Thriving under stress: selective translation of HIV-1 structural protein mRNA during Vpr-mediated impairment of eIF4E translation activity.

Translation is a regulated process and is pivotal to proper cell growth and homeostasis. All retroviruses rely on the host translational machinery for viral protein synthesis and thus may be susceptible to its perturbation in response to stress, co-infection, and/or cell cycle arrest. HIV-1 infection arrests the cell cycle in the G2/M phase, potentially disrupting the regulation of host cell translation. In this study, we present evidence that HIV-1 infection downregulates translation in lymphocytes, attributable to the cell cycle arrest induced by the HIV-1 accessory protein Vpr. The molecular basis of the translation suppression is reduced accumulation of the active form of the translation initiation factor 4E (eIF4E). However, synthesis of viral structural proteins is sustained despite the general suppression of protein production. HIV-1 mRNA translation is sustained due to the distinct composition of the HIV-1 ribonucleoprotein complexes. RNA-coimmunoprecipitation assays determined that the HIV-1 unspliced and singly spliced transcripts are predominantly associated with nuclear cap binding protein 80 (CBP80) in contrast to completely-spliced viral and cellular mRNAs that are associated with eIF4E. The active translation of the nuclear cap binding complex (CBC)-bound viral mRNAs is demonstrated by ribosomal RNA profile analyses. Thus, our findings have uncovered that the maintenance of CBC association is a novel mechanism used by HIV-1 to bypass downregulation of eIF4E activity and sustain viral protein synthesis. We speculate that a subset of CBP80-bound cellular mRNAs contribute to recovery from significant cellular stress, including human retrovirus infection.

Case reports of congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS), which occurs in less than 1 in every 50,000 infants and children, is a rare syndrome first noted in literature by Mellins in 1970. Congenital central hypoventilation syndrome is a condition in which the patient loses the drive to breathe during deep sleep and can mimic many diseases. Until recently, CCHS has largely been a diagnosis of exclusion; fortunately, there is now a genetic test available to confirm the diagnosis. The purpose of this article is to discuss the steps taken to confirm the diagnosis of CCHS. In addition to the history of the disease and clinical manifestations, genetics and prognosis of children with CCHS will be discussed. Two cases are presented for illustration of hospital course and preparation for discharge.

Selective translational repression of HIV-1 RNA by Sam68DeltaC occurs by altering PABP1 binding to unspliced viral RNA.

HIV-1 structural proteins are translated from incompletely spliced 9 kb and 4 kb mRNAs, which are transported to the cytoplasm by Crm1. It has been assumed that once in the cytoplasm, translation of incompletely spliced HIV-1 mRNAs occurs in the same manner as host mRNAs. Previous analyses have demonstrated that Sam68 and a mutant thereof, Sam68DeltaC, have dramatic effects on HIV gene expression, strongly enhancing and inhibiting viral structural protein synthesis, respectively. While investigating the inhibition of incompletely spliced HIV-1 mRNAs by Sam68DeltaC, we determined that the effect was independent of the perinuclear bundling of the viral RNA. Inhibition was dependent upon the nuclear export pathway used, as translation of viral RNA exported via the Tap/CTE export pathway was not blocked by Sam68DeltaC. We demonstrate that inhibition of HIV expression by Sam68DeltaC is correlated with a loss of PABP1 binding with no attendant change in polyadenosine tail length of the affected RNAs. The capacity of Sam68DeltaC to selectively inhibit translation of HIV-1 RNAs exported by Crm1 suggests that it is able to recognize unique characteristics of these viral RNPs, a property that could lead to new therapeutic approaches to controlling HIV-1 replication.

Modulating HIV-1 RNA processing and utilization.

Expression of the integrated HIV-1 provirus is achieved by overcoming multiple barriers to the processing, transport and utilization of the viral RNA. Some of the strategies involve viral encoded proteins (i.e. Rev, Gag). However, in large part it is host factors that play essential roles in the movement of HIV-1 RNA from the site of transcription to its ultimate encapsidation into new virions. Identifying these factors and their mechanism of action provides not only important insights into HIV-1 molecular biology but also that of the cell machinery itself. In this review, we highlight the viral and host factors regulating the splicing, polyadenylation, transport, and translation of HIV-1 RNA. The observations made underline the multiple fate decisions that must be made at each stage of the viral RNA metabolic pathway and highlight potential new avenues for controlling HIV-1 replication.

Developing and implementing national health identifiers in resource limited countries: why, what, who, when and how?

Many resource-limited countries are scaling up health services and health-information systems (HISs). The HIV Cascade framework aims to link treatment services and programs to improve outcomes and impact. It has been adapted to HIV prevention services, other infectious and non-communicable diseases, and programs for specific populations. Where successful, it links the use of health services by individuals across different disease categories, time and space. This allows for the development of longitudinal health records for individuals and de-identified individual level information is used to monitor and evaluate the use, cost, outcome and impact of health services. Contemporary digital technology enables countries to develop and implement integrated HIS to support person centred services, a major aim of the Sustainable Development Goals. The key to link the diverse sources of information together is a national health identifier (NHID). In a country with robust civil protections, this should be given at birth, be unique to the individual, linked to vital registration services and recorded every time that an individual uses health services anywhere in the country: it is more than just a number as it is part of a wider system. Many countries would benefit from practical guidance on developing and implementing NHIDs. Organizations such as ASTM and ISO, describe the technical requirements for the NHID system, but few countries have received little practical guidance. A WHO/UNAIDS stake-holders workshop was held in Geneva, Switzerland in July 2016, to provide a 'road map' for countries and included policy-makers, information and healthcare professionals, and members of civil society. As part of any NHID system, countries need to strengthen and secure the protection of personal health information. While often the technology is available, the solution is not just technical. It requires political will and collaboration among all stakeholders to be successful.

Evaluation of a non-name-based HIV reporting system in San Francisco.

OBJECTIVE: To develop and evaluate a non-name-based HIV reporting system. METHODS: A population-based study of the accuracy of a set of non-name codes and a prospective study of a laboratory-initiated HIV surveillance system conducted at a county hospital (site 1) and a health maintenance organization (site 2). Participants were persons reported with AIDS in San Francisco and patients with a positive test result for HIV antibody, p24 antigen, viral load, or a CD4 count at the study sites. RESULTS: Proper match rate was 95% for records with complete codes and records with at least 50% of the codes. Proper non-match rate was 99% for records with all code elements and 96% for records with at least 50% of the elements. Completeness of reporting was 89% (site 1) and 87% (site 2). Median number of days between test and receipt of test report at the health department was 9 days at site 1 and 7 days at site 2. During 1999, 78% of HIV-infected patients at site 1 and 87% at site 2 had an HIV-specific laboratory test. CONCLUSIONS: A non-name-based laboratory reporting system for HIV is feasible.