Unusual Polymorphisms in Human Immunodeficiency Virus Type 1 Associated with Nonprogressive Infection

Factors accounting for long-term nonprogression may include infection with an attenuated strain of human immunodeficiency virus type 1 (HIV-1), genetic polymorphisms in the host, and virus-specific immune responses. In this study, we examined eight individuals with nonprogressing or slowly progressing HIV-1 infection, none of whom were homozygous for host-specific polymorphisms (CCR5-Δ32, CCR2-64I, and SDF-1-3\u27A) which have been associated with slower disease progression. HIV-1 was recovered from seven of the eight, and recovered virus was used for sequencing the full-length HIV-1 genome; full-length HIV-1 genome sequences from the eighth were determined following amplification of viral sequences directly from peripheral blood mononuclear cells (PBMC). Longitudinal studies of one individual with HIV-1 that consistently exhibited a slow/low growth phenotype revealed a single amino acid deletion in a conserved region of the gp41 transmembrane protein that was not seen in any of 131 envelope sequences in the Los Alamos HIV-1 sequence database. Genetic analysis also revealed that five of the eight individuals harbored HIV-1 with unusual 1- or 2-amino-acid deletions in the Gag sequence compared to subgroup B Gag consensus sequences. These deletions in Gag have either never been observed previously or are extremely rare in the database. Three individuals had deletions in Nef, and one had a 4-amino-acid insertion in Vpu. The unusual polymorphisms in Gag, Env, and Nef described here were also found in stored PBMC samples taken 3 to 11 years prior to, or in one case 4 years subsequent to, the time of sampling for the original sequencing. In all, seven of the eight individuals exhibited one or more unusual polymorphisms; a total of 13 unusual polymorphisms were documented in these seven individuals. These polymorphisms may have been present from the time of initial infection or may have appeared in response to immune surveillance or other selective pressures. Our results indicate that unusual, difficult-to-revert polymorphisms in HIV-1 can be found associated with slow progression or nonprogression in a majority of such cases

Ricardo flies Ryanair: Strategic human resource management and competitive advantage in a Single European Aviation Market

How and why are some firms, such as Ryanair, able to consistently record industry-leading profitability that sustains a competitive advantage over their rivals? HRM plays a critical role in four widely recognised profit-generating mechanisms, albeit not always in ways predicted by mainstream strategic HRM. Studies of HRMperformance grounded in the resource-based view (RBV) of the firm invariably focus on the human resources already controlled by the firm – specifically, resources that are rare, inimitable, non-substitutable and can be exploited through organisation (RINO) – rather than strategic factor markets (SFMs) where firms acquire their human resources. In doing so, these studies overlook the industrial relations and wider institutional context that might variously promote, permit or preclude particular HR policies and practices. It is only when different profit-generating mechanisms, either in isolation or combination, are activated under the auspicious conditions of a particular time and place that HRM contributes to sustained competitive advantage

HIV research in Australia: linking basic research findings with clinical and public health outcomes

Despite a population of only 20 million and sustained low prevalence of HIV infection in Australia, Australian researchers have provided many substantial original findings to the fields of HIV pathogenesis, treatment and prevention. More recently, Australian clinicians and scientists have turned their attention to assisting other countries in developing effective responses, particularly within the Asia-Pacific region. It is therefore fitting that the 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention will be held in Sydney in July 2007. The meeting is expected to attract over 5000 participants and will have a dynamic and innovative programme within the three major themes of HIV basic science, clinical research and biomedical prevention

Inefficient Nef-Mediated Downmodulation of CD3 and MHC-I Correlates with Loss of CD4+ T Cells in Natural SIV Infection

Recent data suggest that Nef-mediated downmodulation of TCR-CD3 may protect SIVsmm-infected sooty mangabeys (SMs) against the loss of CD4+ T cells. However, the mechanisms underlying this protective effect remain unclear. To further assess the role of Nef in nonpathogenic SIV infection, we cloned nef alleles from 11 SIVsmm-infected SMs with high (>500) and 15 animals with low (<500) CD4+ T-cells/µl in bulk into proviral HIV-1 IRES/eGFP constructs and analyzed their effects on the phenotype, activation, and apoptosis of primary T cells. We found that not only efficient Nef-mediated downmodulation of TCR-CD3 but also of MHC-I correlated with preserved CD4+ T cell counts, as well as with high numbers of Ki67+CD4+ and CD8+CD28+ T cells and reduced CD95 expression by CD4+ T cells. Moreover, effective MHC-I downregulation correlated with low proportions of effector and high percentages of naïve and memory CD8+ T cells. We found that T cells infected with viruses expressing Nef alleles from the CD4low SM group expressed significantly higher levels of the CD69, interleukin (IL)-2 and programmed death (PD)-1 receptors than those expressing Nefs from the CD4high group. SIVsmm Nef alleles that were less active in downmodulating TCR-CD3 were also less potent in suppressing the activation of virally infected T cells and subsequent cell death. However, only nef alleles from a single animal with very low CD4+ T cell counts rendered T cells hyper-responsive to activation, similar to those of HIV-1. Our data suggest that Nef may protect the natural hosts of SIV against the loss of CD4+ T cells by at least two mechanisms: (i) downmodulation of TCR-CD3 to prevent activation-induced cell death and to suppress the induction of PD-1 that may impair T cell function and survival, and (ii) downmodulation of MHC-I to reduce CTL lysis of virally infected CD4+ T cells and/or bystander CD8+ T cell activation

Elite Suppressors Harbor Low Levels of Integrated HIV DNA and High Levels of 2-LTR Circular HIV DNA Compared to HIV+ Patients On and Off HAART

Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population

Validity and reliability of the novel three-item occupational violence patient risk assessment tool

Aim: To develop and psychometrically test an occupational violence (OV) risk assessment tool in the emergency department (ED). Design: Three studies were conducted in phases: content validity, predictive validity and inter-rater reliability from June 2019 to March 2021. Methods: For content validity, ED end users (mainly nurses) were recruited to rate items that would appropriately assess for OV risk. Subsequently, a risk assessment tool was developed and tested for its predictive validity and inter-rater reliability. For predictive validity, triage notes of ED presentations in a month with the highest OV were assessed for presence of OV risk. Each presentation was then matched with events recorded in the OV incident register. Sensitivity and specificity values were calculated. For inter-rater reliability, two assessors—trained and untrained—independently assessed the triage notes for presence of OV risk. Cohen's kappa was calculated. Results: Two rounds of content validity with a total of N = 81 end users led to the development of a three-domain tool that assesses for OV risk using aggression history, behavioural concerns (i.e., angry, clenched fist, demanding, threatening language or resisting care) and clinical presentation concerns (i.e., alcohol/drug intoxication and erratic cognition). Recommended risk ratings are low (score = 0 risk domain present), moderate (score = 1 risk domain present) and high (score = 2–3 risk domains present), with an area under the curve of 0.77 (95% confidence interval 0.7–0.81, p <.01). Moderate risk rating had a 61% sensitivity and 91% specificity, whereas high risk rating had 37% sensitivity and 97% specificity. Inter-rater reliability ranged from 0.67 to 0.75 (p <.01), suggesting moderate agreement. Conclusions: The novel three-domain OV risk assessment tool was shown to be appropriate and relevant for application in EDs. The tool, developed through a rigorous content validity process, demonstrates acceptable predictive validity and inter-rater reliability. Impact: The developed tool is currently piloted in a single hospital ED, with a view to extend to inpatient settings and other hospitals.Full Tex

The 'dangerous other' in maximum-security prisons

Drawing on data from maximum-security prisons in England, this article explores the way the representation of criminals as ‘dangerous others’ manifests in prison discourse and practice. Following Bourdieu, it is argued that within the ‘habitus of maximum-security’, prison staff become somewhat predisposed to seeing prisoners as essentialised, ‘dangerous others’ who are not ‘like us’, a perspective that is also reinforced in popular and tabloid print media outside the prison walls. The strength of these representations coupled with the habitus of maximum-security thus constrains possibilities for alternative representations of prisoners labelled as ‘dangerous others’ or for alternative ways of structuring the ethos and conditions of maximum-security prisons