Functional stability of HIV-1 envelope trimer affects accessibility to broadly neutralizing antibodies at its apex

ABSTRACT The trimeric envelope glycoprotein spike (Env) of HIV-1 is the target of vaccine development to elicit broadly neutralizing antibodies (bnAbs). Env trimer instability and heterogeneity in principle make subunit interfaces inconsistent targets for the immune response. Here, we investigate how functional stability of Env relates to neutralization sensitivity to V2 bnAbs and V3 crown antibodies that engage subunit interfaces upon binding to unliganded Env. Env heterogeneity was inferred when antibodies neutralized a mutant Env with a plateau of less than 100% neutralization. A statistically significant correlation was found between the stability of mutant Envs and the MPN of V2 bnAb, PG9, as well as an inverse correlation between stability of Env and neutralization by V3 crown antibody, 447-52D. A number of Env-stabilizing mutations and V2 bnAb-enhancing mutations were identified in Env, but they did not always overlap, indicating distinct requirements of functional stabilization versus antibody recognition. Blocking complex glycosylation of Env affected V2 bnAb recognition, as previously described, but also notably increased functional stability of Env. This study shows how instability and heterogeneity affect antibody sensitivity of HIV-1 Env, which is relevant to vaccine design involving its dynamic apex. IMPORTANCE The Env trimer is the only viral protein on the surface of HIV-1 and is the target of neutralizing antibodies that reduce viral infectivity. Quaternary epitopes at the apex of the spike are recognized by some of the most potent and broadly neutralizing antibodies to date. Being that their glycan-protein hybrid epitopes are at subunit interfaces, the resulting heterogeneity can lead to partial neutralization. Here, we screened for mutations in Env that allowed for complete neutralization by the bnAbs. We found that when mutations outside V2 increased V2 bnAb recognition, they often also increased Env stability-of-function and decreased binding by narrowly neutralizing antibodies to the V3 crown. Three mutations together increased neutralization by V2 bnAb and eliminated binding by V3 crown antibodies. These results may aid the design of immunogens that elicit antibodies to the trimer apex. </jats:p

COMPETITIVE STRATEGIES AND ORGANIZATIONAL SURVIVAL OF MANUFACTURING FIRMS IN RIVERS STATE

This study examined the association between competitive strategies and organizational survival of manufacturing firms in Rivers State, As well as the moderating effect of technology on the relationship between competitive strategies and organizational survival. The cross-sectional research design was applied in this study. A total of one hundred and eighty-one (181) managers and supervisors from ten (10) manufacturing firms, constituted the sample elements. The simple random sampling technique was used. Primary data was collected for this study and copies of questionnaire was the main instrument for collection of data. The instrument was subjected to face and content validity and the reliability of the instrument was checked using cronbach alpha test. Seven (7) null hypothesis were formulated and tested using partial least square -structural equation modelling (smart pls). The outcome of the analyses revealed a significant positive association between the dimensions of competitive strategies(cost leadership, differentiation and focus strategy) and the measures of organizational survival (innovation and adaptability). Technology was also found to significantly moderate the relationship. The study concluded that adoption of competitive strategies enhances the survival of organizations. The study recommended that Management should apply cost leadership strategies as it provides an opportunity to enhance the firms innovative capability and adaptability to internal and external environmental thereby maximizing its survival

Pastoral and Bio-medical Responses to HIV and AIDS by the Lutheran Communion in Southern Africa (LUCSA): Case Study of the Thusanang HIV & AIDS Project and Manama Mission Hospital in Zimbabwe

This article is an exposition of the Pastoral and Biomedical Responses to HIV and AIDS programming by LUCSA. This was done through engaging with members and workers of the church regarding their experiences of Home Based Care (HBC) training as a way of managing and holistically responding to the HIV and AIDS epidemic. This study explores the impact of the training for caregivers, nursing staff and pastors in HIV and AIDS management through a case study of the Thusanang HIV &amp; AIDS project and Manama Mission Hospital of the Western Diocese of the Evangelical Lutheran Church in Zimbabwe (ELCZ) in Gwanda South. The study concludes that skills training in HBC and Palliative Care have made a positive and remarkable impact on the lives and work of HBC givers and pastors and that such training has contributed to the retention of caregivers

Sustained Sexual Behavior Change after Acute HIV Diagnosis in Malawi

Background Identification of acute HIV infection (AHI) allows for important opportunities for HIV prevention through behavior change and biomedical intervention. Here, we evaluate changes in sexual risk behaviors among persons with AHI enrolled in a combined behavioral and biomedical intervention designed to reduce onward transmission of HIV. Methods Participants were randomized to standard HIV counseling, a multisession behavioral intervention, or a multisession behavioral intervention plus antiretrovirals. Sexual behaviors were assessed periodically over 1 year. Results Four weeks after diagnosis, the predicted probability of reporting multiple sexual partners decreased from 24% to 9%, and the probability of reporting unprotected sex decreased from 71% to 27%. These declines in sexual risk behaviors were sustained over follow-up irrespective of study arm. Conclusions Diagnosis of AHI alone may be sufficient to achieve immediate and sustained behavior change during this highly infectious period

Guanine nucleotide dissociation inhibitor activity of the triple GoLoco motif protein G18: alanine-to-aspartate mutation restores function to an inactive second GoLoco motif

GoLoco ('Galpha(i/o)-Loco' interaction) motif proteins have recently been identified as novel GDIs (guanine nucleotide dissociation inhibitors) for heterotrimeric G-protein alpha subunits. G18 is a member of the mammalian GoLoco-motif gene family and was uncovered by analyses of human and mouse genomes for anonymous open-reading frames. The encoded G18 polypeptide is predicted to contain three 19-amino-acid GoLoco motifs, which have been shown in other proteins to bind Galpha subunits and inhibit spontaneous nucleotide release. However, the G18 protein has thus far not been characterized biochemically. Here, we have cloned and expressed the G18 protein and assessed its ability to act as a GDI. G18 is capable of simultaneously binding more than one Galpha(i1) subunit. In binding assays with the non-hydrolysable GTP analogue guanosine 5'-[gamma-thio]triphosphate, G18 exhibits GDI activity, slowing the exchange of GDP for GTP by Galpha(i1). Only the first and third GoLoco motifs within G18 are capable of interacting with Galpha subunits, and these bind with low micromolar affinity only to Galpha(i1) in the GDP-bound form, and not to Galpha(o), Galpha(q), Galpha(s) or Galpha12. Mutation of Ala-121 to aspartate in the inactive second GoLoco motif of G18, to restore the signature acidic-glutamine-arginine tripeptide that forms critical contacts with Galpha and its bound nucleotide [Kimple, Kimple, Betts, Sondek and Siderovski (2002) Nature (London) 416, 878-881], results in gain-of-function with respect to Galpha binding and GDI activity

Human Immunodeficiency Virus (HIV)-1 Transmission among Persons with Acute HIV-1 Infection in Malawi: Demographic, Behavioral, and Phylogenetic Relationships

Background: Understanding sexual networks involving acute human immunodeficiency virus (HIV)-1 infections (AHI) may lead to prevention opportunities to mitigate high rates of onward transmission. We evaluated HIV-1 phylogenetic and behavioral characteristics among persons with AHI and their referred partners. Methods: Between 2012 and 2014, 46 persons with AHI in Malawi participated in a combined behavioral and biomedical intervention. Participants referred sexual partners by passive referral. Demographics and sexual behaviors were collected through interviews and HIV-1 genetic relationships were assessed with phylogenetics. Results: Among 45 AHI participants with HIV-1 sequences, none was phylogenetically-linked with another AHI index. There were 19 (42%) AHI participants who referred a single partner that returned for testing. Most partners (n = 17) were HIV-infected, with 15 (88%) presenting with an established infection. There were 14 index-partner pairs that had sequences available; 13 (93%) pairs were phylogenetically-linked dyads. The AHI index was female in 7/13 (54%) dyads. Age-disparate relationships among dyads were common (≥5-year age difference in 67% of dyads), including 3/6 dyads involving a male index and a younger woman. Index participants with a referred partner were more likely to report no casual partners and to be living with their current partner than participants not in dyads. Conclusions: Passive-partner referral successfully identified partners with genetically-similar HIV infections - the likely source of infection - but only 40% of index cases referred partners who presented for HIV-1 testing. Future work evaluating assisted partner notification may help reach susceptible partners or more people with untreated HIV-1 infections connected to acute transmission. Clinical Trials Registration: NCT01450189

The relation of preventive dental behaviors to periodontal health status

. Current recommendations for periodontal health maintenance emphasize toothbrushing, flossing and periodic dental checkups. The purposes of this study were to examine (1) the effects of these practices on periodontal health and (2) the relationships of demographic and socioeconomic variables with these behaviors and with periodontal health. Adults ( n = 319) in the Detroit, Michigan tri-county area were asked how frequently they performed the 3 preventive behaviors. Levels of plaque, gingivitis, calculus, and periodontal attachment were then assessed during in-home dental examinations. There were no statistically significant differences in these health measures between those with acceptable and unacceptable brushing behavior. About 20% of the subjects reported acceptable flossing behavior, and these individuals had significantly less plaque and calculus than other participants. Over 3/4 of subjects reported having a dental checkup at least 1 × a year, and these persons were found to have significantly less plaque, gingivitis, and calculus compared to less frequent attenders. Acceptable brushing behavior was not associated with any particular demographic or socio-economic characteristic, while differences in acceptable flossing behavior were found among age groups. Frequencies of yearly dental checkups varied significantly within every demographic and socioeconomic characteristic.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75510/1/j.1600-051X.1994.tb00303.x.pd

Randomized Controlled Pilot Study of Antiretrovirals and a Behavioral Intervention for Persons with Acute HIV Infection: Opportunity for Interrupting Transmission

Background. Persons with acute HIV infection (AHI) have heightened transmission risk. We evaluated potential transmission reduction using behavioral and biomedical interventions in a randomized controlled pilot study in Malawi. Methods. Persons were randomized 1:2:2 to standard counseling (SC), 5-session behavioral intervention (BI), or behavioral intervention plus 12 weeks of antiretrovirals (ARVs; BIA). All were followed for 26-52 weeks and, regardless of arm, referred for treatment according to Malawi-ARV guidelines. Participants were asked to refer partners for testing. Results. Among 46 persons (9 SC, 18 BI, 19 BIA), the average age was 28; 61% were male. The median viral load (VL) was 5.9 log copies/mL at enrollment. 67% (10/15) of BIA participants were suppressed (<1000 copies/mL) at week 12 vs 25% BI and 50% SC (P = .07). Although the mean number of reported condomless sexual acts in the past week decreased from baseline across all arms (1.5 vs 0.3 acts), 36% experienced incident sexually transmitted infection by 52 weeks (12% SC, 28% BI, 18% BIA). Forty-one percent (19/46) of participants referred partners (44% SC, 44% BI, 37% BIA); 15 of the partners were HIV-infected. Conclusions. Diagnosis of AHI facilitates behavioral and biomedical risk reduction strategies during a high-transmission period that begins years before people are typically identified and started on ARVs. Sexually transmitted infection incidence in this cohort suggests ongoing risk behaviors, reinforcing the importance of early intervention with ARVs to reduce transmission. Early diagnosis coupled with standard AHI counseling and early ARV referral quickly suppresses viremia, may effectively change behavior, and could have tremendous public health benefit in reducing onward transmission

Agroecological management of fall armyworm using soil and botanical treatments reduces crop damage and increases maize yield

IntroductionFall armyworm continues to disrupt smallholder farming systems across sub-Saharan Africa, with sporadic outbreaks and chronic cereal crop losses. Smallholders have been adapting to the pest by increasing crop surveillance for targeted control measures and developing low-cost solutions. For example, some report placing soil or ash in maize whorls where the mechanism of pest control may be suffocation, abrasion leading to desiccation, or through the introduction of soil-borne entomopathogens.MethodsTo verify the efficacy of this approach we evaluated different soil types on maize infested with fall armyworm to assess their efficacy. We also evaluated the efficacy of pesticidal plant species, powdered and placed in leaf whorls to control fall armyworm. Results and discussionDifferent United States Department of Agriculture-characterised soil types (sand, loam, clay) and wood ash were effective in reducing the number of larvae and maize leaf damage by approximately 50%. Maize yield with the synthetic control (chlorpyriphos) was 13,700 kg/ha, which was 42% higher than the untreated control (7,900 kg/ha). Soil and ash treatments yields between 10,400 to 12,400 kg/ha were 24-36% higher than the untreated control. Dry soil applied after watering was most effective regardless of soil type. However, wet soil treatments applied before watering were also highly effective in reducing the number of fall armyworm larvae and reducing insect damage to maize leaves. Botanical powders from Azadirachta indica, Nicotiana tabacum, Cymbopogon citratus and Lippia javanica were also effective when applied to maize leaf whorls. Plant powder treatments and water extracts were significantly effective in reducing the number of larvae and leaf damage. The highest yield obtained with botanicals was observed with A. indica powder (5,600 kg/ha), C. citratus extract (5,800 kg/ha) and N. tabacum extract (5,800 kg/ha), where the synthetic treatment yield was 6,900 kg/ha and the untreated yield was 1,700 kg/ha. We conclude that smallholder farmer innovations in managing fall armyworm are effective low-cost options. Scientific validation of soil treatments and botanicals should help increase the confidence of policy makers and allow knowledge extension services to recommend their use to smallholder farmers, which in turn may reduce reliance on imported synthetic pesticides and improve farmer resilience, circular economies and human and environmental health