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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Adaptive changes in sexual behavior in the high–risk population in response to human monkeypox transmission in Canada can help control the outbreak: Insights from a two–group, two–route epidemic model

Monkeypox, a zoonotic disease, is emerging as a potential sexually transmitted infection/disease, with underlying transmission mechanisms still unclear. We devised a risk-structured, compartmental model, incorporating sexual behavior dynamics. We compared different strategies targeting the high-risk population: a scenario of control policies geared toward the use of condoms and/or sexual abstinence (robust control strategy) with risk compensation behavior change, and a scenario of control strategies with behavior change in response to the doubling rate (adaptive control strategy). Monkeypox's basic reproduction number is 1.464, 0.0066, and 1.461 in the high-risk, low-risk, and total populations, respectively, with the high-risk group being the major driver of monkeypox spread. Policies imposing condom use or sexual abstinence need to achieve a 35% minimum compliance rate to stop further transmission, while a combination of both can curb the spread with 10% compliance to abstinence and 25% to condom use. With risk compensation, the only option is to impose sexual abstinence by at least 35%. Adaptive control is more effective than robust control where the daily sexual contact number is reduced proportionally and remains constant thereafter, shortening the time to epidemic peak, lowering its size, facilitating disease attenuation, and playing a key role in controlling the current outbreak.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Epidemic Intelligence Service Alumni in Public Health Leadership Roles

Since 1951, the Epidemic Intelligence Service (EIS) of the U.S. Centers for Disease Control and Prevention (CDC) has trained physicians, nurses, scientists, veterinarians, and other allied health professionals in applied epidemiology. To understand the program’s effect on graduates’ leadership outcomes, we examined the EIS alumni representation in five select leadership positions. These positions were staffed by 353 individuals, of which 185 (52%) were EIS alumni. Among 12 CDC directors, four (33%) were EIS alumni. EIS alumni accounted for 29 (58%) of the 50 CDC center directors, 61 (35%) of the 175 state epidemiologists, 27 (56%) of the 48 Field Epidemiology Training Program resident advisors, and 70 (90%) of the 78 Career Epidemiology Field Officers. Of the 185 EIS alumni in leadership positions, 136 (74%) were physicians, 22 (12%) were scientists, 21 (11%) were veterinarians, 6 (3%) were nurses, and 94 (51%) were assigned to a state or local health department. Among the 61 EIS alumni who served as state epidemiologists, 40 (66%) of them were assigned to a state or local health department during EIS. Our evaluation suggests that epidemiology training programs can serve as a vital resource for the public health workforce, particularly given the capacity strains brought to light by the COVID-19 pandemic.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation

Mycobacterium tuberculosis (Mtb) infection causes tuberculosis (TB), a disease characterized by development of granulomas. Granulomas consist of activated immune cells that cluster together to limit bacterial growth and restrict dissemination. Control of the TB epidemic has been limited by lengthy drug regimens, antibiotic resistance, and lack of a robustly efficacious vaccine. Fibrosis commonly occurs during treatment and is associated with both positive and negative disease outcomes in TB but little is known about the processes that initiate fibrosis in granulomas. Human and nonhuman primate granulomas undergoing fibrosis can have spindle-shaped macrophages with fibroblast-like morphologies suggesting a relationship between macrophages, fibroblasts, and granuloma fibrosis. This relationship has been difficult to investigate because of the limited availability of human pathology samples, the time scale involved in human TB, and overlap between fibroblast and myeloid cell markers in tissues. To better understand the origins of fibrosis in TB, we used a computational model of TB granuloma biology to identify factors that drive fibrosis over the course of local disease progression. We validated the model with granulomas from nonhuman primates to delineate myeloid cells and lung-resident fibroblasts. Our results suggest that peripheral granuloma fibrosis, which is commonly observed, can arise through macrophage-to-myofibroblast transformation (MMT). Further, we hypothesize that MMT is induced in M1 macrophages through a sequential combination of inflammatory and anti-inflammatory signaling in granuloma macrophages. We predict that MMT may be a mechanism underlying granuloma-associated fibrosis and warrants further investigation into myeloid cells as drivers of fibrotic disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Defining Lipidomic Responses to Coronavirus Infection

Highly pathogenic human coronavirus infection can cause a severe atypical, rapid onset pneumonia with a mortality rate of up to 10% for severe acute respiratory syndrome coronavirus 1 (SARS-CoV 1), 35% for Middle East respiratory syndrome coronavirus (MERS-CoV), or 1% for severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2 causative agent of COVID 19). While medical countermeasures successfully controlled the worldwide SARS-CoV epidemic, the MERS-CoV epidemic is still ongoing and continues to be a concern for travelers in the Middle East and the multi-year SARS-CoV 2 pandemic underscore the importance of defining biomarkers that are diagnostic and/or predictive of severe disease outcomes for respiratory viruses. Systems biology approaches provide global snapshots of infection induced changes in host cells/tissues and provide extremely rich datasets for understanding host pathogen interactions. Metabolites, especially lipids, are critical for viral replication but less is understood about infection induced changes to lipids due to limits in lipid species detection and identification. To characterize how individual lipid species and proteins with lipid associated functions contribute to highly pathogenic human coronavirus replication and disease severity, existing datasets were probed to determine cell type specific lipid responses to MERS-CoV infection and verification studies were performed to determine if modification of the host lipid signature (by inhibiting enzymatic functions that produce specific lipid species) can perturb CoV replication in human lung cells. MERS-CoV infects human lung epithelial, endothelial and fibroblast cells. All three cell types were infected with MERS-CoV and samples collected to analyze lipids, proteins, metabolites, and transcripts from 12 to 48 hours post infection. Time matched mock-infected cells were collected in parallel for each cell type. Following sample and statistical analysis, functional enrichment and bioinformatic analysis was performed to identify differentially expressed lipids and proteins. Two lipid species were found to be significantly upregulated following MERS-CoV infection, ceramides, and triacylglycerol both of which are indicative of cells undergoing apoptotic cell death. In contrast, sphingomyelins (lipid molecules that can serve as a precursor for one pathway for ceramide synthesis) had significantly decreased expression in MERS-CoV infected cells. An inhibitor of acid sphingomyelinase (that converts sphingomyelin to ceramides and phosphorylcholine) reduced MERS-CoV replication suggesting that production of ceramides is key for successful viral replication and transmission. Acyl-CoA-synthetase 3 (ACSL3), the only protein whose function is lipid associated and had increased differential expression in our dataset, regulates the synthesis of triacylglycerol (increased expression). Inhibitors that directly block ACSL3 (Triacsin C) but not steps later in the triacylglycerol synthesis pathway (Etomoxir) inhibit MERS-CoV replication suggesting that triacylglycerol production and/or ACSL3 activity is also key for viral replication. ACSL3 expression is also upregulated in lung cancer cells and is predicted to promote continued cell viability which would also enhance viral replication. The differentially expressed lipid and lipid-associated protein species identified in our studies suggest that MERS-CoV infection is activating cellular death pathways to limit the number of cells that become infected but also stimulating the production of lipid-associated enzymes that can prolong host cell viability and the amount of time progeny virions can be produced and released. As the inhibitors that worked against MERS-CoV infection were also efficacious against SARS-CoV 2 infection, countermeasures that target these host pathways may provide novel ways to block highly pathogenic human coronavirus infection and/or prevent severe disease outcomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Surveilling Influenza Incidence With Centers for Disease Control and Prevention Web Traffic Data: Demonstration Using a Novel Dataset

Influenza epidemics result in a public health and economic burden worldwide. Traditional surveillance techniques, which rely on doctor visits, provide data with a delay of 1 to 2 weeks. A means of obtaining real-time data and forecasting future outbreaks is desirable to provide more timely responses to influenza epidemics. This study aimed to present the first implementation of a novel dataset by demonstrating its ability to supplement traditional disease surveillance at multiple spatial resolutions. We used internet traffic data from the Centers for Disease Control and Prevention (CDC) website to determine the potential usability of this data source. Additionally, we tested the traffic generated by 10 influenza-related pages in 8 states and 9 census divisions within the United States and compared it against clinical surveillance data.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Multidimensional perspectives of geo-epidemiology: from interdisciplinary learning and research to cost–benefit oriented decision-making

Research typically promotes two types of outcomes (inventions and discoveries), which induce a virtuous cycle: something suspected or desired (not previously demonstrated) may become known or feasible once a new tool or procedure is invented and, later, the use of this invention may discover new knowledge. Research also promotes the opposite sequence—from new knowledge to new inventions. This bidirectional process is observed in geo-referenced epidemiology—a field that relates to but may also differ from spatial epidemiology. Geo-epidemiology encompasses several theories and technologies that promote inter/transdisciplinary knowledge integration, education, and research in population health. Based on visual examples derived from geo-referenced studies on epidemics and epizootics, this report demonstrates that this field may extract more (geographically related) information than simple spatial analyses, which then supports more effective and/or less costly interventions. Actual (not simulated) bio-geo-temporal interactions (never captured before the emergence of technologies that analyze geo-referenced data, such as geographical information systems) can now address research questions that relate to several fields, such as Network Theory. Thus, a new opportunity arises before us, which exceeds research: it also demands knowledge integration across disciplines as well as novel educational programs which, to be biomedically and socially justified, should demonstrate cost-effectiveness. Grounded on many bio-temporal-georeferenced examples, this report reviews the literature that supports this hypothesis: novel educational programs that focus on geo-referenced epidemic data may help generate cost-effective policies that prevent or control disease dissemination.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Prevalence and scalable control of localized networks

The ability to control network dynamics is essential for ensuring desirable functionality of many technological, biological, and social systems. Such systems often consist of a large number of network elements, and controlling large-scale networks remains challenging because the computation and communication requirements increase prohibitively fast with network size. Here, we introduce a notion of network locality that can be exploited to make the control of networks scalable, even when the dynamics are nonlinear. We show that network locality is captured by an information metric and is almost universally observed across real and model networks. In localized networks, the optimal control actions and system responses are both shown to be necessarily concentrated in small neighborhoods induced by the information metric. This allows us to develop localized algorithms for determining network controllability and optimizing the placement of driver nodes. This also allows us to develop a localized algorithm for designing local feedback controllers that approach the performance of the corresponding best global controllers, while incurring a computational cost orders-of-magnitude lower. Here, we validate the locality, performance, and efficiency of the algorithms in Kuramoto oscillator networks, as well as three large empirical networks: synchronization dynamics in the Eastern US power grid, epidemic spreading mediated by the global air-transportation network, and Alzheimer’s disease dynamics in a human brain network. Taken together, our results establish that large networks can be controlled with computation and communication costs comparable to those for small networks.

42 ENGINEERING↗
NASA NTRS2014

Meningitis and Climate: From Science to Practice

Meningococcal meningitis is a climate sensitive infectious disease. The regional extent of the Meningitis Belt in Africa, where the majority of epidemics occur, was originally defined by Lapeysonnie in the 1960s. A combination of climatic and environmental conditions and biological and social factors have been associated to the spatial and temporal patterns of epidemics observed since the disease first emerged in West Africa over a century ago. However, there is still a lack of knowledge and data that would allow disentangling the relative effects of the diverse risk factors upon epidemics. The Meningitis Environmental Risk Information Technologies Initiative (MERIT), a collaborative research-to-practice consortium, seeks to inform national and regional prevention and control strategies across the African Meningitis Belt through the provision of new data and tools that better determine risk factors. In particular MERIT seeks to consolidate a body of knowledge that provides evidence of the contribution of climatic and environmental factors to seasonal and year-to-year variations in meningococcal meningitis incidence at both district and national scales. Here we review recent research and practice seeking to provide useful information for the epidemic response strategy of National Ministries of Health in the Meningitis Belt of Africa. In particular the research and derived tools described in this paper have focused at "getting science into policy and practice" by engaging with practitioner communities under the umbrella of MERIT to ensure the relevance of their work to operational decision-making. We limit our focus to that of reactive vaccination for meningococcal meningitis. Important but external to our discussion is the development and implementation of the new conjugate vaccine, which specifically targets meningococcus A

Mineral dust↗
DOE OSTI2021

Autocrine and paracrine interferon signalling as ‘ring vaccination’ and ‘contact tracing’ strategies to suppress virus infection in a host

The innate immune response, particularly the interferon response, represents a first line of defence against viral infections. The interferon molecules produced from infected cells act through autocrine and paracrine signalling to turn host cells into an antiviral state. Although the molecular mechanisms of IFN signalling have been well characterized, how the interferon response collectively contribute to the regulation of host cells to stop or suppress viral infection during early infection remain unclear. Here, we use mathematical models to delineate the roles of the autocrine and the paracrine signalling, and show that their impacts on viral spread are dependent on how infection proceeds. In particular, we found that when infection is well-mixed, the paracrine signalling is not as effective; by contrast, when infection spreads in a spatial manner, a likely scenario during initial infection in tissue, the paracrine signalling can impede the spread of infection by decreasing the number of susceptible cells close to the site of infection. Furthermore, we argue that the interferon response can be seen as a parallel to population-level epidemic prevention strategies such as ‘contact tracing’ or ‘ring vaccination’. Thus, our results here may have implications for the outbreak control at the population scale more broadly.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Assessment of a reconfiguration of the InterSpread Plus US national FMD model as a potential tool to analyze a foot-and-mouth disease outbreak on a single large cattle feedlot in the United States

An incursion of foot-and-mouth disease (FMD) into the United States remains a concern of high importance and would have devastating socioeconomic impacts to the livestock and associated industries. This highly transmissible and infectious disease poses continual risk for introduction into the United States (US), due to the legal and illegal global movement of people, animals, and animal products. While stamping out has been shown to effectively control FMD, depopulation of large cattle feedlots (>50,000 head) presents a number of challenges for responders due to the resources required to depopulate and dispose of large numbers of animals in a timely and effective manner. However, evaluating alternative strategies for FMD control on large feedlots requires a detailed within-farm modeling approach, which can account for the unique structure of these operations. To address this, we developed a single feedlot, within-farm spread model using a novel configuration within the InterSpread Plus (ISP) framework. As proof of concept we designed six scenarios: (i) depopulation - the complete depopulation of the feedlot, (ii) burn-through – a managed “burn-through” where the virus is allowed to spread through the feedlot and only movement restriction and biosecurity are implemented, (iii) firebreak-NV – targeted depopulation of infected pens and adjacent pens without vaccination; (iv) firebreak - targeted depopulation of infected pens and adjacent pens with vaccination of remaining pens; (v) harvest-NV - selective harvest of pens where a 100% movement restriction is applied for 28-30 days, then pens are set for selection to be sent to slaughter, while allowing a controlled “burn-through” without vaccination; and (vi) harvest - selective harvest of pens with vaccination. Overall, the burn-through scenario (ii) had the shortest epidemic duration (31d (30, 33)) median (25th, 75th percentiles), while the firebreak scenario (iv) had the longest (47d (38,55)). Additionally, we found that scenarios implementing depopulation delayed the peak day of infection and reduced the total number of pens infected compared to non-depopulation scenarios.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Molecular Pathogenesis and Immune Evasion of Vesicular Stomatitis New Jersey Virus Inferred from Genes Expression Changes in Infected Porcine Macrophages

The molecular mechanisms associated with the pathogenesis of vesicular stomatitis virus (VSV) in livestock remain poorly understood. Several studies have highlighted the relevant role of macrophages in controlling the systemic dissemination of VSV during infection in different animal models, including mice, cattle, and pigs. To gain more insight into the molecular mechanisms used by VSV to impair the immune response in macrophages, we used microarrays to determine the transcriptomic changes produced by VSV infection in primary cultures of porcine macrophages. The results indicated that VSV infection induced the massive expression of multiple anorexic, pyrogenic, proinflammatory, and immunosuppressive genes. Overall, the interferon (IFN) response appeared to be suppressed, leading to the absence of stimulation of interferon-stimulated genes (ISG). Interestingly, VSV infection promoted the expression of several genes known to downregulate the expression of IFNβ. This represents an alternate mechanism for VSV control of the IFN response, beyond the recognized mechanisms mediated by the matrix protein. Although there was no significant differential gene expression in macrophages infected with a highly virulent epidemic strain compared to a less virulent endemic strain, the endemic strain consistently induced higher expression of all upregulated cytokines and chemokines. Collectively, this study provides novel insights into VSV molecular pathogenesis and immune evasion that warrant further investigation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

AeDES: a next-generation monitoring and forecasting system for environmental suitability of Aedes-borne disease transmission

Aedes-borne diseases, such as dengue and chikungunya, are responsible for more than 50 million infections worldwide every year, with an overall increase of 30-fold in the last 50 years, mainly due to city population growth, more frequent travels and ecological changes. In the United States of America, the vast majority of Aedes-borne infections are imported from endemic regions by travelers, who can become new sources of mosquito infection upon their return home if the exposed population is susceptible to the disease, and if suitable environmental conditions for the mosquitoes and the virus are present. Since the susceptibility of the human population can be determined via periodic monitoring campaigns, the environmental suitability for the presence of mosquitoes and viruses becomes one of the most important pieces of information for decision makers in the health sector. We present a next-generation monitoring and forecasting system for Aedes-borne diseases’ environmental suitability (AeDES) of transmission in the conterminous United States and transboundary regions, using calibrated ento-epidemiological models, climate models and temperature observations. After analyzing the seasonal predictive skill of AeDES, we briefly consider the recent Zika epidemic, and the compound effects of the current Central American dengue outbreak happening during the SARS-CoV-2 pandemic, to illustrate how a combination of tailored deterministic and probabilistic forecasts can inform key prevention and control strategies .

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2025

Phylodynamics of SARS-CoV-2 Lineages B.1.1.7, B.1.1.529 and B.1.617.2 in Nigeria Suggests Divergent Evolutionary Trajectories

Background: The early months of the COVID-19 pandemic were characterized by high transmission rates and mortality, compounded by the emergence of multiple SARS-CoV-2 lineages, including Variants of Concern (VOCs). This study investigates the phylodynamic and spatio-temporal trends of VOCs during the peak of the pandemic in Nigeria. Methods: Whole-genome sequencing (WGS) data from three major VOCs circulating in Nigeria, B.1.1.7 (Alpha), B.1.617.2 (Delta), and B.1.1.529 (Omicron), were analyzed using tools such as Nextclade, R Studio v 4.2.3, and BEAST X v 10.5.0. The spatial distribution, evolutionary history, viral ancestral introductions, and geographic dispersal patterns were characterized. Results: Three major lineages following WHO nomenclature were identified: Alpha, Delta, and Omicron. The Delta variant exhibited the widest geographic spread, detected in 14 states, while the Alpha variant was the least distributed, identified in only eight states but present across most epidemiological weeks studied. Evolutionary rates varied slightly, with Alpha exhibiting the slowest rate (2.66 × 10 −4 substitutions/site/year). Viral population analyses showed distinct patterns: Omicron sustained elevated population growth over time, while Delta declined after initial expansion. The earliest Times to Most Recent Common Ancestor (TMRCA) were consistent with the earliest outbreaks of SARS-CoV-2 globally. Geographic transmission analysis indicated a predominant coastal-to-inland spread for all variants, with Omicron showing the most diffuse dispersal, highlighting commercial routes as significant drivers of viral diffusion. Conclusion: The SARS-CoV-2 epidemic in Nigeria was characterized by multiple variant introductions and a dominant coastal-to-inland spread, emphasizing that despite lockdown measures, commercial trade routes played a critical role in viral dissemination. These findings provide insights into pandemic control strategies and future outbreak preparedness.

Nigeria↗
NASA NTRS2001

The Effect of Regional Climate Variability on Outbreak of Bartonellosis Epidemics in Peru

Bartonellosis is a vector-borne, highly fatal, emerging infectious disease, which has been known in the Peruvian Andes since the early 1600s and has continued to be a problem in many mountain valleys in Peru and other Andean South American countries. The causative bacterium, Bartonella bacilliformis (Bb), is believed to be transmitted to humans by bites of the sand fly Lutzomyia verrucarum. According to available medical records, the transmission of infection often occurs in river valleys of the Andes Mountains at an altitude between 800 and 3500 meters above sea level. It shows a seasonal pattern, which usually begins to rise in December, peaks in February and March, and is at its lowest from July until November. The epidemics of bartonellosis also vary interannually, occurring every four to eight years, and appear to be associated with the El Nino cycle. In response to the National Oceanic and Atmospheric Administration (NOAA) announcement on climate variability and human health, which was constructed to stimulate integrated multidisciplinary research in the area of climate variability and health interactions, we have conducted a study to investigate the relationship between the El Nino induced regional climate variation and the outbreak of bartonellosis epidemics in Peru. Two test sites, Caraz and Cusco, were selected for this study. According to reports, Caraz has a long-standing history of endemic transmission and Cusco, which is located about five degrees poleward of Caraz, had no recorded epidemics until the most recent 1997/1998 El Nino event. The goal of this study is to clarify the relative importance of climatic risk factors for each area that could be predicted in advance, thus allowing implementation of cost-effective control measures, which would reduce disease morbidity and mortality.

Zhou, Jia-Yu↗
DOE OSTI2021

ComStock/COVID-19: U.S. Commercial Building Stock Analysis of COVID-19 Mitigation Strategies

ComStock is a DOE platform, with NREL as the lead developer, that models the U.S. commercial building stock using OpenStudio/EnergyPlus to perform physics-based building energy modeling simulations. The ASHRAE Epidemic Taskforce (ASHRAE-ETF) has released several COVID-19 mitigation strategies for commercial buildings. ComStock was used to analyze the impact of four strategies on the existing commercial building stock. These strategies are upgrading to MERV-13 filters, disabling demand control ventilation (DCV), increasing minimum outdoor air to 100%, and HVAC flushing mode operation. Results show the impact of each measure on energy consumption, electric consumption, gas consumption and peak electric.

30 DIRECT ENERGY CONVERSION↗
DOE OSTI2023

U.S. Commercial Building Stock Analysis of COVID-19 Mitigation Strategies

The COVID-19 pandemic highlights the importance of improving building indoor air quality to reduce occupants' chances of contracting airborne illness. The ASHRAE Epidemic Task Force (ASHRAE-ETF) released several COVID-19 mitigation strategies at the onset of the pandemic. This study explores four of those recommendations for reducing transmission of COVID-19 inside buildings: (1) 100% outdoor air ventilation, (2) MERV-13 or better filters, (3) demand control ventilation removal, and (4) HVAC flushing mode. These recommendations were simulated and assessed using ComStock, a model of the U.S. commercial building stock. The study showed the 100% outdoor air ventilation recommendation had the largest impact on energy consumption, noncoincident peak demand, and thermostat violations. Removing demand control ventilation had the smallest national aggregate impact, installing MERV-13 filters led to slight increases in energy use and peak demand, and HVAC outdoor air flushing led to modest energy use and peak demand increases.

building energy modelling↗
DOE OSTI2022

U.S. Commercial Building Stock Analysis of COVID-19 Mitigation Strategies: Preprint

The COVID-19 pandemic highlights the importance of improving building indoor air quality to reduce occupants’ chances of contracting airborne illness. The ASHRAE Epidemic Task Force (ASHRAE-ETF) released several COVID-19 mitigation strategies at the onset of the pandemic. This study explores four of those recommendations for reducing transmission of COVID-19 inside buildings: (1) 100% outdoor air ventilation, (2) MERV-13 or better filters, (3) demand control ventilation removal, and (4) HVAC flushing mode. These recommendations were simulated and assessed using ComStock, a model of the U.S. commercial building stock. The study showed the 100% outdoor air ventilation recommendation had the largest impact on energy consumption, noncoincident peak demand, and thermostat violations. Removing demand control ventilation had the smallest national aggregate impact, installing MERV-13 filters led to slight increases in energy use and peak demand, and HVAC outdoor air flushing led to modest energy use and peak demand increases.

building energy modelling↗
DOE OSTI2022

Long-Term and Low-Level Envelope C2V3 Stimulation by Highly Diverse Virus Isolates Leads to Frequent Development of Broad and Elite Antibody Neutralization in HIV-1-Infected Individuals

A minority of HIV-1-infected patients produce broadly neutralizing antibodies (bNAbs). Identification of viral and host correlates of bNAb production may help develop vaccines. We aimed to characterize the neutralizing response and viral and host-associated factors in Angola, which has one of the oldest, most dynamic, and most diverse HIV-1 epidemics in the world. Three hundred twenty-two HIV-1-infected adults from Angola were included in this retrospective study. Phylogenetic analysis of C2V3C3 env gene sequences was used for virus subtyping. Env-binding antibody reactivity was tested against polypeptides comprising the C2, V3, and C3 regions. Neutralizing-antibody responses were determined against a reference panel of tier 2 Env pseudoviruses in TZM-bl cells; neutralizing epitope specificities were predicted using ClustVis. All subtypes were found, along with untypeable strains and recombinant forms. Notably, 56% of the patients developed cross neutralizing, broadly neutralizing, or elite neutralizing responses. Broad and elite neutralization was associated with longer infection time, subtype C, lower CD4 + T cell counts, higher age, and higher titer of C2V3C3-specific antibodies relative to failure to develop bNAbs. Neutralizing antibodies targeted the V3-glycan supersite in most patients. V3 and C3 regions were significantly less variable in elite neutralizers than in weak neutralizers and nonneutralizers, suggesting an active role of V3C3-directed bNAbs in controlling HIV-1 replication and diversification. In conclusion, prolonged and low-level envelope V3C3 stimulation by highly diverse and ancestral HIV-1 isolates promotes the frequent elicitation of bNAbs. These results provide important clues for the development of an effective HIV-1 vaccine. Studies on neutralization by antibodies and their determinants in HIV-1-infected individuals have mostly been conducted in relatively recent epidemics caused by subtype B and C viruses. Results have suggested that elicitation of broadly neutralizing antibodies (bNAbs) is uncommon. The mechanisms underlying the elicitation of bNAbs are still largely unknown. We performed the first characterization of the plasma neutralizing response in a cohort of HIV-1-infected patients from Angola. Angola is characterized by an old and dynamic epidemic caused by highly diverse HIV-1 variants. Remarkably, more than half of the patients produced bNAbs, mostly targeting the V3-glycan supersite in HIV-1. This was associated with higher age, longer infection time, lower CD4 + T cell counts, subtype C infection, or higher titer of C2V3C3-specific antibodies relative to patients that did not develop bNAbs. These results may help develop the next generation of vaccine candidates for HIV-1.

59 BASIC BIOLOGICAL SCIENCES↗