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School of Clinical Medicine

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Browsing School of Clinical Medicine by Author "Archary, Derseree."

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    Inflammation and cellular immune phenotypes in TB/HIV co-infection = Ukuvuvukala nezinswebu zamasosha omzimba ezinhlayiya ku-TB/HIV.
    (2023) Maseko, Thando Glory.; Sivro, Aida.; Archary, Derseree.
    South Africa has the highest burdens of TB and HIV. HIV induced inflammatory and immune changes are known to increase the risk of TB recurrence and lead to poor disease outcome in co-infected patients. Here we characterised soluble inflammatory, NK and CD4+ T cell profiles in TB and TB/HIV disease. We utilized peripheral blood specimens from the CAPRISA 011 IMPRESS study to characterize NK and memory CD4+ T helper cell phenotypes during active TB and post TB treatment in individuals with or without HIV co infection. We also characterized the effects of these phenotypes on mycobacterial clearance and TB disease severity measured by the presence of lung cavitation. We additionally characterised plasma cytokine/chemokine markers of cavitary disease in drug-resistant TB patients from the CAPRISA 020 InDEX study. TB/HIV co infection led to the expansion of functionally impaired CD56neg NK cell subset. TB treatment completion resulted in restoration of total NK cells, NK cell subset redistribution and downregulation of several NK cell activating and inhibitory receptors. Higher percentage of peripheral CD56bright cells was associated with longer time to culture conversion, while higher expression of NKp46 on CD56dim NK cells was associated with lower odds of lung cavitation in the overall cohort and the TB/HIV co infected participants. With regards to memory CD4+ T cell responses, TB/HIV co infection led to higher percentage of Th2 cells, α4β1 and α4β7 integrin expressing memory CD4+ T cells, and lower percentage of Th9 cells. Increased IL-6 expression during MDR/XDR-TB was associated with higher risk of lung cavitation in CAPRISA 020 participants. Additionally smoking and previous history of TB were associated with increased risk of cavitary disease while HIV and higher BMI were associated with reduced risk of cavitation during MDR/XDR TB. We identified distinct changes in systemic inflammatory and NK cell and memory CD4+ T cell populations with respect to active disease, treatment completion, bacterial clearance and disease severity in TB and TB-HIV co-infected individuals. These results highlight biologically plausible and novel mechanisms by which concurrent HIV infection impairs the host immune control of Mtb infection. Iqoqa. INingizimu Afrikha inomthwalo omkhulu we-TB ne-HIV. I-HIV ifike nokuvuvukala nezinguquko kumasosha omzimba okwaziwa njengokukhulisa ubungozi bokubuya kwe-TB okuholela emiphumeleni emibi yesifo ezigulini eziphethwe nangezinye izifo. Lapha sibona ukuvuvukala okuncibikalayo, i-NK ne-CD4+ ubunjalo bezinhlayiya zika-T ezifweni ze-TB ne-HIV. Sasebenzisa izimelabunjalo zegazi ezingasekugcineni ocwaningweni lwe-CAPRISA 011 IMPRESS ukuze kubonakale i-NK nememori ye-CD4+ yenswebu yenhlayiya engumsizi ka-T ngesikhathi i-TB isenamandla nangemuva kokwelashelwa i-TB kulowo osuke enayo noma engenayo i-HIV nezinye izifo. Sichaza nomthelela wezinswebu zokucaciswa kwemycobacterial nokwenzeka ngamandla kwesifo se-TB okulinganiswa ngobukhona bezimbobo emaphashini. Sibuye sichaze ngabakhombisi besifo sezimbombo zesifo seplasma cytokine/chemokine ezigulini ezimelana nekhambi le-TB ocwaningweni lwe-CAPRISA 020 InDEX. Izifo ezingosomathuba ze-TB/HIV ziholela ekukhuleni kokuphazamiseka kokusebenza kwesethi encane yenhlayiya ye-CD56neg NK. Ukuqedelwa ukwelashelwa i-TB kuholela ekwenziweni kabusha kwezinhlayiya ze-NK, ukusabalaliswa kabusha kwesethi encane ye-NK kanye nokulawulwa maphansi kwezinhlayiya eziningi ze-NK ezenza izamukeli zisebenze noma ziphazamiseke. Iphesenti eliphezulu lezinhlayiya ze-CD56bright zazihlobaniswa nesikhathi eside sokubonakala kwenguquko, ngenkathi izinga eliphezulu lokuziveza kwezinhlayiya ze-NKp46 ku-CD56dim NK kwakuhlobaniswa nezinga eliphansi lokubhoboka kwamaphaphu eqoqweni lonke labantu beminyaka elinganayo kanye nababambiqhaza abane-TB/HIV kodwa bebenezinye izifo ezibaphethe. Ngokwezimpendulo zenhlayiya yememori ye-CD4+ T, izifo mixhantela ye-TB/HIV kwaholela ephesentini eliphezulu lezinhlayiya ze-Th2, i-α4β1 ne-α4β7 i-integrin ikhombisa izinhlayiya zememori ye-CD4+ T nephesenti eliphansi lezinhlayiya ze-Th9. Ukukhula kokuziveza kwe- IL-6 ngesikhathi i-MDR/XDR-TB ihlobaniswa nobungozi bezinga eliphezulu bokubhoboka kwamaphaphu kubabambiqhaza be-CAPRISA 020. Ngaphezu kwalokho ukubhema nomlando owedlule we-TB wahlobaniswa nokukhula kobungcuphe kwesifo sezimbobo emaphashini ngenkathi i-HIV ne-BMI ephezulu kwahlobaniswa nokwehla kobungcuphe bezimbobo emaphashini ngesikhathi se- MDR/XDR TB. Sathola izinguquko ezibonakalayo zabasengcupheni ohlelweni lokuvuvukala, izinhlayiya ze-NK kanye nezinhlayiya ze-CD4+ T ngokwesifo esimandla, ukuqedelwa kokwelashwa, ukuqedwa kwegciwane nokuba mandla kwesifo se-TB ne-HIV kulowo onezinye izifo ezimphethe. Imiphumela yagqamisa iqiniso elikholekayo nendlela yokwelapha okuyiyona okubuye kube nokutheleleka nge-HIV ngesikhathi esisodwa okuyikhona okuphazamisa umgcinikulawulwa kwamasosha omzimba esifo seMtb.
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    Neutralizing antibody responses and viral evolution in a longitudinal cohort of HIV subtype C infected antiretroviral-naïve individuals.
    (2011) Archary, Derseree.; Coovadia, Hoosen Mahomed.; Ndung'u, Peter Thumbi.
    Background: HIV-1 envelope (Env) diversity is arguably the most significant challenge for the development of an efficacious vaccine. An ideal vaccine would elicit the production of broadly neutralizing antibodies (nAb), capable of retaining potent activity against a diverse panel of viral isolates. The evolutionary forces that shape the diversity of envelope and ensuing nAb responses are incompletely understood in HIV-1 subtype C infection, the dominant subtype globally. Therefore there is an urgent need to define the patterns of envelope diversity, determine the correlates of immune protection and to discover subtype C immunogens in order to develop a globally relevant vaccine. Methods: We applied the single genome sequencing strategy to study plasma derived viruses from four slow progressors and four progressors over a median of 21 months between study entry and study exit. The participants‘ samples were from the Sinikithemba cohort of antiretroviral therapy-naïve chronically infected individuals and were termed slow progressors or progressors based on CD4 T-cell counts and viral loads over two years. We analyzed env sequence diversity, divergence patterns and envelope characteristics across the entire HIV-1 subtype C gp160. We studied the evolution of autologous nAb (AnAb) and heterologous nAb responses in order to test the hypothesis that slow disease progression is associated with more potent autologous or heterologous nAb responses. Furthermore, genotypic env characteristics were correlated to potency of neutralization in order to understand possible differences in nAb responses with divergent rates of disease progression and to describe genotypic differences associated with differential nAb potencies. In addition, the binding affinities of HIV-specific immunoglobulins (IgGs) and the affinities of the IgGs to various Fcγ receptors (both activating- FcγRI, FcγRIIa, FcγRIIIa; inhibitory- FcγRIIb) were assessed. These binding affinities were used as a surrogate for the recruitment of effector functions of cells of the innate immune system e.g. macrophages or natural killer cells to initiate antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody dependent cell-mediated viral inhibition (ADCVI) and these were correlated to markers of disease progression namely CD4 T-cell counts and viral loads. Results: Intra-patient diversity was higher in slow progressors for regions C2 (p=0.0006), V3 (p=0.01) and C3 (p=0.005) compared to progressors. Consistent with this finding, slow progressors also had significantly increased amino acid length in V1-V4 with fewer potential N-linked glycosylation sites (PNGs) compared to progressors (p=0.009 and p=0.02 respectively). Similarly, in progressors, the gp41 region was significantly longer and had significantly fewer PNGs compared to slow progressors (p=0.02 for both parameters). Positive selection was prominent in regions V1, C3, V4, C4 and gp41 in slow progressors, whereas in progressors, it was prominent in gp41. Signature consensus sequence differences between the groups occurred mainly in gp41. Neutralizing antibodies (nAb) evolved over time in progressors, as evidenced by significantly higher nAb IC50 titers to baseline (study entry) viruses when tested against study exit time-point plasma compared to contemporaneous responses (p=0.003). In contrast, slow progressors‘ nAb titers did not differ significantly between study entry and study exit time points. nAb IC50 titers significantly correlated with amino acid lengths for C3-V5 (p=0.03) and V1-V5 (p=0.04) for slow progressors and V1-V2 for progressors (p=0.04). Slow progressors and progressors displayed preferential heterologous activity against the subtype C panel. There were no significant differences in breadth of responses between the groups for either subtype A or C. Neutralization breadth and titers to subtype B reference strains however, was significantly higher in progressors compared to slow progressors (both p<0.03) with increasing nAb breadth from study entry to study exit in progressors. Progressors had cross-reactive neutralizing antibodies that targeted V2 and V3. Binding affinities of non-neutralizing antibodies to HIV-specific gp120, gp41 and p24 and to activating and inhibitory Fcγ receptors (FcγRs) were similar in both groups. However, in slow progressors, CD4 T-cell counts correlated inversely with antibody binding affinity for the activating FcγRIIa (p=0.005). Conclusions: These data suggest that separate regions of Env are under differential selective forces, and the heterogeneity of env diversity and evolution differ with HIV-1 disease course. Single genome sequence analysis of circulating viruses in slow progressors and progressors indicate that diversity, length polymorphisms, sites under positive selection pressure, and PNGs consistently map to specific regions in Env. Cross-reactive neutralizing antibodies targeting epitopes in V2 and V3 indicate that nAb breadth may be dictated by a limited number of target Env epitopes. Certain key N-linked glycosylation sites were shown to be crucial for antibody neutralization. The potencies of autologous nAbs were directly affected by the amino acid lengths in certain regions of Env gp160 and by the numbers of PNGs. Target vaccine immunogens may have to be given over long periods of time and may have to include multiple subtype immunogens to elicit the production of potent, broad cross neutralizing antibodies with high binding affinity. Overall, the data suggest that neither nAbs nor non-neutralizing antibodies could be directly associated with disease attenuation in this cohort of chronically infected individuals. However, continuous evolution of nAbs was a potential marker of HIV-1 disease progression. Further studies on larger cohorts to identify people with potent nAbs and to identify specific targets of these antibodies are needed. Furthermore studies of non-neutralizing antibodies in HIV-1 infection using functional assays will be required in order to determine their role in HIV-1 pathogenesis.