Department of Microbiology/Immunology

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Browsing Department of Microbiology/Immunology by Author "Chachage, Mkunde"

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    Altered Lipid Profiles and Vaccine Induced-Humoral Responses in Children Living With HIV on Antiretroviral Therapy in Tanzania
    (Frontiers Media S.A., 2021-11-09) Mbuya, Wilbert; Mwakyula, Issakwisa; Olomi, Willyelimina; Agrea, Peter; Nicoli, Francesco; Ngatunga, Cecilia; Mujwahuzi, Leodegard; Mwanyika, Paul; Chachage, Mkunde
    People living with HIV, even under therapy, have a high burden of age-related co-morbidities including an increased risk of dyslipidemia (which often predisposes to cardiovascular diseases) and immune-aging. In this study, lipid profiles and antibody responses to measles and pertussis toxin vaccines were compared between ART experienced HIV+ children (n=64) aged 5-10 years, and their age- and sex-matched HIV- controls (n=47). Prevalence of high-density lipoprotein cholesterol (HDL-c) and triglyceride-driven dyslipidemia was higher among treated HIV+ children than in controls (51.6% vs 27.7% respectively, p < 0.019). In a multivariate Poisson regression model adjusted for age, sex and BMI, the association between low HDL-c, hypertriglyceridemia and HIV remained significantly high (for HDL-c: ARR: 0.89, 95% CI: 0.82 – 0.96, p = 0.003; for triglycerides: ARR: 1.54, 95% CI: 1.31 – 1.81, p < 0.001). Among HIV+ children, the use of lopinavir/ritonavir, a protease-based antiretroviral therapy was also associated elevation of triglyceride levels (p = 0.032). Also, HIV+ children had a 2.8-fold reduction of anti-measles IgG titers and 17.1-fold reduction of anti-pertussis toxin IgG levels when compared to HIV- children. Our findings suggest that dyslipidemia and inadequate vaccine-induced antibody responses observed in this population of young African HIV+ children might increase their risk for premature onset of cardiovascular illnesses and acquisition of preventable diseases.
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    Depletion of Human Papilloma Virus E6- and E7-Oncoprotein-Specific T-Cell Responses in Women Living With HIV
    (Frontiers Media S.A., 2021-10-25) Mbuya, Wilbert; Mcharo, Ruby; Mhizde, Jacklina; Mnkai, Jonathan; Mahenge, Anifrid; Mwakatima, Maria; Mwalongo, Wolfram; Hoelscher, Michael; Saathoff, Elmar; Rwegoshora, France; Torres, Liset; Kroidl, Arne; Geldmacher, Christof; Held, Kathrin; Chachage, Mkunde; Sembo, Margareth; Haule, Antelmo; Maboko, Leonard; Geisenberger, Otto; Agrea, Peter; Koup, Richard A.
    Background: Cervical cancer - caused by persistent High Risk Human Papilloma Virus (HR HPV) infections - is the second most common cancer affecting women globally. HIV infection increases the risk for HPV persistence, associated disease progression and malignant cell transformation. We therefore hypothesized that this risk increase is directly linked to HIV infection associated dysfunction or depletion of HPV-oncoprotein-specific T-cell responses. Methods: The 2H study specifically included HIV+ and HIV- women with and without cervical lesions and cancer to analyze HPV oncogene-specific T cell responses in relation to HPV infection, cervical lesion status and HIV status. Oncoprotein E6 and E7 specific T-cell responses were quantified for the most relevant types HPV16, 18 and 45 and control antigens (CMV-pp65) and M.tb-PPD in 373 women, using fresh peripheral blood mononuclear cells in an IFN-γ release ELISpot assay. Results: Overall, systemic E6- and E7-oncoprotein-specific T-cell responses were infrequent and of low magnitude, when compared to CMV-pp65 and M.tb-PPD (p < 0.001 for all HR HPV types). Within HIV negative women infected with either HPV16, 18 or 45, HPV16 infected women had lowest frequency of autologous-type-E6/E7-specific T-cell responses (33%, 16/49), as compared to HPV18 (46% (6/13), p = 0.516) and HPV45 (69% (9/13), p = 0.026) infected women. Prevalent HPV18 and 45, but not HPV16 infections were linked to detectable oncoprotein-specific T-cell responses, and for these infections, HIV infection significantly diminished T-cell responses targeting the autologous infecting genotype. Within women living with HIV, low CD4 T-cell counts, detectable HIV viremia as well as cancerous and precancerous lesions were significantly associated with depletion of HPV oncoprotein-specific T-cell responses. Discussion: Depletion of HPV-oncoprotein-specific T-cell responses likely contributes to the increased risk for HR HPV persistence and associated cancerogenesis in women living with HIV. The low inherent immunogenicity of HPV16 oncoproteins may contribute to the exceptional potential for cancerogenesis associated with HPV16 infections.
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    Distinct Immune Profiles of Exhausted Effector and Memory CD8+ T Cells in Individuals With Filarial Lymphedema
    (Frontiers Media S.A., 2021-08-11) Horn, Sacha; Borrero-Wolff, Dennis; Ritter, Manuel; Arndts, Kathrin; Wiszniewsky, Anna; Debrah, Linda Batsa; Debrah, Alexander Y.; Osei-Mensah, Jubin; Chachage, Mkunde; Hoerauf, Achim; Kroidl, Inge; Layland, Laura E.
    CD8+ T cells are crucial for the clearance of viral infections, and current research begins to highlight their importance in parasitic diseases too. In-depth research about characteristics of CD8+ T-cell subsets and exhaustion remains uncertain, especially during filariasis, a chronic helminth infection. Lymphatic filariasis, elicited by Wuchereria bancrofti, remains a serious health problem in endemic areas in Ghana, especially in those suffering from morbidity due to lymphedema (LE). In this observational study, the characteristics and profiles of CD8+ T cells were compared between asymptomatic Wuchereria bancrofti-infected individuals, uninfected endemic normals, and those with LE (grades 2–6). Focusing on exhausted memory (CD8+exmem: CD8+ T-betdimEomeshi) and effector (CD8+exeff: CD8+T-bethiEomesdim) CD8+ T-cell subsets, advanced flow cytometry revealed that LE individuals presented reduced frequencies of IFN-γ+CD8+exmem T cells expressing Tim-3 or LAG-3 which negatively correlated to the presence of LE. Moreover, the LE cohort further showed significantly higher frequencies of IL-10+CD8+exeff T cells expressing either Tim-3, LAG-3, CD39, KLRG-1, or PD-1, all associated markers of exhaustion, and that these frequencies positively correlated with the presence of LE. In summary, this study shows that distinct exhausted CD8+ T-cell subsets are prominent in individuals suffering from LE, suggesting that enhanced inflammation and constant immune activation might drive exhaustion of CD8+ T cells. Since T-cell exhaustion is known to be associated with insufficient control of persisting antigen, the data presented here reveals that these CD8+ T-cell exhaustion patterns in filarial LE should be taken into consideration for prevention and control management of LE.
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    The gut-microbiome contribution to HIV-associated cardiovascular disease and metabolic disorders
    (Elsevier, 2021-12) Chachage, Mkunde
    During the past decade, there has been a great effort in characterizing the gut microbiome of individuals living with HIV and its influence on HIV-metabolic disorders. Herein, the current understanding of the changes in the composition and function of the gut microbiome in the context of HIV infection, cardiovascular disease, and HIV-associated metabolic disorders is reviewed. A focus is especially given to bacteria gut microbiome and their produced metabolites, including tryptophan, short-chain fatty acids, and trimethylamine-N-oxide, and discuss current literatures that have investigated their role in HIV pathogenesis and HIV metabolic disorders. This review finally calls for future studies to focus on interrogating the mechanism of host-gut microbiome interaction in relation to HIV and HIV comorbidities by using multiomics approaches and on geographically diverse populations.
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    HPV Type Distribution in HIV Positive and Negative Women With or Without Cervical Dysplasia or Cancer in East Africa
    (Frontiers Media S.A., 2021-11-30) Mcharo, Ruby; Lennemann, Tessa; France, John; Torres, Liset; Gari, Mercè; Mbuya, Wilbert; Mwalongo, Wolfram; Mahenge, Anifrid; Bauer, Asli; Mnkai, Jonathan; Glasmeyer, Laura; Judick, Mona; Paul, Matilda; Schroeder, Nicolas; Msomba, Bareke; Sembo, Magreth; Chiwerengo, Nhamo; Hoelscher, Michael; Geisenberger, Otto; Lelle, Ralph J.; Saathoff, Elmar; Maboko, Leonard; Chachage, Mkunde; Kroidl, Arne; Geldmacher, Christof
    Background: Women living with HIV in sub-Saharan Africa are at increased risk to develop cervical cancer (CC), which is caused by persistent infection with 13 oncogenic human papilloma viruses (HR-HPVs). It is important to accurately identify and target HIV-positive women at highest risk to develop CC for early therapeutic intervention. Methods: A total of 2,134 HIV+ and HIV− women from South-West Tanzania were prospectively screened for cervical cancer and precancerous lesions. Women with cervical cancer (n=236), high- and low-grade squamous intraepithelial lesions (HSIL: n=68, LSIL: n=74), and without lesion (n=426) underwent high-resolution HPV genotyping. Results: Eighty percent of women who were diagnosed with HSIL or LSIL were living with HIV. Any lesion, young age, HIV status, and depleted CD4 T cell counts were independent risk factors for HPV infections, which were predominantly caused by HR-HPV types. While multiple HR-HPV type infections were predominant in HIV+ women with HSIL, single-type infections predominated in HIV+ CC cases (p=0.0006). HPV16, 18, and 45 accounted for 85% (68/80) and 75% (82/110) of HIV+ and HIV− CC cases, respectively. Of note, HPV35, the most frequent HPV type in HSIL-positive women living with HIV, was rarely detected as a single-type infection in HSIL and cancer cases. Conclusion: HPV16, 18, and 45 should receive special attention for molecular diagnostic algorithms during CC prevention programs for HIV+ women from sub-Saharan Africa. HPV35 may have a high potential to induce HSIL in women living with HIV, but less potential to cause cervical cancer in single-type infections.