Distinct viral reservoirs in individuals with spontaneous control of HIV-1.

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.

Cost-effectiveness of intervention combinations towards the elimination of vertical transmission of HIV in limited-resource settings: a mathematical modelling study.

BACKGROUND: Since 2000, there has been a substantial global reduction in the vertical transmission of HIV. Despite effective interventions, gaps still remain in progress towards elimination in many low-income and middle-income countries. We developed a mathematical model to determine the most cost-effective combinations of interventions to prevent vertical transmission. METHODS: We developed a 12-month Markov model to follow a cohort of women of childbearing age (aged 15-49 years) in Zambia (n=1 107 255) who were either pregnant, in delivery, or breastfeeding; the population included in the model reflects the estimated number of pregnant women in Zambia from the 2018 Zambia Demographic and Health Survey. The model incorporated nine interventions: infant prophylaxis; three different HIV retesting schedule options; oral pre-exposure prophylaxis; maternal peer-support groups; regimen shift; tracing of loss to follow-up; and point-of-care viral load testing. We analysed incident HIV infections among mothers and infants, intervention costs, and evaluated 190 scenarios of different combinations of inventions to calculate the incremental cost-effectiveness ratios (ICERs) over 1 year. FINDINGS: Three interventions with the greatest reduction in vertical transmission, individually, were support groups for 80% of those in need (35% reduction in infant infections), HIV retesting schedules (6·5% reduction), and infant prophylaxis (4·5% reduction). Of all 190 scenarios evaluated, eight were on the cost-effectiveness frontier (ie, were considered to be cost-effective); all eight included increasing infant prophylaxis, regimen shift, and use of support groups. Excluding the highest-cost scenarios, for a 1-22% increase in total budget, 23-43% of infant infections could be prevented, producing ICERs between US$244 and $16 242. INTERPRETATION: Using the interventions modelled, it is possible to reduce vertical transmission and to cost-effectively prevent up to 1734 infant HIV infections (43% reduction) in Zambia over a period of 1 year. To optimise their effect, these interventions must be scaled with fidelity. Future work is needed to incorporate evidence on additional innovative interventions and HIV risk factors, and to apply the model to other country contexts to support targeted implementation and resource use. FUNDING: The ELMA Foundation.

Cost-effectiveness of SARS-CoV-2 self-testing at routine gatherings to minimize community-level infections in lower-middle income countries: A mathematical modeling study.

Places of worship serve as a venue for both mass and routine gathering around the world, and therefore are associated with risk of large-scale SARS-CoV-2 transmission. However, such routine gatherings also offer an opportunity to distribute self-tests to members of the community to potentially help mitigate transmission and reduce broader community spread of SARS-CoV-2. Over the past four years, self-testing strategies have been an impactful tool for countries' response to the COVID-19 pandemic, especially early on to mitigate the spread when vaccination and treatment options were limited. We used an agent-based mathematical model to estimate the impact of various strategies of symptomatic and asymptomatic self-testing for a fixed percentage of weekly routine gatherings at places of worship on community transmission of SARS-CoV-2 in Brazil, Georgia, and Zambia. Testing strategies assessed included weekly and bi-weekly self-testing across varying levels of vaccine effectiveness, vaccine coverage, and reproductive numbers to simulate developing stages of the COVID-19 pandemic. Self-testing symptomatic people attending routine gatherings can cost-effectively reduce the spread of SARS-CoV-2 within places of worship and the community, resulting in incremental cost-effectiveness ratios of $69-$303 USD. This trend is especially true in contexts where population level attendance at such gatherings is high, demonstrating that a distribution approach is more impactful when a greater proportion of the population is reached. Asymptomatic self-testing of attendees at 100% of places of worship in a country results in the greatest percent of infections averted and is consistently cost-effective but remains costly. Budgetary needs for asymptomatic testing are expensive and likely unaffordable for lower-middle income countries (520-1550x greater than that of symptomatic testing alone), promoting that strategies to strengthen symptomatic testing should remain a higher priority.

Impact and cost-effectiveness of SARS-CoV-2 self-testing strategies in schools: a multicountry modelling analysis.

OBJECTIVES: To determine the most epidemiologically effective and cost-effective school-based SARS-CoV-2 antigen-detection rapid diagnostic test (Ag-RDT) self-testing strategies among teachers and students. DESIGN: Mathematical modelling and economic evaluation. SETTING AND PARTICIPANTS: Simulated school and community populations were parameterised to Brazil, Georgia and Zambia, with SARS-CoV-2 self-testing strategies targeted to teachers and students in primary and secondary schools under varying epidemic conditions. INTERVENTIONS: SARS-CoV-2 Ag-RDT self-testing strategies for only teachers or teachers and students-only symptomatically or symptomatically and asymptomatically at 5%, 10%, 40% or 100% of schools at varying frequencies. OUTCOME MEASURES: Outcomes were assessed in terms of total infections and symptomatic days among teachers and students, as well as total infections and deaths within the community under the intervention compared with baseline. The incremental cost-effectiveness ratios (ICERs) were calculated for infections prevented among teachers and students. RESULTS: With respect to both the reduction in infections and total cost, symptomatic testing of all teachers and students appears to be the most cost-effective strategy. Symptomatic testing can prevent up to 69·3%, 64·5% and 75·5% of school infections in Brazil, Georgia and Zambia, respectively, depending on the epidemic conditions, with additional reductions in community infections. ICERs for symptomatic testing range from US$2 to US$19 per additional school infection averted as compared with symptomatic testing of teachers alone. CONCLUSIONS: Symptomatic testing of teachers and students has the potential to cost-effectively reduce a substantial number of school and community infections.

Cost of SARS-CoV-2 self-test distribution programmes by different modalities: a micro-costing study in five countries (Brazil, Georgia, Malaysia, Ethiopia and the Philippines).

OBJECTIVE: Diagnostic testing is an important tool to combat the COVID-19 pandemic, yet access to and uptake of testing vary widely 3 years into the pandemic. The WHO recommends the use of COVID-19 self-testing as an option to help expand testing access. We aimed to calculate the cost of providing COVID-19 self-testing across countries and distribution modalities. DESIGN: We estimated economic costs from the provider perspective to calculate the total cost and the cost per self-test kit distributed for three scenarios that differed by costing period (pilot, annual), the number of tests distributed (actual, planned, scaled assuming an epidemic peak) and self-test kit costs (pilot purchase price, 50% reduction). SETTING: We used data collected between August and December 2022 in Brazil, Georgia, Malaysia, Ethiopia and the Philippines from pilot implementation studies designed to provide COVID-19 self-tests in a variety of settings-namely, workplace and healthcare facilities. RESULTS: Across all five countries, 173 000 kits were distributed during pilot implementation with the cost/test distributed ranging from $2.44 to $12.78. The cost/self-test kit distributed was lowest in the scenario that assumed implementation over a longer period (year), with higher test demand (peak) and a test kit price reduction of 50% ($1.04-3.07). Across all countries and scenarios, test procurement occupied the greatest proportion of costs: 58-87% for countries with off-site self-testing (outside the workplace, for example, home) and 15-50% for countries with on-site self-testing (at the workplace). Staffing was the next key cost driver, particularly for distribution modalities that had on-site self-testing (29-35%) versus off-site self-testing (7-27%). CONCLUSIONS: Our results indicate that it is likely to cost between $2.44 and $12.78 per test to distribute COVID-19 self-tests across common settings in five heterogeneous countries. Cost-effectiveness analyses using these results will allow policymakers to make informed decisions on optimally scaling up COVID-19 self-test distribution programmes across diverse settings and evolving needs.

Progressive transformation of the HIV-1 reservoir cell profile over two decades of antiviral therapy.

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions.

Optimal use of COVID-19 Ag-RDT screening at border crossings to prevent community transmission: A modeling analysis.

Countries around the world have implemented restrictions on mobility, especially cross-border travel to reduce or prevent SARS-CoV-2 community transmission. Rapid antigen testing (Ag-RDT), with on-site administration and rapid turnaround time may provide a valuable screening measure to ease cross-border travel while minimizing risk of local transmission. To maximize impact, we developed an optimal Ag-RDT screening algorithm for cross-border entry. Using a previously developed mathematical model, we determined the daily number of imported COVID-19 cases that would generate no more than a relative 1% increase in cases over one month for different effective reproductive numbers (Rt) and COVID-19 prevalence within the recipient country. We then developed an algorithm-for differing levels of Rt, arrivals per day, mode of travel, and SARS-CoV-2 prevalence amongst travelers-to determine the minimum proportion of people that would need Ag-RDT testing at border crossings to ensure no greater than the relative 1% community spread increase. When daily international arrivals and/or COVID-19 prevalence amongst arrivals increases, the proportion of arrivals required to test using Ag-RDT increases. At very high numbers of international arrivals/COVID-19 prevalence, Ag-RDT testing is not sufficient to prevent increased community spread, especially when recipient country prevalence and Rt are low. In these cases, Ag-RDT screening would need to be supplemented with other measures to prevent an increase in community transmission. An efficient Ag-RDT algorithm for SARS-CoV-2 testing depends strongly on the epidemic status within the recipient country, volume of travel, proportion of land and air arrivals, test sensitivity, and COVID-19 prevalence among travelers.

Signatures of immune selection in intact and defective proviruses distinguish HIV-1 elite controllers.

Increasing evidence suggests that durable drug-free control of HIV-1 replication is enabled by effective cellular immune responses that may induce an attenuated viral reservoir configuration with a weaker ability to drive viral rebound. Here, we comprehensively tracked effects of antiviral immune responses on intact and defective proviral sequences from elite controllers (ECs), analyzing both classical escape mutations and HIV-1 chromosomal integration sites as biomarkers of antiviral immune selection pressure. We observed that, within ECs, defective proviruses were commonly located in permissive genic euchromatin positions, which represented an apparent contrast to autologous intact proviruses that were frequently located in heterochromatin regions; this suggests differential immune selection pressure on intact versus defective proviruses in ECs. In comparison to individuals receiving antiretroviral therapy, intact and defective proviruses from ECs showed reduced frequencies of escape mutations in cytotoxic T cell epitopes and antibody contact regions, possibly due to the small and poorly inducible reservoir that may be insufficient to drive effective viral escape in ECs. About 15% of ECs harbored nef deletions in intact proviruses, consistent with increased viral vulnerability to host immunity in the setting of nef dysfunction. Together, these results suggest a distinct signature of immune footprints in proviral sequences from ECs.

HIV-1 DNA sequence diversity and evolution during acute subtype C infection.

Little is known about the genotypic make-up of HIV-1 DNA genomes during the earliest stages of HIV-1 infection. Here, we use near-full-length, single genome next-generation sequencing to longitudinally genotype and quantify subtype C HIV-1 DNA in four women identified during acute HIV-1 infection in Durban, South Africa, through twice-weekly screening of high-risk participants. In contrast to chronically HIV-1-infected patients, we found that at the earliest phases of infection in these four participants, the majority of viral DNA genomes are intact, lack APOBEC-3G/F-associated hypermutations, have limited genome truncations, and over one year show little indication of cytotoxic T cell-driven immune selections. Viral sequence divergence during acute infection is predominantly fueled by single-base substitutions and is limited by treatment initiation during the earliest stages of disease. Our observations provide rare longitudinal insights of HIV-1 DNA sequence profiles during the first year of infection to inform future HIV cure research.