Browsing by Author "Archary, Derseree."

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Broadly neutralizing antibody specificities detected in the genital tract of HIV-1 infected women.
(Wolters Kluwer., 2016) Mkhize, Nonhlanhla N.; Durgiah, Raveshni.; Ashley, Vicki C.; Archary, Derseree.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Moore, Penelope L.; Yates, Nicole L.; Passmore, Jo-Ann Shelley.; Tomaras, Georgia D.; Morris, Lynn.
Abstract available in PDF file..
Bugs, drugs, and HIV : the role of the vaginal microbiome in HIV risk and antiretroviral efficacy for HIV prevention.
(BioMed Central., 2017) Liebenberg, Lenine Julie.; Archary, Derseree.; Sivro, Aida.; Kwon, Douglas S.
Abstract available in pdf.
Characterization of anti-HIV-1 neutralizing and binding antibodies in chronic HIV-1 subtype C infection.
(Elsevier., 2012) Archary, Derseree.; Rong, Rong.; Gordon, Michelle Lucille.; Boliar, Saikat.; Madiga, Maphuti C.; Gray, Elin Solomonovna.; Dugast, Anne-Sophie.; Hermanus, Tandile.; Goulder, Philip Jeremy Renshaw.; Coovadia, Hoosen Mahomed.; Werner, Lise.; Morris, Lynn.; Alter, Galit.; Derdeyn, Cynthia A.; Ndung'u, Peter Thumbi.
Neutralizing (nAbs) and high affinity binding antibodies may be critical for an efficacious HIV-1 vaccine. We characterized virus-specific nAbs and binding antibody responses over 21 months in eight HIV-1 subtype C chronically infected individuals with heterogeneous rates of disease progression. Autologous nAb titers of study exit plasma against study entry viruses were significantly higher than contemporaneous responses at study entry (p=0.002) and exit (p=0.01). NAb breadth and potencies against subtype C viruses were significantly higher than for subtype A (p=0.03 and p=0.01) or B viruses (p=0.03; p=0.05) respectively. Gp41-IgG binding affinity was higher than gp120-IgG (p=0.0002). IgG–FcγR1 affinity was significantly higher than FcγRIIIa (p<0.005) at study entry and FcγRIIb (p<0.05) or FcγRIIIa (p<0.005) at study exit. Evolving IgG binding suggests alteration of immune function mediated by binding antibodies. Evolution of nAbs was a potential marker of HIV-1 disease progression.
Characterization of immunoglobulin (Ig) isotypes, IgG subclasses and cytokines in the blood and genital tracts of HIV infected and healthy women from an observational cohort study (CAPRISA 082)
(2020) Zuma, Mandisa Nokukhanya.; Archary, Derseree.; Sorbia, Parveen.
Background: Heterosexual transmission remains the dominant route of HIV infections in women. Immune responses that predict HIV acquisition during pre-exposure prophylaxis (PrEP) remain undefined. We hypothesized that increased genital tract antibodies and cytokines pre-HIV infection predict HIV acquisition in seroconverters compared to non-seroconverters irrespective of PrEP use. Methods: Plasma and Softcup specimens were collected from n=12 seroconverters (cases) and n=48 non-seroconverters (controls) in the CAPRISA 082 study at five time points. Of 12 cases-, nine took PrEP, while 29 of 48 controls took PrEP. IgG1, IgG2, IgG3, IgG4, IgM and IgA, and nine cytokines: MIP-1􀄮, MIP-1􀈕, IP-10, MCP-1, and IL-8, TNF-􀄮, IL-1􀄮, IL-1􀈕, and IL-6 pre- and post-HIV infection, were measured using multiplexed technology. Results: Baseline levels of IgG subclasses, Ig isotypes, and mucosal cytokines were similar between cases and controls. Over time within the cases, plasma IgA significantly declined, in controls, plasma IgG2, IgG3, and IgM significantly declined over time (p<0.05). In cases and controls on PrEP, plasma IgG3 trended higher compared to no PrEP (p<0.1). Relative to baseline, only within the controls, mucosal IgG1, IgG2, IgG3, IgG4, IgM, and IgA declined significantly. Mucosal IgM significantly predicted four-fold increased HIV risk (p=0.01). Eight of nine cytokines in the genital tract were significantly elevated in the cases compared to controls (all p<0.05). In cases and controls who used PrEP relative to no PrEP, IP-10 was significantly lower (p=0.04 and p=0.009). Baseline mucosal IL-8 significantly correlated with mucosal IgG1, IgG2, total IgG, and IgM (p<0.001 for all). Conclusions: Although no significant elevated genital antibodies or cytokines pre-HIV infection were found, significantly different patterns of antibodies and cytokines were observed in this cohort. Plasma IgG3, one of the most effective of the IgG􀂶s eliciting diverse antibod􀁜 functions, was increased in PrEP users. Mucosal IgM was associated with increased HIV-acquisition risk, while pleiotropic IP-10, a reported risk factor was modulated in PrEP users among cases. Collectively, these data suggest that PrEP use may modulate or preserve specific immune responses that can modify HIV risk. As PrEP uptake increases, its effect on mucosal and systemic immunity is important for informing on prevention strategies where PrEP may be given alone or in combination with HIV vaccine for added efficacy.
Distinct genital tract HIV-specific antibody profiles associated with Tenofovir gel.
(Nature., 2016) Archary, Derseree.; Seaton, Kelly E.; Passmore, Jo-Ann Shelley.; Werner, Lise.; Deal, Aaron W.; Dunphy, Laura J.; Arnold, Kelly B.; Yates, Nicole L.; Lauffenburger, Douglas A.; Bergin, Philip.; Liebenberg, Lenine Julie.; Samsunder, Natasha.; Mureithi, Marianne W.; Altfeld, Marcus.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Tomaras, Georgia D.
Abstract available in PDF file.
Drug transporter expression and genetic polymorphisms in HIV endemic settings.
(2023) Zondo, Nomusa Margaret.; Archary, Derseree.; Sobia, Parveen.
Abstract available in a PDF.
The effect of genital tract inflammation on HIV-specific binding antibodies, IgG subclass and Isotype transudation.
(2019) Pillay, Thevani.; Archary, Derseree.; Baxter, Cheryl.
Abstract available in PDF file.
Functional assessment on non-neutralizing binding antibodies in the blood and genital tracts of women with breakthrough HIV infection from the CAPRISA 004 1% tenofovir gel trial.
(2017) Fisher, Kimone Leigh.; Archary, Derseree.; Baxter, Cheryl.
Abstract available in PDF file.
Genital inflammation undermines the effectiveness of tenofovir gel in preventing HIV acquisition in women.
(Nature Publishing Group., 2018) McKinnon, Lyle R.; Liebenberg, Lenine Julie.; Yende-Zuma, Fortunate Nonhlanhla.; Archary, Derseree.; Ngcapu, Sinaye.; Sivro, Aida.; Nagelkerke, Nico.; Garcia Lerma, Gerardo.; Kashuba, Angela D. M.; Masson, Lindi.; Mansoor, Leila Essop.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Passmore, Jo-Ann Shelley.
Abstract available in pdf.
Genital—systemic chemokine gradients and the risk of HIV acquisition in women.
(Wolters Kluwer Health., 2017) Liebenberg, Lenine Julie.; Masson, Lindi.; Arnold, Kelly B.; McKinnon, Lyle R.; Werner, Lise.; Proctor, Elizabeth.; Archary, Derseree.; Mansoor, Leila Essop.; Lauffenburger, Douglas A.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Passmore, Jo-Ann Shelley.
Abstract available in pdf.
In vitro modelling of the impact of anti-inflammatory drugs on cellular cytotoxicity, activation and inflammation.
(2020) Cromarty, Ross Thomas.; Archary, Derseree.
The relationship between inflammation and HIV has been a major focus of HIV research. In people living with HIV (PLWH), HIV-associated immune activation drives HIV disease progression. While genital inflammation has been significantly associated with increased risk for HIV acquisition and transmission, immune correlates for reduced HIV risk remain less well defined. In HIV-exposed seronegative individuals, the immune quiescent phenotype, characterised by regulated immune activation and inflammation, has been implicated in reducing HIV acquisition risk. Targeted management of inflammation, therefore, is a plausible strategy to mitigate the risk of HIV infection, and to slow HIV disease progression. Therefore, we sought to investigate how anti-inflammatory drugs affect TLR-mediated inflammation and impact HIV infection of CD4+ T cells. This study utilized an in vitro peripheral blood mononuclear cell (PBMC) model. PBMCs were either treated with the anti12 inflammatory drugs ibuprofen (IBF) or betamethasone (BMS) or were left untreated. Thereafter they were either left unstimulated or were stimulated with phytohaemagglutinin (PHA) or Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), LPS (TLR4) or R848 (TLR7/8) before exposure to HIV NL4-3 AD8. To assess inflammation, multiplexed ELISA was used to measure 28 proinflammatory, chemotactic, growth-related, adaptive response-related or regulatory cytokines. Flow cytometry was used to measure activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. Despite minimal immune activation, TLR stimulation elicited significant cytokine responses (p<0.05). TLR4 stimulation significantly reduced HIV infection of CD4+ T cells (p<0.01). With the addition of IBF, minimal immunosuppressive effects were observed. In contrast, BMS significantly dampened inflammation (p<0.05) and immune activation (p<0.05) regardless of the stimulation condition. Regardless of global immunosuppression, only with TLR4 stimulation did BMS significantly reduce HIV infection of CD4+ T cells (p=0.02). The finding that TLR4 stimulation reduces rather than increases susceptibility of CD4+ T cells to HIV infection, while BMS only affected HIV infection in the TLR4 condition, strongly suggests that additional factors, and not only inflammation play a powerful, although complex, role in determining HIV infection risk. Together, these data emphasize the importance of understanding signalling pathways induced during inflammation to identify novel targets to mitigate HIV infection.
Inflammation and cellular immune phenotypes in TB/HIV co-infection.
(2023) Maseko, Thando Glory.; Sivro, Aida.; Archary, Derseree.
Abstract available in PDF.
Investigation of multiple concurrent Human papillomavirus infections, oncogenicity, and STI co-infection as risk factors for Human immunodeficiency virus infection.
(2017) Jewanraj, Janine.; Liebenberg, Lenine Julie.; Archary, Derseree.
Background: Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STIs) globally and a necessary factor for cervical cancer development. While HPV infection has been associated with increased Human immunodeficiency virus (HIV) risk, the underlying mechanisms remain unclear. Since STIs upregulate cytokine production and immune cell recruitment, and reduce epithelial barrier integrity, this study investigated whether the immune responses associated with HPV infection contribute to a genital immune environment conducive to an increased risk of HIV infection. Methods: This study included a baseline assessment of 167 HIV negative women participating in the CAPRISA 008 trial. The Roche Linear Array was used to detect the presence of 37 HPV genotypes in cervicovaginal lavage (CVL) pellets. The concentrations of 48 cytokines and 9 matrix metalloproteinases (MMPs) were assessed in matching CVL supernatants by multiplex ELISA. The frequencies of activated or proliferating T cells, NK cells, and of HIV target cells were assessed on cervical cytobrush-derived specimens by flow cytometry. Multiplex PCR was conducted to determine infection with common discharge-associated STIs. Results: The study demonstrated a 50.8% HPV prevalence. HPV infection was associated with younger age, older male partners, not living with a regular partner, and higher parity. HPV infection was also associated with greater levels of IL-5, IL-6 and G-CSF, an association otherwise masked by the inflammatory nature of other STI. Concomitant HPV/STI infection resulted in reduced concentrations of IL-6 and IL-1RA relative to HPV-STI+ women. In multivariate analyses controlling for other STI and nugent score, HPV-infected women had increased concentrations of SDF-1α (β = 0.148 pg/ml). Women with HR-HPV had higher concentrations of MCP-1 (β = 0.127 pg/ml) and IL-13 (β = 0.117 pg/ml), and greater frequencies of lymphocytes (β = 1.987 pg/ml) relative to those infected with LR-HPV. Having multiple HPV infections was associated with reduced concentrations of IL-5 (β = -0.170 pg/ml). Conclusion: While discharge-related STIs are inflammatory, a more subtle immune profile was associated with HPV infection that did not overtly relate to an increased potential for HIV risk. However, this study demonstrated an association between HR-HPV and biomarkers of inflammation, suggesting the need for longitudinal investigation to confirm a biological mechanism for the relationship between persistent HR-HPV infection and HIV acquisition.
Modulation of female genital tract-derived dendritic cell migration and activation in response to inflammatory cytokines and toll-like receptor agonists.
(Shey, M.S., Maharaj, N., Archary, D., Ngcapu, S., Garrett, N., Abdool Karim, S.S. and Passmore, J.A.S. 2016. Modulation of female genital tract-derived dendritic cell migration and activation in response to inflammatory cytokines and toll-like receptor agonists. PloS One 11(5), e0155668., 2016) Shey, Muki Shehu.; Maharaj, Niren Ray.; Archary, Derseree.; Ngcapu, Sinaye.; Garrett, Nigel Joel.; Abdool Karim, Salim Safurdeen.; Passmore, Jo-Ann Shelley.
Abstract available in pdf.
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.
Randomized cross-sectional study to compare HIV-1 specific antibody and cytokine concentrations in female genital secretions obtained by menstrual cup and cervicovaginal lavage.
(Public Library of Science., 2015) Archary, Derseree.; Liebenberg, Lenine Julie.; Werner, Lise.; Tulsi, Sahil.; Majola, Nelisile.; Naicker, Nivashnee.; Dlamini, Sarah Alexandra.; Hope, Thomas J.; Samsunder, Natasha.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Passmore, Jo-Ann Shelley.; Garrett, Nigel Joel.
Abstract available in pdf.
Role of local or systemic Schistosoma infections in driving inflammation and HIV risk in women enrolled in the CAPRISA 004 cohort.
(2016) Tulsi, Sahil.; Archary, Derseree.; Horsnell, William.; Passmore, Jo-Ann Shelley.
Female genitourinary schistosomiasis (FGS) has been associated with increased HIV susceptibility, presumably through lesions secondary to parasitic eggs in situ in the female genital tract. We determined the prevalence of FGS infection by real-time PCR (indicative of local involvement of parasitic eggs in the genital mucosae) and sero-prevalence of schistosomiasis (indicating prior exposure to parasitic infection) in HIV-uninfected KZN women (n=383) who had participated in the CAPRISA004 trial. The hypothesis for this study was that FGS, and genital tract inflammation are risk factors for HIV-acquisition. DNA PCR was used to confirm the presence of FGS, ELISAs were used for detection of Schistosoma spp IgG and multiplex technology was used to detect genital tract cytokines in the cervicovaginal lavages (CVLs). The median age of the women in this study was 23 years (range 20-26 years). Of the 383 HIV negative women, 52/383 (13.8%) became HIV-infected by study exit with an HIV incidence rate of 9.1 per 100 women-years ( 95% CI: 6.8 – 11.9). Nine of 383 (2.3%) women had a positive DNA PCR for Schistosoma spp indicative of prevalent genital schistosomiasis. Of these 9 women, 4/9 (44%) acquired HIV infection by study exit with a 4.0 times increased risk for HIV-infection (OR of 4.05- 95% CI 1.8-8.9, p=0.01) than PCR-negative women. Schistosoma haematobium, the endemic species in KZN has high sequence homology with S. mansoni antigen which was used to detect IgG in the plasma samples. Of the 383 plasma samples from study entry, 21/383 (5.5%) and 19/383 (4.96%) of study participants had detectable levels of IgG to S. mansoni at study exit. . Only, MCP-3, a chemokine was significantly higher in FGS+ compared to FGS- healthy HIV negative women. Genital tract pro-inflammatory cytokines at study exit were significantly higher in FGS-HIV+ women for IL-1β, MIF, IL-1A & IL-6 compared to FGS-HIV- women (p<0.0001, p=0.0014, p=0.0088, p=0.0069 respectively). Anti-inflammatory cytokine data in FGS-HIV+ women showed higher median levels of IL-1RA & IL-2RA compared to FGS –HIV- women (p<0.0001 & p=0.0012 respectively). Mixed responses of both pro and anti-inflammatory cytokines in the presence or absence of FGS may be an indication that HIV infection is driving these signatures and causing dysregulation. The presence of parasite DNA in the genital tract was significantly associated with increased risk for HIV acquistion. Taken together, these results highlight the importance of understanding the complex interplay of parasitic infections, and host immunity as potential risk factors for HIV acquistion in regions with high HIV and parasite burden.