Antibody and B Cell Subset Perturbations in Human Immunodeficiency Virus-Uninfected Patients With Cryptococcosis.
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ABSTRACT:
SUBMITTER: Rohatgi S
PROVIDER: S-EPMC5767948 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
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Antibody and B Cell Subset Perturbations in Human Immunodeficiency Virus-Uninfected Patients With Cryptococcosis.
Rohatgi Soma S Nakouzi Antonio A Carreño Leandro J LJ Slosar-Cheah Magdalena M Kuniholm Mark H MH Wang Tao T Pappas Peter G PG Pirofski Liise-Anne LA
Open forum infectious diseases 20171118 1
The importance of antibody immunity in protection against <i>Cryptococcus neoformans</i> remains unresolved. We measured serum <i>C neoformans</i>-specific and total antibody levels and peripheral blood B cell subsets of 12 previously healthy patients with cryptococcosis (cases) and 21 controls. Before and after adjustment for age, sex, and race, cryptococcal capsular polysaccharide immunoglobulin G was higher in cases than controls, whereas total B and memory B cell levels were lower. These ass ...[more]
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Project description:IntroductionHIV-exposed uninfected (HEU) newborns suffer from higher risks of opportunistic infections during the first months of life compared to HIV-unexposed uninfected (HUU) newborns. Alterations in thymic mass, amounts of T helper (Th) cells, T-cell receptor diversity, and activation markers have been found in HEU newborns, suggesting alterations in T cell ontogeny and differentiation. However, little is known about the ability of these cells to produce specialized Th responses from CD4+ T cells.MethodTo characterize the Th cell profile, we evaluated the frequency of Th1 (CD183+ CD194- CD196- /CXCR3+ CCR4- CCR6- ), Th2 (CD183- CD194+ CD196- /CXCR3- CCR4+ CCR6- ), Th17 (CD183- CD194+ CD196+ /CXCR3- CCR4+ CCR6+ ), and CD4+ CD25++ blood T-cell phenotypes in 50 HEU and 25 HUU newborns. Early activation markers on CD4+ T cells and the Th cytokine profile produced from mononuclear cells under polyclonal T cell stimulation were also studied. Additionally, we probed the ability of CD4+ T cells to differentiate into interferon (IFN)-γ-producing Th1 CD4+ T cells in vitro.ResultsLower percentages of differentiated Th1 , Th2 , Th17, and CD4+ CD25++ T cells were found in blood from HEU newborns than in blood from HUU newborns. However, polyclonally stimulated Th cells showed a similar ability to express CD69 and CD279 but produced less secreted interleukin (IL)-2 and IL-4. Interestingly, under Th1 differentiation conditions, the percentages of CD4+ IFN-γ+ T cells and soluble IFN-γ were higher in HEU newborns than in HUU newborns.ConclusionHEU neonates are born with reduced proportions of differentiated Th1 /Th2 /Th17 and CD4+ CD25++ T cells, but the intrinsic abilities of CD4+ T cells to acquire a Th1 profile are not affected by the adverse maternal milieu during development.
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Project description:BACKGROUND:Persons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth. METHODS:This is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts. RESULTS:Seroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively. CONCLUSION:Antibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.
| S-EPMC6938204 | biostudies-literature
Project description:Perinatal HIV infection and congenital cytomegalovirus (CMV) infection may increase the risk for hearing loss. We examined 1,435 infants enrolled in the Surveillance Monitoring of ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, a prospective study of the safety of in utero antiretroviral (ARV) exposures. We determined the proportion of perinatally HIV-exposed uninfected (HEU) newborns who were referred for additional hearing testing, and evaluated the association between in utero ARV exposures and newborn hearing screening results. Using a nested case-control design, we also examined congenital CMV infection in infants with and without screening referral. Congenital CMV infection was determined based on CMV DNA detection using a nested PCR assay in peripheral blood mononuclear cells obtained within 14 days of birth. Among the 1,435 infants (70% black, 31% Hispanic, 51% male), 45 (3.1%) did not pass the hearing screen and were referred for further hearing testing. Based on exact logistic regression models controlling for maternal use of tobacco and ototoxic medications, first trimester exposure to Tenofovir was associated with lower odds of a newborn hearing screening referral [adjusted odds ratio (aOR) = 0.41, 95% confidence interval (CI): 0.14-1.00]. Exposure to Atazanavir was linked to higher odds of newborn screening referral, although not attaining significance [aOR = 1.84, 95% CI: 0.92-3.56]. Maternal ARV use may have varying effects on newborn hearing screenings. These results highlight the importance for audiologists to be knowledgeable of in utero ARV exposures in HEU children because of the possibility of higher referrals in these children.
| S-EPMC5407375 | biostudies-literature
Project description:In South Africa, up to 40% of pregnant women are living with human immunodeficiency virus (HIV), and 30-45% are obese. However, little is known about the dual burden of HIV and obesity in the postpartum period. In a cohort of HIV-uninfected and HIV-infected pregnant women initiating antiretroviral therapy in Cape Town, South Africa, we examined maternal anthropometry (weight and body mass index [BMI]) from 6 weeks through 12 months postpartum. Using multinomial logistic regression, we estimated associations between baseline sociodemographic, clinical, behavioural, and HIV factors and being overweight-obese I (BMI 25 to <35), or obese II-III (BMI >35), compared with being underweight or normal weight (BMI <25), at 12 months postpartum. Among 877 women, we estimated that 43% of HIV-infected women and 51% of HIV-uninfected women were obese I-III at enrollment into antenatal care, and 51% of women were obese I-III by 12 months postpartum. On average, both HIV-infected and HIV-uninfected women gained, rather than lost, weight between 6 weeks and 12 months postpartum, but HIV-uninfected women gained more weight (3.3 kg vs. 1.7 kg). Women who were obese I-III pre-pregnancy were more likely to gain weight postpartum. In multivariable analyses, HIV-infection status, being married/cohabitating, higher gravidity, and high blood pressure were independently associated with being obese II-III at 12 months postpartum. Obesity during pregnancy is a growing public health concern in low- and middle-income countries, including South Africa. Additional research to understand how obesity and HIV infection affect maternal and child health outcomes is urgently needed.
| S-EPMC7296802 | biostudies-literature
Project description:To estimate the prevalence of elevated point-of-care (POC) capillary blood lactate concentrations in human immunodeficiency virus (HIV)-exposed, uninfected children (HEU) and to determine if POC lactate varies with in utero antiretroviral (ARV) exposure.The Surveillance Monitoring for Antiretroviral Therapy Toxicities protocol of the Pediatric HIV/AIDS Cohort Study enrolled 1934 children between 2007 and 2009, 0 to 12 years of age, born to HIV-infected mothers. POC lactate was measured annually on capillary blood using the Lactate Pro device. Associations of POC lactate with in utero ARV exposure and other characteristics were evaluated using logistic regression models, adjusting for maternal characteristics and other confounders.Of 1641 children with POC measurements (median age, 3.0 years), 3.4% had POC lactate >3 mmol/L. Median POC lactate level decreased with age (1.9 mmol/L, 1.7 mmol/L, and 1.6 mmol/L for children 0-<6 months [99% ?6 weeks of life], 6-<24 months, and ?24 months of age, respectively; P < 0.001). Prevalence of elevated POC lactate did not differ by in utero ARV exposure drug class, but was significantly higher in children exposed in utero to emtricitabine or efavirenz, cocaine or opiates, and those of white race.POC lactate testing is a useful rapid laboratory screening assay for HEU children with ARV exposure. ARV use during pregnancy has resulted in a dramatic decrease in mother-to-child transmission of HIV, and the risk of elevated lactate in HEU children is low. However, as new ARVs and more complex regimens are used during pregnancy by HIV-infected women, continued monitoring for infant toxicities is essential.
| S-EPMC3242409 | biostudies-literature
Project description:Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)-infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents.To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children.Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012.First-trimester exposure to any ARV and to specific ARV medications.The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics.Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs.Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.
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Project description:Untreated human immunodeficiency virus (HIV) infection is characterized by depletion of CD4(+) T cells, ultimately leading to the impairment of host immune defenses and death. HIV-infected CD4(+) T cells die from direct virus-induced apoptosis and CD8 T-cell-mediated elimination, but a broader and more profound depletion occurs in uninfected CD4(+) T cells via multiple indirect effects of infection. We fit mathematical models to data from experiments that tested an HIV eradication strategy in which five macaques with a proportion of CD4(+) T cells resistant to simian-human immunodeficiency virus (SHIV) entry were challenged with SHIV89.6P, a highly pathogenic dual-tropic chimeric SIV-HIV viral strain that results in rapid loss of both SHIV-susceptible and SHIV-resistant CD4(+) T cells. Our results suggest that uninfected (bystander) cell death accounts for the majority of CD4(+) T-lymphocyte loss, with at least 60% and 99% of CD4(+) T cell death occurring in uninfected cells during acute and established infection, respectively. Mechanisms to limit the profound indirect killing effects associated with HIV infection may be associated with immune preservation and improved long-term survival.HIV infection induces a massive depletion of CD4(+) T cells, leading to profound immunodeficiency, opportunistic infections, and eventually death. While HIV induces apoptosis (programmed cell death) by directly entering and replicating in CD4(+) T cells, uninfected CD4(+) T cells also undergo apoptosis due to ongoing toxic inflammation in the region of infection. In this paper, we use mathematical models in conjunction with data from simian-human immunodeficiency virus SHIV89.6P infection in macaques (a model of HIV infection in humans) to estimate the percentage of cell death that occurs in uninfected cells during the initial period of infection. We reveal that the vast majority of cell death occurs in these cells, which are not infected. The "bystander effects" that lead to enormous reductions in the number of uninfected CD4(+) T cells may be a target for future interventions that aim to limit the extent of damage caused by HIV.
| S-EPMC3957925 | biostudies-literature
Project description:The effect of early versus deferred antiretroviral treatment (ART) on plasma concentration of lipopolysaccharide (LPS) and host LPS-binding molecules in human immunodeficiency virus (HIV)-infected infants up to 1 year of age was investigated.We evaluated 54 perinatally HIV-infected and 22 HIV-exposed uninfected infants (controls) at the first and second semester of life. All HIV-infected infants had a baseline CD4 of ? 25%, participated in the Comprehensive International Program of Research on AIDS Children with HIV Early Antiretroviral Therapy trial in South Africa, and were randomized in the following groups: group 1 (n = 20), ART deferred until CD4 < 25% or severe HIV disease; and group 2 (n = 34), ART initiation within 6 to 12 weeks of age. LPS, endotoxin-core antibodies, soluble CD14 (sCD14), and LPS-binding protein (LBP) were measured in cryopreserved plasma. T-cell activation was measured in fresh whole blood.At the first semester, LPS concentration was higher in HIV-infected infants than in controls; sCD14, LBP, and T-cell activation were higher in group 1 than in group 2 and controls. Although LPS was not correlated with study variables, viral load was positively associated with sCD14, LBP, or endotoxin-core antibodies. At the second semester, LPS was not detectable and elevated host LPS-control molecules values were sustained in all groups and in conjunction with ART in all HIV-infected infants.Although plasma concentration of LPS was higher in perinatally HIV-infected infants 0 to 6 months of age than in controls independent of ART initiation strategy, concentration of LPS-control molecules was higher in infants with deferred ART, suggesting the presence of increased microbial translocation in HIV-infected infants with sustained early viral replication.
| S-EPMC3173518 | biostudies-literature
Project description:BACKGROUND:Human Immunodeficiency Virus-Infected (HIV+) persons have elevated risks for various manifestations of cardiovascular disease (CVD). No studies to our knowledge have compared atrial fibrillation (AF) and atrial flutter (AFL) prevalence and associated characteristics for HIV+ persons and matched uninfected controls. METHODS AND FINDINGS:Persons with diagnoses of HIV receiving care at a large urban academic medical center were frequency-matched 1:2 on age, sex, race, zip code, and clinic location with uninfected persons. Possible AF/AFL was screened for using administrative codes and diagnoses of AF/AFL were subsequently adjudicated using electrocardiography and physician notes; adjudication was performed given the inconsistent validity of administrative code-derived AF diagnoses found in previous studies. There were 101 confirmed AF/AFL cases (2.00%) among 5,052 HIV+ patients and 159 confirmed AF/AFL cases (1.57%) among 10,121 uninfected controls [Odds Ratio (OR) 1.27, 95% Confidence Interval (CI) 0.99-1.64; p = 0.056]. The association between HIV serostatus and AF/AFL was attenuated after adjustment for demographics and CVD risk factors. Among HIV+ persons, nadir CD4+ T cell count <200 cells/mm3 was associated with approximately twofold elevated odds of AF/AFL even after adjustment for demographics and CVD risk factors (Multivariable-adjusted OR 1.98, 95% CI 1.21-3.25). There was no significant association between log10 of peak HIV viral load and AF/AFL (Multivariable-adjusted OR 1.03, 95% CI 0.86-1.24). Older age, diabetes, hypertension, and chronic obstructive pulmonary disease were associated with similarly elevated odds of AF/AFL for HIV+ persons and uninfected controls. CONCLUSION:HIV-related immunosuppression (nadir CD4 T cell count <200 cells/mm3) and traditional CVD risk factors are associated with significantly elevated odds of AF/AFL among HIV+ persons. Although atrial fibrillation and flutter was more common among HIV+ versus uninfected persons in this cohort, this difference was attenuated by adjustment for demographics and CVD risk factors.
| S-EPMC5860783 | biostudies-literature
Project description:BackgroundLimitations in the sensitivity and accessibility of diagnostic tools for childhood tuberculosis contribute to the substantial gap between estimated cases and cases notified to national tuberculosis programs. Thus, tools to make accurate and rapid clinical diagnoses are necessary to initiate antituberculosis treatment in more children.MethodsWe analyzed data from a prospective cohort of children <13 years old being routinely evaluated for pulmonary tuberculosis in Cape Town, South Africa, from March 2012 to November 2017. We developed a regression model to describe the contributions of baseline clinical evaluation to the diagnosis of tuberculosis using standardized, retrospective case definitions. We included baseline chest radiographic and Xpert MTB/RIF assay results to the model to develop an algorithm with ≥90% sensitivity in predicting tuberculosis.ResultsData from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age, 16.2 months; interquartile range, 9.8-30.9 months); 242 (50.6%) were retrospectively classified with tuberculosis, bacteriologically confirmed in 104 (43.0%). The area under the receiver operating characteristic curve for the final model was 0.87. Clinical evidence identified 71.4% of all tuberculosis cases in this cohort, and inclusion of baseline chest radiographic results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of >90% among children <2 years old or with low weight for age.ConclusionsClinical evidence alone was sufficient to make most clinical antituberculosis treatment decisions. The use of evidence-based algorithms may improve decentralized, rapid treatment initiation, reducing the global burden of childhood mortality.
| S-EPMC8366829 | biostudies-literature