Browsing by Author "de Voux, Alex"

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    Constitutively active CCR5 chemokine receptors differ in mediating HIV envelope-dependent fusion
    (Public Library of Science, 2013) de Voux, Alex; Chan, Mei-Chi; Folefoc, Asongna T; Madziva, Michael T; Flanagan, Colleen A
    The CCR5 chemokine receptor is a rhodopsin-like G protein-coupled receptor that mediates the effects of pro-inflammatory β-chemokines. CCR5 is also the major co-receptor for entry of human immunodeficiency virus (HIV) into human cells. G protein-coupled receptors exist in ensembles of active and inactive conformations. Active receptor conformations can be stabilized by mutations. Although binding of the HIV envelope protein to CCR5 stimulates cellular signaling, the CCR5 conformation that induces fusion of the viral membrane with cellular membranes is not known. We mutated conserved amino acids to generate constitutively active CCR5 receptors, which are stabilized in active conformations, and tested the ability of constitutively active CCR5 receptors to mediate HIV envelope-directed membrane fusion. Mutation of the Asp 3.49(125) and Arg 6.32(225) residues of CCR5 did not cause constitutive activity, but Lys or Pro substitutions for Thr 2.56(82) , in the TxP motif, caused high basal inositol phosphate signaling. Signaling did not increase in response to MIP-1β, suggesting that the Thr 2.56(82) mutants were fully stabilized in active conformations. The Thr 2.56(82) Lys mutation severely decreased cell surface CCR5 expression. Combining the Thr 2.56(82) Lys mutation with an Arg 6.32(225) Gln mutation partially reversed the decrease in expression. Mutants with Thr 2.56(82) Lys substitutions were poor mediators of HIV envelope-directed membrane fusion, but mutants with the Thr 2.65(82) Pro substitution exhibited full co-receptor function. Our results suggest that the Thr 2.65(82) Lys and Thr 2.65(82) Pro mutations stabilize distinct constitutively active CCR5 conformations. Lys in position 2.65(82) stabilizes activated receptor conformations that appear to be constitutively internalized and do not induce envelope-dependent membrane fusion, whereas Pro stabilizes activated conformations that are not constitutively internalized and fully mediate envelope-directed membrane fusion.
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    Examining patterns of intimate partner violence and depression amongst a cohort of pregnant and postpartum women in Cape Town, South Africa
    (2024) Bagg, Kayla; de Voux, Alex
    Depression and intimate partner violence (IPV) frequently co-occur among women in South Africa (SA) with elevated risk in the antenatal and postnatal period. Both phenomena have also been shown to reduce uptake and adherence to human immunodeficiency virus (HIV) treatments. In this secondary analysis, we examined patterns of IPV exposure and depression in a cohort of pregnant HIV-negative women on oral pre-exposure prophylaxis (PrEP). Data from 1195 women at enrolment was retrospectively analyzed from an existing dataset. Participants were recruited from two midwife obstetric units in Cape Town and followed from enrolment to 12 months post-partum with 3-monthly interviews. Women between the ages of 16–18 years were 3.15 (95% CI: 1.30, 7.07) times as likely to score above 11 on the Edinburgh Postnatal Depression Scale (EPDS), indicating depression, compared to women >25 years. Women who self-reported experiencing IPV at baseline had 2.77 (95% CI: 1.61, 4.61) times the odds of an EPDS score ³11 compared to those who did not report experiencing IPV at baseline. In conjunction with this, the London Measure of Unplanned Pregnancies (LMUP) was used to determine the pregnancy intentions of the mothers. The prevalence of maternal mental health problems during pregnancy and postpartum is alarming, particularly among women in low- and middle-income countries (LMIC). These include IPV and depression which could lead to poor adherence to oral pre-exposure prophylaxis (PrEP) and ultimately HIV infection. Screening for depression in the postpartum period may also have an impact on IPV victimization. Identifying pregnant women who are experiencing either IPV or depression and linking them with the necessary services, may improve PrEP outcomes.
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    Syphilis in Pregnancy: Exploring the prevalence and vertical transmission prevention cascade of syphilis using routinely collected electronic health data, Cape Town Metropolitan District, 2017–2022
    (2025) Gammon, Jessica; de Voux, Alex; Le Roux David
    Introduction: Congenital Syphilis (CS), an important cause of perinatal morbidity and mortality, is notifiable in South Africa. CS results from vertical transmission of inadequately treated syphilis in pregnancy, a treatable sexually transmitted infection caused by Treponema pallidum. Gaps in our understanding of syphilis epidemiology exist amidst concerns of penicillin stockouts increasing CS cases. We evaluated current management and outcomes of syphilis in pregnancy in Cape Town. Methods: We retrospectively reviewed routinely collected electronic health data on a pregnant cohort and their infants from the Western Cape Provincial Health Data Centre. Clinical administration data, pharmacy and laboratory data were collated for patients identified as pregnant between January 2017 and December 2022. Pregnant women's laboratory TPAb (Treponema pallidum antibody) and RPR (rapid plasma reagin) results were reviewed. Results: 419 376 pregnancies were identified, resulting in 425 128 outcomes. 47% of pregnancies had a documented laboratory syphilis test, with 6812 (1.6%) of total pregnancies testing RPR positive. A total of 996 infants had a positive RPR, with a RPR seropositivity in infants of 267 per 100 000 live births. 636 (64%) of these infants were born to mothers who had tested positive for syphilis in pregnancy, and the remainder were either born to mothers who did not have a lab test for syphilis in pregnancy, or who had screened negative for syphilis in pregnancy. The proportion of seropositive pregnancies increased over time from 764 (1.2%) in 2017 to 1324 (1.9%) in 2022. Testing practices differed between geographic service areas with some doing laboratory tests for syphilis for all pregnancies and others doing confirmatory laboratory tests only after positive point-of-care treponemal tests. Of the syphilis seropositive pregnancies, 69% had no electronic evidence of appropriate treatment. 28% had recorded benzathine benzylpenicillin; 3% received amoxicillin with enzyme inhibitor; <1% received ceftriaxone. Only 23% of syphilis-positive women had a follow-up RPR titre. The risk of adverse pregnancy outcomes was higher among syphilis seropositive compared to seronegative women; neonatal deaths RR 1.91 (95% CI 1.53-2.38) and RR of stillbirths 2.52 (95% CI 2.25, 2.82). The risk of adverse perinatal outcomes was higher in those with high-titre active syphilis than low-titre syphilis. Conclusion: Routine electronic health data can provide oversight of CS prevention. Electronic capturing of pharmacy data is suspected to be incomplete and requires independent verification. There is an increasing prevalence trend of syphilis in pregnancy, resulting in preventable stillbirths and neonatal deaths. Increasing syphilis prevalence requires a public health response to ensure adequate treatment and repeat RPR titres to monitor response. Cases treated with an alternative regimen should be audited to assess outcomes. RPR seropositivity in infants is higher than national estimates and is likely an underestimate.