that EVs bearing PD-L1 (OR = 1.93; 95% CI: 1.10 - 3.38), CD40 (OR = 1.97, 95% CI: 1.09 - 3.58), TNF-RII (OR = 5.06; 95% CI: 1.99 - 12.85) and/or IL-6Rα (OR = 4.67; 95% CI: 1.40 - 15.53) were significantly and positively associated with AIDS-NHL risk. In addition, EVs bearing these molecules were significantly and positively associated with non-CNS lymphoma: PD-L1 (OR = 1.94; 95% CI: 1.01 - 3.72); CD40 (OR = 2.66; 95% CI: 1.12 - 6.35); TNF-RII (OR = 9.64; 95% CI: 2.52 - 36.86); IL-6Rα (OR = 8.34; 95% CI: 1.73 - 40.15). These findings suggest that EVs bearing PD-L1, CD40, TNF-RII and/or IL-6Rα could serve as biomarkers for the early detection of NHL in PLWH.
Journal Article