The HIV-1 capsid serves as a nanoscale reaction vessel for reverse transcription.

The viral capsid performs critical functions during HIV-1 infection and is a validated target for antiviral therapy. Previous studies have established that the proper structure and stability of the capsid are required for efficient HIV-1 reverse transcription in target cells. Moreover, it has recently been demonstrated that permeabilized virions and purified HIV-1 cores undergo efficient reverse transcription in vitro when the capsid is stabilized by addition of the host cell metabolite inositol hexakisphosphate (IP6). However, the molecular mechanism by which the capsid promotes reverse transcription is undefined. Here we show that wild type HIV-1 particles can undergo efficient reverse transcription in vitro in the absence of a membrane-permeabilizing agent. This activity, originally termed "natural endogenous reverse transcription" (NERT), depends on expression of the viral envelope glycoprotein during virus assembly and its incorporation into virions. Truncation of the gp41 cytoplasmic tail markedly reduced NERT activity, indicating that gp41 permits the entry of nucleotides into virions. Protease treatment of virions markedly reduced NERT suggesting the presence of a proteinaceous membrane channel. By contrast to reverse transcription in permeabilized virions, NERT required neither the addition of IP6 nor a mature capsid, indicating that an intact viral membrane can substitute for the function of the viral capsid during reverse transcription in vitro. Collectively, these results demonstrate that the viral capsid functions as a nanoscale container for reverse transcription during HIV-1 infection.

Addressing child health inequity through case management of under-five malaria in Nigeria: an extended cost-effectiveness analysis.

BACKGROUND: Under-five malaria in Nigeria is a leading cause of global child mortality, accounting for 95,000 annual child deaths. High out-of-pocket medical expenditure contributes to under-five malaria mortality by discouraging care-seeking and use of effective anti-malarials in the poorest households. The significant inequity in child health outcomes in Nigeria stresses the need to evaluate the outcomes of potential interventions across socioeconomic lines. METHODS: Using a decision tree model, an extended cost-effectiveness analysis was done to determine the effects of subsidies covering the direct and indirect costs of case management of under-five malaria in Nigeria. This analysis estimates the number of child deaths averted, out-of-pocket (OOP) expenditure averted, cases of catastrophic health expenditure (CHE) averted, and cost of implementation. An optimization analysis was also done to determine how to optimally allocate money across wealth groups using different combinations of interventions. RESULTS: Fully subsidizing direct medical, non-medical, and indirect costs could annually avert over 19,000 under-five deaths, 8600 cases of CHE, and US$187 million in OOP spending. Per US$1 million invested, this corresponds to an annual reduction of 76 under-five deaths, 34 cases of CHE, and over US$730,000 in OOP expenditure. Due to low initial treatment coverage in poorer socioeconomic groups, health and financial-risk protection benefits would be pro-poor, with the poorest 40% of Nigerians accounting for 72% of all deaths averted, 55% of all OOP expenditure averted, and 74% of all cases of CHE averted. Subsidies targeted to the poor would see greater benefits per dollar spent than broad, non-targeted subsidies. In an optimization scenario, the strategy of fully subsidizing direct medical costs would be dominated by a partial subsidy of direct medical costs as well as a full subsidy of direct medical, nonmedical, and indirect costs. CONCLUSION: Subsidizing case management of under-five malaria for the poorest and most vulnerable would reduce illness-related impoverishment and child mortality in Nigeria while preserving limited financial resources. This study is an example of how focusing a targeted policy-intervention on a single, high-burden disease can yield large health and financial-risk protection benefits in a low and middle-income country context and address equity consideration in evidence-informed policymaking.

Heterogeneity in the Effectiveness of Non-pharmaceutical Interventions During the First SARS-CoV2 Wave in the United States.

Background: Attempts to quantify effect sizes of non-pharmaceutical interventions (NPI) to control COVID-19 in the US have not accounted for heterogeneity in social or environmental factors that may influence NPI effectiveness. This study quantifies national and sub-national effect sizes of NPIs during the early months of the pandemic in the US. Methods: Daily county-level COVID-19 cases and deaths during the first wave (January 2020 through phased removal of interventions) were obtained. County-level cases, doubling times, and death rates were compared to four increasingly restrictive NPI levels. Socio-demographic, climate and mobility factors were analyzed to explain and evaluate NPI heterogeneity, with mobility used to approximate NPI compliance. Analyses were conducted separately for the US and for each Census regions (Pacific, Mountain, east/West North Central, East/West South Central, South Atlantic, Middle Atlantic and New England). A stepped-wedge cluster-randomized trial analysis was used, leveraging the phased implementation of policies. Results: Aggressive (level 4) NPIs were associated with slower COVID-19 propagation, particularly in high compliance counties. Longer duration of level 4 NPIs was associated with lower case rates (log beta -0.028, 95% CI -0.04 to -0.02) and longer doubling times (log beta 0.02, 95% CI 0.01-0.03). Effects varied by Census region, for example, level 4 effects on doubling time in Pacific states were opposite to those in Middle Atlantic and New England states. NPI heterogeneity can be explained by differential timing of policy initiation and by variable socio-demographic county characteristics that predict compliance, particularly poverty and racial/ethnic population. Climate exhibits relatively consistent relationships across Census regions, for example, higher minimum temperature and specific humidity were associated with lower doubling times and higher death rates for this period of analysis in South Central, South Atlantic, Middle Atlantic, and New England states. Conclusion and Relevance: Heterogeneity exists in both the effectiveness of NPIs across US Census regions and policy compliance. This county-level variability indicates that control strategies are best designed at community-levels where policies can be tuned based on knowledge of local disparities and compliance with public health ordinances.