Improved HIV-positive infant survival is correlated with high levels of HIV-specific ADCC activity in multiple cohorts.
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ABSTRACT:
SUBMITTER: Yaffe ZA
PROVIDER: S-EPMC8080236 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We evaluated the impact of Option A on HIV-free infant survival and mother-to-child transmission (MTCT) in Zimbabwe.Serial cross-sectional community-based serosurveys.We analyzed serosurvey data collected in 2012 and 2014 among mother-infant pairs from catchment areas of 132 health facilities from five of 10 provinces in Zimbabwe. Eligible infants (alive or deceased) were born 9-18 months before each survey to mothers at least 16 years old. We randomly selected mother-infant pairs and conducted questionnaires, verbal autopsies, and collected blood samples. We estimated the HIV-free infant survival and MTCT rate within each catchment area and compared the 2012 and 2014 estimates using a paired t test and number of HIV infections averted because of the intervention.We analyzed 7249 mother-infant pairs with viable maternal specimens collected in 2012 and 8551 in 2014. The mean difference in the catchment area level MTCT between 2014 and 2012 was -5.2 percentage points (95% confidence interval?=?-8.1, -2.3, P?<?0.001). The mean difference in the catchment area level HIV-free survival was 5.5 percentage points (95% confidence interval?=?2.6, 8.5, P?<?0.001). Between 2012 and 2014, 1779 infant infections were averted compared with the pre-Option A regimen. The association between HIV-free infant survival and duration of Option A implementation was NS at the multivariate level (P?=?0.093).We found a substantial and statistically significant increase in HIV-free survival and decrease in MTCT among infants aged 9-18 months following Option A rollout in Zimbabwe. This is the only evaluation of Option A and shows the effectiveness of Option A and Zimbabwe's remarkable progress toward eMTCT.
| S-EPMC4889511 | biostudies-literature
Project description:To determine how infant feeding recommendations can maximize HIV-free survival (HFS) among HIV-exposed, uninfected African infants, balancing risks of breast milk-associated HIV infection with setting-specific risks of illness and death associated with replacement feeding.Validated mathematical model of HIV-exposed, uninfected infants, with published data from Africa.We projected 24-month HFS using combinations of: maternal CD4, antiretroviral drug availability, and relative risk of mortality among replacement-fed compared to breastfed infants ('RR-RF', range 1.0-6.0). For each combination, we identified the 'optimal' breastfeeding duration (0-24 months) maximizing HFS. We compared HFS under an 'individualized' approach, based on the above parameters, to the WHO 'public health approach' (12 months breastfeeding for all HIV-infected women).Projected HFS was 65-93%. When the value of RR-RF is 1.0, replacement feeding from birth maximized HFS. At a commonly reported RR-RF value (2.0), optimal breastfeeding duration was 3-12 months, depending on maternal CD4 and antiretroviral drug availability. As the value of RR-RF increased, optimal breastfeeding duration increased. Compared to the public health approach, an individualized approach improved absolute HFS by less than 1% if RR-RF value was 2.0-4.0, by 3% if RR-RF value was 1.0 or 6.0, and by greater amounts if access to antiretroviral drugs was limited.Tailoring breastfeeding duration to maternal CD4, antiretroviral drug availability, and local replacement feeding safety can optimize HFS among HIV-exposed infants. An individualized approach leads to moderate gains in HFS, but only when mortality risks from replacement feeding are very low or very high, or antiretroviral drug availability is limited. The WHO public health approach is beneficial in most resource-limited settings.
| S-EPMC4098721 | biostudies-literature
Project description:BackgroundGlioblastoma (GBM) confers a dismal prognosis despite advances in current therapy. Cancer-testis antigens (CTA) comprise families of tumor-associated antigens that are immunogenic in different cancers. The aim of this study was to determine the expression profile of a large number of CTA genes in GBM.MethodsWe selected, from 153 CTA genes, those genes potentially expressed in GBM. The expression pattern of 30 CTA was then evaluated by RT-PCR in a series of 48 GBM and 5 normal brain samples. The presence of CTCFL protein was also evaluated by immunohistochemical staining.ResultsAmong the genes with no expression in normal brain, ACTL8 (57%), OIP5 (54%), XAGE3 (44%) and CTCFL (15%) were frequently expressed in GBM, while over 85% of the tumors expressed at least 1 of these four CTA. Coexpression of two or more CTA occurred in 49% of cases. CTCFL protein expression was detected in 13% of the GBM and was negative in normal brain samples. GBM expressing 3-4 CTA was associated with significantly better overall survival (OS) rates (P = 0.017). By multivariate analysis, mRNA positivity for 3-4 CTA (P = 0.044), radiotherapy (P = 0.010) and chemotherapy (P = 0.001) were independent prognostic factors for OS.ConclusionsGBM frequently express ACTL8, OIP5, XAGE3 and CTCFL. A relatively high percentage of tumors expressed at least one of these four CTA, opening the perspective for their utility in antigen-specific immunotherapy. Furthermore, mRNA positivity for 3-4 CTA is an independent predictor of better OS for GBM patients.
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Project description:Despite the nutritional, physiological and emotional benefits of breastfeeding, HIV-positive mothers cannot practise exclusive breastfeeding for six months because of a range of influences on their feeding choice - thereby creating a caveat for morbidity in infants.This study explored factors influencing the infant feeding choice of HIV-positive mothers at a peri-urban hospital in Tembisa, South Africa.This study was qualitative and was conducted among 30 purposefully selected postnatal HIV-positive mothers at Tembisa hospital, Gauteng, from May to June 2011. In-depth interviews were conducted mainly in isiZulu and Sepedi which were then transcribed into English. An open coding system of analysis was used for thematic analysis.Nurses significantly influenced the feeding choices of new mothers - sometimes with inconsistent information. The grandmothers of infants also influenced the new mothers' feeding options, in some cases with the new mother coming under duress. Other relatives like the sisters and aunts of mothers appeared to significantly affect feeding choices. The time frames expressed for the initiation of a supplementary diet were as follows: before 1 month, at 1 month and at 4 months. The main reason was the belief that infants required more than breast milk as sustenance during this period.In the postnatal hospital setting of this study, the feeding choices of mothers were influenced by nursing personnel. Nursing personnel could marry the influential 'authority' they have with correct and consistent information, in order to change feeding behaviour. Significant 'others' like grandmothers and other relatives also influenced decisions on infant feeding. As such, family dynamics need to be considered when encouraging breastfeeding.
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Project description:Antiretroviral treatment (ART) for HIV-positive patients has expanded rapidly in Asia over the last 10 years. Our study aimed to describe the time trends and risk factors for overall survival in patients receiving first-line ART in Asia.We included HIV-positive adult patients who initiated ART between 2003-2013 (n=16,546), from seven sites across six Asia-Pacific countries. Patient follow-up was to May 2014. We compared survival for each country and overall by time period of ART initiation using Kaplan-Meier curves. Factors associated with mortality were assessed using Cox regression, stratified by site. We also summarized first-line ART regimens, CD4+ T-cell count at ART initiation, and CD4+ T-cell and HIV viral load testing frequencies.There were 880 deaths observed over 54,532 person-years of follow-up, a crude rate of 1.61 (95% CI 1.51, 1.72) per 100 person-years. Survival significantly improved in more recent years of ART initiation. The survival probability at 4 years follow-up for those initiating ART in 2003-2005 was 92.1%, 2006-2009 was 94.3% and 2010-2013 was 94.5% (P<0.001). Factors associated with higher mortality risk included initiating ART in earlier time periods, older age, male sex, injecting drug use as HIV exposure and lower pre-ART CD4+ T-cell count. Concurrent with improved survival was increased tenofovir use, ART initiation at higher CD4+ T-cell counts and greater monitoring of CD4+ T-cells and HIV viral load.Our results suggest that HIV-positive patients from Asia have improved survival in more recent years of ART initiation. This is likely a consequence of improvements in treatment, patient management and monitoring over time.
| S-EPMC4980281 | biostudies-literature
Project description:A cure for HIV-1 (HIV) remains unrealized due to a reservoir of latently infected cells that persist during antiretroviral therapy (ART), with reservoir size associated with adverse health outcomes and inversely with time to viral rebound upon ART cessation. Once established during ART, the HIV reservoir decays minimally over time; thus, understanding factors that impact the size of the HIV reservoir near its establishment is key to improving the health of people living with HIV and for the development of novel cure strategies. Yet, to date, few correlates of HIV reservoir size have been identified, particularly in pediatric populations. Here, we employed a cross-subtype intact proviral DNA assay (CS-IPDA) to quantify HIV provirus between one- and two-years post-ART initiation in a cohort of Kenyan children (n = 72), which had a median of 99 intact (range: 0-2469), 1340 defective (range: 172-3.84 × 104), and 1729 total (range: 178-5.11 × 104) HIV proviral copies per one million T cells. Additionally, pre-ART plasma was tested for HIV Env-specific antibody-dependent cellular cytotoxicity (ADCC) activity. We found that pre-ART gp120-specific ADCC activity inversely correlated with defective provirus levels (n = 68, r = -0.285, p = 0.0214) but not the intact reservoir (n = 68, r = -0.0321, p-value = 0.800). Pre-ART gp41-specific ADCC did not significantly correlate with either proviral population (n = 68; intact: r = -0.0512, p-value = 0.686; defective: r = -0.109, p-value = 0.389). This suggests specific host immune factors prior to ART initiation can impact proviruses that persist during ART.
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Project description:BACKGROUND:Resistin is a polypeptide hormone secreted by adipose tissue. A prior hospital-based case-control study reported serum resistin levels to be inversely associated with risk of multiple myeloma (MM). To date, this association has not been investigated prospectively. METHODS:We measured resistin concentrations for pre-diagnosis peripheral blood samples from 178 MM cases and 358 individually matched controls from three cohorts participating in the MM cohort consortium. RESULTS:In overall analyses, higher resistin levels were weakly associated with reduced MM risk. For men, we observed a statistically significant inverse association between resistin levels and MM (odds ratio, 0.44; 95% confidence interval (CI) 0.24-0.83 and 0.54; 95% CI 0.29-0.99, for the third and fourth quartiles, respectively, vs the lowest quartile; Ptrend=0.03). No association was observed for women. CONCLUSIONS:This study provides the first prospective evidence that low circulating resistin levels may be associated with an increased risk of MM, particularly for men.
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Project description:HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.
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Project description:Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ? 0.001 in BT474; p ? 0.01 in SKBR3) and in vivo (p ? 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ? 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ? 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ? 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.
| S-EPMC4196152 | biostudies-literature
Project description:The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite effective antiretroviral therapies. Multiple etiologies have been proposed over the last several years to account for this phenomenon, including the neurotoxic effects of antiretrovirals and co-morbid substance abuse; however, no underlying molecular mechanism has been identified. Emerging evidence in several fields has linked the gut to brain diseases, but the effect of the gut on the brain during HIV infection has not been explored. Saliva is the most accessible gut biofluid, and is therefore of great scientific interest for diagnostic and prognostic purposes. This study presents a longitudinal, liquid chromatography-mass spectrometry-based quantitative proteomics study investigating saliva samples taken from 8 HIV-positive (HIV+), 11 -negative (HIV-) heroin addicts. In addition, saliva samples were investigated from 11 HIV-, non-heroin addicted healthy controls. In the HIV+ group, 58 proteins were identified that show significant correlations with cognitive scores, implicating disruption of protein quality control pathways by HIV. Notably, only one protein from the HIV- heroin addict cohort showed a significant correlation with cognitive scores, and no proteins correlated with cognitive scores in the healthy control group. In addition, the majority of correlated proteins have been shown to be associated with exosomes, allowing us to propose that the salivary glands and/or oral epithelium may modulate brain function during HIV infection through the release of discrete packets of proteins in the form of exosomes.
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