Dr
Alex Kayongo
Current Organisation
Makerere University College of Health Sciences
Current Job Title
Immunology Research Fellow
Biography
Publications
24-hour ambulatory blood pressure monitoring and hypertension related risk among HIV-positive and HIV-negative individuals: cross sectional study findings from rural Uganda
As urbanization increases in low- and middle-income countries (LMICs), urban populations will be increasingly exposed to a range of environmental risk factors for non-communicable diseases. Inadequate living conditions in urban settings may influence mechanisms that regulate gene expression, leading to the development of non-communicable respiratory diseases. We conducted a systematic review of the literature to assess the relationship between respiratory health and epigenetic factors to urban environmental exposures observed in LMICs using MEDLINE, PubMed, EMBASE, and Google Scholar searching a combination of the terms: epigenetics, chronic respiratory diseases (CRDs), lung development, chronic obstructive airway disease, and asthma. A total of 2835 articles were obtained, and 48 articles were included in this review. We found that environmental factors during early development are related to epigenetic effects that may be associated with a higher risk of CRDs. Epigenetic dysregulation of gene expression of the histone deacetylase (HDAC) and histone acetyltransferase gene families was likely involved in lung health of slum dwellers. Respiratory-related environmental exposures influence HDAC function and deoxyribonucleic acid methylation and are important risk factors in the development of CRD. Additional epigenetic research is needed to improve our understanding of associations between environmental exposures and non-communicable respiratory diseases.
Abstract Background: World over, there are antiretroviral therapy naïve individuals infected with HIV who maintain their CD4+T cell count above 500 cells/μl over 7-10 years and viral loads well controlled below undetectable levels (termed elite controllers, ECs) or at least 2,000 copies/mL (termed viremic controllers, VCs) for at least 12 months. Mechanisms responsible for HIV control in these individuals have not been fully elucidated. We hypothesized that CD4+T cells from elite and viremic controllers are naturally resistant to HIV-1 infection by blocking R5-tropic viral entry. We conducted a case-controlled study in which archived peripheral blood from 31 ECs/VCs and 15 progressors were investigated using in vitro HIV-1 infectivity assays. Results: Briey, we puried CD4+T cells from peripheral blood using EasySep CD4+ positive selection kit followed by CD4+T cell activation using IL-2, anti-CD28 and anti-CD3. Three days post-activation, CD4+T cells were spinoculated and co-cultured with vesicular stomatitis virus G (VSV-G)-pseudotyped HIV, R5 (ADA-enveloped)- and X4 (NL4.3-enveloped v)-tropic HIV-1. Three days post infection, we quantied and compared the percentage infection of CD4+T cells in cases and controls. We demonstrate that a subgroup of Ugandan elite and viremic controllers possess CD4+T cells that are specically resistant to R5-tropic virus, remaining fully susceptible to X4-tropic virus. Conclusion: Our study suggests that a subgroup of Ugandan elite and viremic controllers naturally control HIV-1 infection by blocking R5-tropic viral entry. Further research is needed to explore mechanisms of HIV control in the African population
Abstract Introduction: The association between HIV status and hypertension is not well described within sub-Saharan Africa. We examined prevalence and risk factors for hypertension among HIV positive and negative individuals living in a rural district of Uganda. Methods: We conducted a cross-sectional analysis in two concurrent cohorts of 600 HIV negative and 721 HIV seropositive individuals aged ≥35 years. Results: Of the 721 HIV positive participants, 59.8% were women and the median age was 44.3 years, while for HIV negative individuals, 55% were women and the median age was 47.8 years. Over 90% of HIV positive individuals were on antiretroviral treatment. The prevalence of hypertension (≥140/≥90 mmHg) was 33.5% in HIV negative individuals and 23.9% in HIV positive individuals. Age (adjusted OR = 1.05, 95% CI 1.03 to 1.06) and BMI (adjusted OR = 1.08, 95% CI 1.05 to 1.12) were associated with higher odds of hypertension. Having HIV was associated with lower odds of hypertension (adjusted OR = 0.66, 95% CI 0.50 to 0.88), lower systolic blood pressure (–5.1 mmHg, 95% CI: –7.4 to –2.4) and lower diastolic blood pressure (–4.0 mmHg, 95% CI: –5.6 to –2.5). We did not observe differences in the odds of hypertension by CD4 count, viral load or ART among HIV positive individuals in this sample. Conclusions: Hypertension was prevalent in one third of HIV negative individuals and in one fourth of HIV positive patients. While access to health information among individuals attending HIV clinics may explain observed differences, more research is needed to understand plausible biological and social mechanisms that could explain lower blood pressure among people living with HIV in Uganda.
Abstract An update of the International Primary Care Respiratory Group (IPCRG) Research Needs Statement is currently being undertaken using an e-Delphi method. The aim of this analysis is to identify the main respiratory research themes from the perspective of primary care practitioners worldwide. Participants were recruited via the IPCRG network of 34 member countries. An initial open questionnaire elicited participants’ views on the most important respiratory conditions seen in their daily practice and invited suggestions of 5-10 relevant research questions within these conditions in the following domains: diagnosis, management, monitoring, self-management and prognosis. Using thematic qualitative analysis we identified the main cross-cutting research themes. 112 participants (69% physicians, 10% nurses, 21% other, 64% had special interest in respiratory) from 27 countries responded with 608 suggested research questions. Asthma was reported as the most clinically important condition (25.7%) followed by COPD (24.5%) and URTI (5.8%). Five themes emerged from the thematic analysis: uncertainties about diagnosis/management of respiratory conditions; need for contextually relevant and accessible guidance; need for methods to improve patient empowerment and self-management; role of the wider healthcare team; need for simple point-of-care tests. The eDelphi method is successful in identifying relevant research questions and the main themes pertinent to primary care worldwide. These research questions now need to be prioritised for investigation by the international community.
BACKGROUND:Tripartite Motif Containing 5 alpha (TRIM5α), a restriction factor produced ubiquitously in cells and tissues of the body plays an important role in the immune response against HIV. TRIM5α targets the HIV capsid for proteosomal destruction. Cyclophilin A, an intracellular protein has also been reported to influence HIV infectivity in a cell-specific manner. Accordingly, variations in TRIM5α and Cyclophilin A genes have been documented to influence HIV-1 disease progression. However, these variations have not been documented among Elite controllers in Uganda and whether they play a role in viral suppression remains largely undocumented. Our study focused on identifying the variations in TRIM5α and Cyclophilin A genes among HIV-1 Elite controllers and non-controllers in Uganda. RESULTS:From the sequence analysis, the rs10838525 G > A mutation in exon 2 of TRIM5α was only found among elite controllers (30%) while the rs3824949 in the 5'UTR was seen among 25% of the non-controllers. In the Cyclophilin A promoter, rs6850 was seen among 62.5% of the non-controllers and only among 10% elite controllers. Furthermore, rs17860048 in the Cyclophillin A promoter was predominantly seen among elite controllers (30%) and 12.5% non-controllers. From gene expression analysis, we noted that the respective genes were generally elevated among elite controllers, however, this difference was not statistically significant (TRIM5α p = 0.6095; Cyclophilin A p = 0.6389). CONCLUSION:Variations in TRIM5α and Cyclophillin A promoter may influence HIV viral suppression. The rs10838525 SNP in TRIM5α may contribute to viral suppression among HIV-1 elite controllers. The rs6850 in the cyclophillin A gene may be responsible for HIV-1 rapid progression among HIV-1 non-controllers. These SNPs should be investigated mechanistically to determine their precise role in HIV-1 viral suppression.
In Sub-Saharan Africa, COPD remains prevalent but its association with HIV is not well characterized especially in rural settings. We assessed for COPD prevalence, associated factors and lung function profile among HIV-infected individuals attending ART clinics in rural Nakaseke district of Uganda. We enrolled HIV-positive participants from four HIV treatment centers in rural Uganda. Participants underwent spirometry testing following standard guidelines. We defined COPD as a post-bronchodilator FEV1/FVC ratio less than the fifth percentile of the NHANES III African-American reference. We assessed for factors associated with COPD and lung function profiles using multivariable logistic and linear regression analyses. We analyzed data from 722 HIV-positive participants (mean age 48.0 years, 59.7% women). Over 90% of participants were on ART for a median duration of 4 years (IQR 2-7 years), with a median viral load of 0 copies/mL (IQR 0-0 copies/mL), current and baseline CD4 + T cell count of 478 cells/mm3 (IQR 346-663 cells/mm3) and 335 cells/mm3 (IQR 187-523 cells/mm3) respectively. The prevalence of COPD was 6.22%. COPD was associated with worse respiratory symptoms and health status. History of pulmonary tuberculosis was strongly associated with COPD (adjusted OR = 4.92, 95% CI 1.71 to 14.15, p = 0.003) and reduced lung function. Use of ART, CD4+T cell count and viral load were not associated with COPD or reduced lung function. In conclusion, we report a COPD prevalence of 6.22% in HIV-infected individuals in rural Uganda. Pulmonary tuberculosis remains the strongest predictor of COPD risk and reduced lung function in well-controlled HIV.
Abstract Background Pulmonary tuberculosis (TB) is the leading infectious cause of death globally with an estimated 1.7 billion people currently infected with Mycobacterium tuberculosis and at risk of developing TB. While the treatment of drug-susceptible pulmonary TB is highly effective, up to 50% of TB survivors have varying degrees of residual pathological and functional conditions potentially leading to chronic sequelae. Post-TB patients have reported respiratory symptoms, reduced quality of life, and increased risk of mortality. The objectives of this study are to describe the prevalence and lung function in individuals with post-TB exposure status in Uganda. Methods We performed a secondary data analysis of the Lung Function in Nakaseke and Kampala (LiNK) study, which is a population-based cohort in urban and rural settings in Uganda. Trained fieldworkers randomly selected homes and administered standard questionnaires to adults 35 years or older that were full-time residents of each setting. Prior TB diagnosis and treatment was self-reported by participants. Results Among the study population (N = 1559), 50 participants (3.2%) self-reported successfully treated TB. Among this subset of participants 21 (42.0%) were HIV positive, 9 (18.0%) were ever smokers, 6 (12.0%) were current smokers, and no participants had a prior COPD diagnosis. Mean (SD) age and body-mass index (BMI) at enrollment was 48.5 (SD 10.7) years and 22.2 (SD 3.9) kg/m2 respectively. The mean ± SD pre-bronchodilator FEV1/FVC was 72.9% (12.1%) for patients with successfully treated TB and 79.6% (0.08%) (p< 0.0001) for those without prior TB. Within these groups, 30% of patients with successfully treated TB and 9% of patients without prior TB had an FEV1/FVC suggestive of possible COPD.
RATIONALE:Detailed data on the characteristics and outcomes of patients with COVID-19 in sub-Saharan Africa are limited. OBJECTIVE:We determined the clinical characteristics and treatment outcomes of patients diagnosed with COVID-19 in Uganda. MEASUREMENTS:As of the 16 May 2020, a total of 203 cases had been confirmed. We report on the first 56 patients; 29 received hydroxychloroquine (HCQ) and 27 did not. Endpoints included admission to intensive care, mechanical ventilation or death during hospitalisation. MAIN RESULTS:The median age was 34.2 years; 67.9% were male; and 14.6% were <18 years. Up 57.1% of the patients were asymptomatic. The most common symptoms were fever (21.4%), cough (19.6%), rhinorrhea (16.1%), headache (12.5%), muscle ache (7.1%) and fatigue (7.1%). Rates of comorbidities were 10.7% (pre-existing hypertension), 10.7% (diabetes) and 7.1% (HIV), Body Mass Index (BMI) of ≥30 36.6%. 37.0% had a blood pressure (BP) of >130/90 mm Hg, and 27.8% had BP of >140/90 mm Hg. Laboratory derangements were leucopenia (10.6%), lymphopenia (11.1%) and thrombocytopenia (26.3%). Abnormal chest X-ray was observed in 14.3%. No patients reached the primary endpoint. Time to clinical recovery was shorter among patients who received HCQ, but this difference did not reach statistical significance. CONCLUSION:Most of the patients with COVID-19 presented with mild disease and exhibited a clinical trajectory not similar to other countries. Outcomes did not differ by HCQ treatment status in line with other concluded studies on the benefit of using HCQ in the treatment of COVID-19.
Project Title
Microbiome fuels Th17 mediated airway inflammation in COPD among HIV-infected individuals
EDCTP Project
TMA2020CDF-3194
EDCTP Program
EDCTP2
EDCTP Project Call
Career Development Fellowship (CDF)
Host Organisation
| Department | Institution | Country |
|---|---|---|
| College of Health Sciences | Makerere University | UG |
Project Objectives
To establish a relationship between airway microbiome and Th17/Treg cellular phenotypes among HIV- infected individuals with COPD. To investigate bacterial mediated Th17 upregulation of pro-inflammatory genes among HIV-infected individuals with COPD To investigate the role of bacterial outer membrane vesicles (OMVs) in mediating dysbiosis driven Th17 immune responses among HIV individuals.
Study Design
Case-controlled study
Project Summary
Chronic obstructive pulmonary disease (COPD) is increasing in prevalence among people living with HIV/AIDS (PLWHA) as the widespread use of ART has increased longevity in this population. Currently, it’s not fully known what drives chronic lung inflammation in PLWH despite being virologically suppressed on ART. There is a need to explore factors driving chronic airway inflammation among PLWHA. The airway microbiome has been implicated in the pathogenesis of COPD. Preliminary analysis from our study revealed that specific microbes were significantly enriched in PLWHA with COPD with more lung bacteria impacted by HIV than COPD. These findings suggest that HIV-associated changes in unique airway microbial genera may be driving COPD among PLWHA in our cohort. Currently, we don’t know how such genera drive chronic airway inflammation. We broadly aimed at investigating the airway microbiome-immune crosstalk among HIV-infected individuals diagnosed with COPD in a rural Ugandan population. Specifically, we investigated for Th17-mediated airway inflammation driven by the airway microbiome in COPD. We conducted a detailed airway microbiome-immune profiling of a Ugandan COPD cohort using high dimensional mass flow cytometry combined with 16S rRNA amplicon sequencing, microbiome-derived OMV assay and airway transcriptomic profiling. We identify broad immune profiles across a COPD population in rural Uganda. Interestingly, a reduction in microbiome richness and evenness significantly correlated with a high frequency of double negative T cells (thymocytes), naïve helper T cells, mucosal homing effector T, and Natural Killer cells. Using a confounder-aware algorithm for biomarker search, we summarized the effect size of the top microbiome signatures on immune phenotypes. Among these, Streptococcus spp significantly affected the proportions of Th17 and NKT immune cells. Enrichment with Streptococcal spp was associated with increased Th17-like immune cells. On the contrary, depletion of Streptococcal spp was associated with increased NKT cell response. In conclusion, the airway-microbiome immune crosstalk in a Ugandan COPD cohort was driven by Streptococcus, associated with Th17 and NKT cell immune responses. Further interrogation of induced sputum transcriptomic profile in relation to the airway 16SrRNA amplicon sequence data illuminated the relationship between the airway microbiome and the mucosal immune responses in a rural Ugandan HIV-COPD cohort. Pro-inflammatory gene signatures, ccl4, ccl3, ilr1, irak2, cxcl2, hivep2, ccl3l3, cxcl8, ccl4l2, rel, and cxcl9 enriched the airways of a COPD population and positively correlated with microbiome-derived outer membrane vesicles, a marker of live bacterial biomass. Depletion of keystone species or enrichment of specific pathobionts in the airways drove a pro-inflammatory gene signature expression, an effect possibly driven by microbiome-derived outer membrane vesicles (OMVs) signaling via TLRs to activate the NF-kB and chemokine signaling pathways.