Browsing by Author "Walzl, Gerhard."

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Considerations for biomarker-targeted intervention strategies for tuberculosis disease prevention.
(Elsevier., 2018) Fiore-Gartland, Andrew.; Carpp, Lindsay N.; Naidoo, Kogieleum.; Thompson, Ethan.; Zak, Daniel E.; Self, Steven G.; Churchyard, Gavin J.; Walzl, Gerhard.; Penn-Nicholson, Adam.; Scriba, Thomas J.; Hatherill, Mark.
Abstract available in pdf.
Genital inflammation and the risk of HIV acquisition in women.
(Oxford University Press., 2015) Masson, Lindi.; Passmore, Jo-Ann Shelley.; Liebenberg, Lenine Julie.; Werner, Lise.; Baxter, Cheryl.; Arnold, Kelly B.; Williamson, Carolyn.; Little, Francesca.; Mansoor, Leila Essop.; Naranbhai, Vivek.; Lauffenburger, Douglas A.; Ronacher, Katharina.; Walzl, Gerhard.; Garrett, Nigel Joel.; Williams, Brent L.; Couto-Rodriguez, Mara.; Hornig, Mady.; Lipkin, Walter Ian.; Grobler, Anna Christina.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Abstract available in pdf.
Genital tract inflammation during early HIV-infection predicts higher plasma viral load set point in women.
(Oxford University Press., 2011) Roberts, Lindi.; Passmore, Jo-Ann Shelley.; Mlisana, Koleka Patience.; Williamson, Carolyn.; Little, Francesca.; Bebell, Lisa M.; Walzl, Gerhard.; Abrahams, Melissa-Rose.; Woodman, Zenda.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Background. The biggest challenge in human immunodeficiency virus type 1 (HIV-1) prevention in Africa is the high HIV-1 burden in young women. In macaques, proinflammatory cytokine production in the genital tract is necessary for target cell recruitment and establishment of simian immunodeficiency virus (SIV) infection following vaginal inoculation. The purpose of this study was to assess if genital inflammation during early HIV-1 infection predisposes women to rapid disease progression. Methods. Inflammatory cytokine concentrations were measured in cervicovaginal lavage (CVL) from 49 women 6, 17, 30, and 55 weeks after HIV-1 infection and from 22 of these women before infection. Associations between genital inflammation and viral load set point and blood CD4 cell counts 12 months after infection were investigated. Results. Elevated genital cytokine concentrations 6 and 17 weeks after HIV-1 infection were associated with higher viral load set points and, to a lesser extent, with CD4 depletion. CVL cytokine concentrations during early infection did not differ relative to preinfection but were elevated in women who had vaginal discharge, detectable HIV-1 RNA in their genital tracts, and lower blood CD4 counts. Conclusion. Genital inflammation during early HIV-1 infection was associated with higher viral load set point and CD4 depletion, which are markers of rapid disease progression. Strategies aimed at reducing genital inflammation during early HIV-1 infection may slow disease progression.
The influence of helminths on immune responses to HIV.
(2009) Mkhize-Kwitshana, Zilungile Lynette.; Walzl, Gerhard.; Taylor, Myra.
In South Africa, co-infection with HIV and intestinal parasites is a major challenge in disadvantaged communities who live in densely populated under-serviced urban informal settlements. This pilot cross sectional study evaluates the immunological effects of co-infection with Ascaris lumbricoides and Trichuris trichura on the immune response to HIV. The work was a substudy of a prospective double blind, placebo-controlled investigation to test whether regular deworming changes the immune profile of HIV positive individuals with concurrent helminth infection. The substudy has a cross sectional design and presents pilot data that defines immune profiles of HIV-1 positive individuals with and without gastrointestinal helminth (Ascaris lumbricoides and Trichuris trichura) infection. The hypothesis was that concurrent helminth infection adversely affects immune responses against HIV. It was conducted in an area of high helminth endemnicity and limited infrastructural resources. Individuals with known HIV infection were recruited from an HIV Support Group and HIV negative individuals residing in the same area (for demographic matching) were used for comparison. The substudy was to provide pilot data for future larger scale and possible interventional studies. The current work is limited by the cross sectional design, moderate sample size and practical challenges. The profile of lymphocyte phenotypes, viral loads, eosinophils, activation markers, expression of the nuclear proliferation antigen-Ki67 and activation regulator antigen CTLA-4 were analysed using flow cytometry in HIV positive and negative subgroups with or without helminth infection. The type-1, type-2 and inflammatory cytokines were analysed using multiplex cytokine array technology. These were correlated with immune responses to HIV. Non parametric statistics were used to describe differences in the variables between the subgroups. A major finding of the study was the result of the supplementary use of the serological marker, Ascaris lumbricoides-specific IgE in addition to the presence (or absence) of helminth eggs in stools to classify intestinal helminth infection status. Two significant outcomes of this measure were the enhancement of diagnosis of current or recent helminth infection and, more importantly, the distinction of different phenotypes of individuals who displayed different immunological responses to co-infection with HIV and helminths. The different helminth infection phenotypes are defined by stool egg positivity (egg⁺) or negativity (egg⁻) with either high or low Ascaris-specific IgE (IgEhi or IgElo) respectively. The four subgroups, egg⁺IgEhi, egg⁺IgElo, egg⁻IgEhi and egg⁻IgElo showed different interactions with regards to immune response to HIV. It should be noted that no Trichuris specific IgE tests are commercially available but that there is significant antigenic cross-reactivity with Ascaris antigen. The presence of helminth stool eggs and high Ascaris IgE (egg⁺IgEhi) was associated with the following characteristics: reduction in numbers of all lymphocyte populations, frequent eosinophilia, highly activated immune profiles, antigen specific proliferative hyporesponsiveness, impaired type 1 cytokine responses in unstimulated and antigen stimulated cells and increased TNFα levels. In HIV infected individuals, the egg⁺IgEhi helminth infection status was associated with lower but not significant CD4⁺ counts and higher viral loads. A strong negative correlation was observed between viral loads, CD4⁺ and CD8⁺ cells in this subgroup. Subgroups with high IgE (egg⁺IgEhi and egg⁻IgEhi) had elevated Th2 markers with lower CD4⁺ counts and higher viral loads in the HIV⁺ group. The inverse correlation between viral load and CD4⁺ counts found in all the HIV⁺ participants was strongest in these two subgroups. Individuals with parasite eggs in stool and low Ascaris IgE (egg⁺/IgElo) presented a modified Th2 profile. This subgroup had high absolute numbers of all lymphocyte subsets in both HIV⁻ and HIV⁺ groups with higher CD4⁺ counts in the HIV⁻ and lower viral load in the HIV⁺ groups as well as higher interferon gamma, lower IL-4 and higher IL-10. In conclusion, the results suggest that helminth infections may be associated with deleterious effects on the immune responses to HIV in certain groups of susceptible individuals. The underlying reasons for the different stool egg/Ascaris IgE combinations in settings with high exposure to helminthes is currently not clear but genetic predisposition and environmental factors could play a role. Future studies of helminth- HIV co-infection have to ensure adequate definition of helminth infection status by the use of both stool examination and measurement of helminth-specific IgE as the infection phenotype is associated with differential effects on HIV associated immune responses. This may also apply to co-infection with other pathogens, including tuberculosis. The long-term effect of helminth co-infection in HIV positive people was not assessed in this study but requires further studies.
Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression.
(Lippincott Williams & Wilkins., 2010) Roberts, Lindi.; Williamson, Carolyn.; Little, Francesca.; Bebell, Lisa M.; Mlisana, Koleka Patience.; Burgers, Wendy A.; Passmore, Jo-Ann Shelley.; van Loggerenberg, Francois.; Walzl, Gerhard.; Djoba Siawaya, Joel Fleury.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.
Background: Both T-cell activation during early HIV-1 infection and soluble markers of immune activation during chronic infection are predictive of HIV disease progression. Although the acute phase of HIV infection is associated with increased pro-inflammatory cytokine production, the relationship between cytokine concentrations and HIV pathogenesis is unknown. Objectives: To identify cytokine biomarkers measurable in plasma during acute HIV-1 infection that predict HIV disease progression. Design: Study including 40 South African women who became infected with HIV-1 and were followed longitudinally from the time of infection. Methods: The concentrations of 30 cytokines in plasma from women with acute HIV-1 infection were measured and associations between cytokine levels and both viral load set point 12 months postinfection and time taken for CD4 cell counts to fall below 350 cells/ul were determined using multivariate and Cox proportional hazards regression. Results: We found that the concentrations of five plasma cytokines, IL-12p40, IL-12p70, IFN-y, IL-7 and IL-15 in women with acute infection predicted 66% of the variation in viral load set point 12 months postinfection. IL-12p40, IL-12p70 and IFN-y were significantly associated with lower viral load, whereas IL-7 and IL-15 were associated with higher viral load. Plasma concentrations of IL-12p40 and granulocyte–macrophage colony-stimulating factor during acute infection were associated with maintenance of CD4 cell counts above 350 cells/ul, whereas IL-1a, eotaxin and IL-7 were associated with more rapid CD4 loss. Conclusion: A small panel of plasma cytokines during acute HIV-1 infection was predictive of long-term HIV disease prognosis in this group of South African women.
Symptomatic vaginal discharge is a poor predictor of sexually transmitted infections and genital tract inflammation in high-risk women in South Africa.
(Oxford University Press., 2011) Mlisana, Koleka Patience.; Naicker, Nivashnee.; Werner, Lise.; Roberts, Lindi.; van Loggerenberg, Francois.; Baxter, Cheryl.; Passmore, Jo-Ann Shelley.; Grobler, Anna Christina.; Sturm, Adriaan Willem.; Williamson, Carolyn.; Ronacher, Katharina.; Walzl, Gerhard.; Abdool Karim, Salim Safurdeen.
Background. Diagnosis and treatment of sexually transmitted infections (STIs) is a public health priority, particularly in regions where the incidence of human immunodeficiency virus (HIV) infection is high. In most developing countries, STIs are managed syndromically. We assessed the adequacy of syndromic diagnosis of STIs, compared with laboratory diagnosis of STIs, and evaluated the association between STI diagnosis and the risk of HIV acquisition in a cohort of high-risk women. Methods. HIV-uninfected high-risk women (n = 242) were followed for 24 months. Symptoms of STIs were recorded, and laboratory diagnosis of common STI pathogens was conducted every 6 months. Forty-two cytokines were measured by Luminex in cervicovaginal lavage specimens at enrollment. Human immunodeficiency virus type 1 (HIV-1) infection was evaluated monthly. Results. Only 12.3% of women (25 of 204) who had a laboratory-diagnosed, discharge-causing STI had clinically evident discharge. Vaginal discharge was thus a poor predictor of laboratory-diagnosed STIs (sensitivity, 12.3%; specificity, 93.8%). Cervicovaginal cytokine concentrations did not differ between women with asymptomatic STIs and those with symptomatic STIs and were elevated in women with asymptomatic STIs, compared with women with no STIs or bacterial vaginosis. Although laboratory-diagnosed STIs were associated with increased risk of HIV infection (hazard ratio, 3.3 [95% confidence interval, 1.5–7.2)], clinical symptoms were not. Conclusions. Syndromic STI diagnosis dependent on vaginal discharge was poorly predictive of laboratory-diagnosed STI. Laboratory-diagnosed STIs were associated with increased susceptibility to HIV acquisition, while vaginal discharge was not.