Browsing by Author "Thobakgale, Christina Fanesa."

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CD8+ T cell breadth and ex vivo virus inhibition capacity distinguish between viremic controllers with and without protective HLA class I alleles.
(American Society for Microbiology., 2016) Koofhethile, Catherine Kegakilwe.; Ndhlovu, Zaza Mtine.; Thobakgale, Christina Fanesa.; Prado, Julia G.; Ismail, Nasreen.; Mncube, Zenele.; Mkhize, Lungile.; Van der Stok, Mary Elizabeth.; Yende-Zuma, Fortunate Nonhlanhla.; Walker, Bruce D.; Goulder, Philip Jeremy Renshaw.; Ndung'u, Peter Thumbi.
Abstract available in PDF file.
HIV-specific CD8+ T cell responses in infected infacts enrolled on a study of early highly active antiretroviral treatment (HAART) and supervised treatment interruption (STI).
(2011) Thobakgale, Christina Fanesa.; Kiepiela, Photini.; Ndung'u, Peter Thumbi.; Goulder, Philip Jeremy Renshaw.
The manifestation of HIV-1 infection is different in children and adults. Most of the children who acquire HIV perinatally progress to disease within the first two years of life, while adults can remain asymptomatic for up to ten years. However, a small minority group of children can control the virus for years in the absence of antiretroviral therapy. We characterized CD8+ T cell responses critical for the containment of HIV infection in a cohort of infants HIV infected from birth using IFN- γ ELISPOT, multicolour flow cytometry and viral sequencing of the Gag protein. We investigated whether the age at the time of infection, specificity and functionality of the generated responses, genetic make up and the maternal immune responses to HIV, influenced disease progression in the child. We found that the majority of in-utero infected infants mounted CD8+ T cell responses from the first days of life. In contrast to chronically infected children or adults, the specificity of the initial response in acutely infected infants was directed towards Env and Rev proteins and CD4+ T cell responses were minimal during the first 6 months of life. Slow progression to disease was associated with possession of one of the protective HLA-B alleles by either the mother or the child (P=0.007) and targeting of Gag epitopes presented by the protective HLA-B alleles. Mothers who expressed protective alleles but whose children did not possess these alleles, transmitted less fit viruses that benefited their children. Furthermore, slow progressor children had more polyfunctional CD8+ T cell responses in early infection when compared to rapid progressors (P=0.05). The ability of infants to induce CD8+ T cell responses early in life is encouraging for vaccine interventions. The differences in the specificity of the initial responses between adults and children, insufficient priming of these responses as a result of minimal CD4+ T cell help during infancy and possession of non-protective HLA alleles shared between mother and child, may explain the rapid disease progression generally noted in most infants. However, slow progression to disease in the minority group of children may be attributed to functional capacity of the CD8+ T cells generated by the child, mediation by protective HLA alleles, acquisition of low fitness viruses from the mother or de novo attenuation of the virus by the child’s own immune responses.
The interaction between nutrition, immunity and coinfections with human immunodeficiency virus and intestinal parasites in South African adults: investigating the use of prealbumin as a tool for nutritional assessment.
(2019) Mkhize, Brenda Thabisile.; Mkhize-Kwitshana, Zilungile Lynette.; Thobakgale, Christina Fanesa.
Highly prevalent HIV and helminth single infections continue to plague a significant proportion of the South African population. The geographic overlap of these infections lands to the expectation that high prevalence of co-infection with HIV and intestinal helminths exists, although this data for the South African adult population is lacking. Each of these single infections has an impact on the immune system, resulting in impaired responses due to the chronic activation. Also, both infections have an impact on the nutritional status, which may affect the potency of the immune responses, further compromising the immunity. A potent immune system requires adequate nutrition. Obesity, a form of malnutrition may mask micro- and macronutrient deficiency. Furthermore, obesity may result in low-grade inflammation, which may result is dysregulated responses. Therefore, malnutrition may start a cyclical process that may further predispose to infection, which in turn may result in malnutrition, where the cause-and-effect thread between malnutrition, infection and immune deficiency is indiscernible. Based on this, it was hypothesized that the HIV-intestinal helminth co-infection may have a deleterious effect on the nutrition and immunity of affected individuals, which may accelerate HIV progression. Thus, the aim of the study was to investigate the interaction between HIV and intestinal helminth single and co-infection with nutrition and immunity in an adult population (n = 263) in KwaZulu-Natal, a province with high prevalence of both HIV and intestinal helminths infections. The study expected to find an association between the co-infection with lower micro- and macro-nutrient levels, higher HIV viral load, increased immune activation, increased gene expression of Th2 and Treg cytokine responses and decreased Th1 cytokine responses compared to those singly infected and those uninfected with HIV and intestinal helminths. However, the study found no significant association between HIV and intestinal helminth single or co-infection with micro- and macronutrient deficiency, although a general pattern of low intake of the nutrients was noted among the investigated cohort, who had a substantial proportion being overweight and obese. Difficulty in the assessment of nutritional status in the milieu of HIV and intestinal helminth co-infection, obesity and inflammation was noted. Furthermore, HIV-intestinal helminth co-infection was associated with an antiviral cytokine response profile of highly expressed IFN-γ and TNF-α cytokine genes and reduced viral load. The co-infected individuals with the IgEhiIgG4hi intestinal helminth infection phenotype had a compromised immune profile of low CD4 counts. We recommend that antihelminthic interventions are included in the HIV management programmes, particularly in adults.
Interleukin 1-Beta (IL-1β) production by innate cells following TLR stimulation correlates with TB recurrence in art-treated HIV-infected patients.
(Wolters Kluwer Health., 2017) Thobakgale, Christina Fanesa.; Naidoo, Kewreshini Kasturi.; McKinnon, Lyle R.; Werner, Lise.; Samsunder, Natasha.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.; Altfeld, Marcus.; Naidoo, Kogieleum.
Abstract available.
Protective HLA class I alleles : investigation of viral control and lack of control in chronic HIV-1 subtype C infection.
(2015) Koofhethile, Catherine Kegakilwe.; Ndung'u, Peter Thumbi.; Thobakgale, Christina Fanesa.
Abstract available in PDF file.
Sex differences in the Kinetics of immune reconstitution under antiretroviral therapy.
(2017) Mazibuko, Noluthando Y.; Thobakgale, Christina Fanesa.; Ndung'u, Peter Thumbi.
The human immunodeficiency virus type 1 (HIV-1) remains a global health threat and is increasingly becoming a female epidemic due to gender inequalities. The introduction of antiretroviral therapy (ART) has greatly increased the life span while reducing AIDS-related deaths in HIV-1-infected people. However, some patients experience adverse effects during ART due to an acute inflammatory response termed immune reconstitution inflammatory syndrome (IRIS), which is a paradoxical clinical worsening upon initiation of ART that is thought to be due to a hyperactive or uncontrolled immune restoration. Studies have shown that females infected with HIV-1 elicit a stronger immune response and faster disease progression compared to men with the same viral load. Given the above mentioned higher baseline levels of immune activation in HIV-1 infected females, we hypothesized that immune restoration during ART will have significant sex-based differential outcomes. The aim of this project was to understand the impact of immune reconstitution in HIV-1-infected men and women during ART by investigating antigen presenting cells (monocytes, myeloid dendritic cells (mDCs) and plasmacytoid dendritic (pDCs) cells) phenotype and function. In total, we investigated cryopreserved samples from eleven HIV-1-infected males and thirteen HIV-1-infected females from which peripheral blood mononuclear cells (PBMCs) and plasma samples were longitudinally collected at defined time points, including before the initiation of ART (TP01), after 1-4 months (TP02) and after 5-8 months of treatment initiation. Changes in toll-like receptor (TLR) responsiveness were analyzed following stimulation with the following toll-like receptor (TLR) ligands: TLR4 ligand Lipopolysaccharide, TLR7/8 ligand CL097, and the TLR9 ligand ODN2216/ CpG. Multiparameter flow cytometry was used to analyze the cytokine production upon TLR stimulation as well as the level of immune activation by analyzing phenotypic characteristics of antigen-presenting cells including monocytes subsets. In addition, multiplex analysis was used to determine levels of plasma pro-inflammatory cytokines (IFN-ɣ, IFN-α, IL-1β, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, TNF-α, IL-12p70, GM-CSF, MIP-1β and IP-10), in males and females at all time-points. Our results show that the expression of immune activation markers (measured by HLA-DR+ and CD38+ on T cells) did not significantly differ between males and females, although females showed elevated levels of both activated CD8+ and CD4+ T cells at baseline, the activation levels decreased upon ART initiation. Furthermore, our results demonstrated an increase in the proportion of classical monocytes (CD14++CD16-) in females compared to males at baseline (p=0.03). We did not observe any significant differences in the percentage of intermediate (CD14++CD16+) and non-classical monocytes (CD14+CD16++) between males and females at any time point analyzed. Similarly, no sex differences were evident after TLR ligand stimulation on monocytes in terms of cytokines measured (IFN-α, TNF-α, MIP-1β and IL-12). Interestingly, upon TLR9 stimulation, a significantly higher percentage of pDCs from females produced IFN-α (p=0.001, TP03), MIP-1β (p=0.001, at TP02) and TNF-α (p˂0.01, p˂0.001, TP02 and TP03 respectively) during ART compared to males. In addition, females had increased IFN-α (p=0.01) and TNF-α (p=0.004) production on pDCs during ART compared to baseline following TLR9 stimulation. Taken together, our data suggest sex-specific differences in the level of immune reconstitution during ART, as females show signs of elevated immune response and inflammation compared to males Therefore, these findings may provide a basis for future studies in larger cohorts aimed at adapting ART therapy based on sex differences in disease progression rates in men and women.