Immunological approaches to HIV cure.

Combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection has proven remarkably successful - for those who can access and afford it - yet HIV infection persists indefinitely in a reservoir of cells, despite effective ART and despite host antiviral immune responses. An HIV cure is therefore the next aspirational goal and challenge, though approaches differ in their objectives - with 'functional cures' aiming for durable viral control in the absence of ART, and 'sterilizing cures' aiming for the more difficult to realize objective of complete viral eradication. Mechanisms of HIV persistence, including viral latency, anatomical sequestration, suboptimal immune functioning, reservoir replenishment, target cell-intrinsic immune resistance, and, potentially, target cell distraction of immune effectors, likely need to be overcome in order to achieve a cure. A small fraction of people living with HIV (PLWH) naturally control infection via immune-mediated mechanisms, however, providing both sound rationale and optimism that an immunological approach to cure is possible. Herein we review up to date knowledge and emerging evidence on: the mechanisms contributing to HIV persistence, as well as potential strategies to overcome these barriers; promising immunological approaches to achieve viral control and elimination of reservoir-harboring cells, including harnessing adaptive immune responses to HIV and engineered therapies, as well as enhancers of their functions and of complementary innate immune functioning; and combination strategies that are most likely to succeed. Ultimately, a cure must be safe, effective, durable, and, eventually, scalable in order to be widely acceptable and available.

Combined Surface-Subsurface Stream Restoration Structures Can Optimize Hyporheic Attenuation of Stream Water Contaminants.

There is a design-to-function knowledge gap regarding how engineered stream restoration structures can maximize hyporheic contaminant attenuation. Surface and subsurface structures have each been studied in isolation as techniques to restore hyporheic exchange, but surface-subsurface structures have not been investigated or optimized in an integrated manner. Here, we used a numerical model to systematically evaluate key design variables for combined surface (i.e., weir height and length) and subsurface (i.e., upstream and downstream baffle plate spacing) structures. We also compared performance metrics that place differing emphasis on hyporheic flux versus transit times. We found that surface structures tended to create higher flux, shorter transit time flowpaths, whereas subsurface structures promoted moderate-flux, longer transit time flowpaths. Optimal combined surface-subsurface structures could increase fluxes and transit times simultaneously, thus providing conditions for contaminant attenuation that were many times more effective than surface or subsurface structures alone. All performance metrics were improved by the presence of an upstream plate and the absence of a downstream plate. Increasing the weir length tended to improve all metrics, whereas the optimal weir height varied based on metrics. These findings may improve stream restoration by better aligning specific restoration goals with appropriate performance metrics and hyporheic structure designs.

The Intact Non-Inducible Latent HIV-1 Reservoir is Established In an In Vitro Primary TCM Cell Model of Latency.

The establishment of HIV-1 latency has hindered an HIV-1 cure. "Shock and Kill" strategies to target this reservoir aim to induce the latent provirus with latency reversing agents (LRAs). However, recent studies have shown that the majority of the intact HIV-1 viral reservoir found in ART-suppressed HIV infected individuals is not inducible. We sought to understand whether this non-inducible reservoir is established, and thus able to be studied, in an in vitro primary TCM model of latency. Furthermore, we wanted to expand this model system to include R5-tropic and non-B subtype viruses. To that end, we generated our TCM model of latency with an R5 subtype B virus, AD8 and an R5 subtype C virus, MJ4. Our results demonstrate that both intact and defective proviruses are generated in this model. Less than 50% of intact proviruses are inducible regardless of viral strain in the context of maximal stimulation through the TCR or with different clinically relevant LRAs including the HDAC inhibitors SAHA and MS-275, the PKC agonist Ingenol 3,20-dibenzoate or the SMAC mimetic AZD-5582. Our findings suggest that current LRA strategies are insufficient to effectively reactivate intact latent HIV-1 proviruses in primary CD4 TCM cells and that the mechanisms involved in the generation of the non-inducible HIV-1 reservoir can be studied using this primary in vitro model.Importance: HIV-1 establishes a latent reservoir that persists under antiretroviral therapy. Antiretroviral therapy is able to stop the spread of the virus and the progression of the disease but does not target this latent reservoir. If antiretroviral therapy is stopped, the virus is able to resume replication and the disease progresses. Recently, it has been demonstrated that most of the latent reservoir capable of generating replication competent virus cannot be induced in the laboratory setting. However, the mechanisms that influence the generation of this intact and non-inducible latent reservoir are still under investigation. Here we demonstrate the generation of defective, intact and intact non-inducible latent HIV-1 in a TCM model of latency using different HIV-1 strains. Thus, the mechanisms which control inducibility can be studied using this primary cell model of latency, which may accelerate our understanding of the latent reservoir and the development of curative strategies.

Selective BCL-XL Antagonists Eliminate Infected Cells from a Primary-Cell Model of HIV Latency but Not from Ex Vivo Reservoirs.

HIV persists, despite immune responses and antiretroviral therapy, in viral reservoirs that seed rebound viremia if therapy is interrupted. Previously, we showed that the BCL-2 protein contributes to HIV persistence by conferring a survival advantage to reservoir-harboring cells. Here, we demonstrate that many of the BCL-2 family members are overexpressed in HIV-infected CD4+ T cells, indicating increased tension between proapoptotic and prosurvival family members-and suggesting that inhibition of prosurvival members may disproportionately affect the survival of HIV-infected cells. Based on these results, we chose to study BCL-XL due to its consistent overexpression and the availability of selective antagonists. Infection of primary CD4+ T cells with HIV resulted in increased BCL-XL protein expression, and treatment with two selective BCL-XL antagonists, A-1155463 and A-1551852, led to selective death of productively infected CD4+ T cells. In a primary cell model of latency, both BCL-XL antagonists drove reductions in HIV DNA and in infectious cell frequencies both alone and in combination with the latency reversing agent bryostatin-1, with little off-target cytotoxicity. However, these antagonists, with or without bryostatin-1 or in combination with the highly potent latency reversing agent combination phorbol myristate acetate (PMA) + ionomycin, failed to reduce total HIV DNA and infectious reservoirs in ex vivo CD4+ T cells from antiretroviral therapy (ART)-suppressed donors. Our results add to growing evidence that bona fide reservoir-harboring cells are resistant to multiple "kick and kill" modalities-relative to latency models. We also interpret our results as encouraging further exploration of BCL-XL antagonists for cure, where combination approaches, including with immune effectors, may unlock the ability to eliminate ex vivo reservoirs. IMPORTANCE Although antiretroviral therapy (ART) has transformed HIV infection into a manageable chronic condition, there is no safe or scalable cure. HIV persists in "reservoirs" of infected cells that reinitiate disease progression if ART is interrupted. Whereas most efforts to eliminate this reservoir have focused on exposing these cells to immune-mediated clearance by reversing viral latency, recent work shows that these cells also resist being killed. Here, we identify a "prosurvival" factor, BCL-XL, that is overexpressed in HIV-infected cells, and demonstrate selective toxicity to these cells by BCL-XL antagonists. These antagonists also reduced reservoirs in a primary-cell latency model but were insufficient to reduce "natural" reservoirs in ex vivo CD4+ T cells-adding to growing evidence that the latter are resilient in a way that is not reflected in models. We nonetheless suggest that the selective toxicity of BCL-XL antagonists to HIV-infected cells supports their prioritization for testing in combinations aimed at reducing ex vivo reservoirs.

Hardware Selection and Performance of Low-Cost Fluorometers.

Access to and extensive use of fluorometric analyses is limited, despite its extensive utility in environmental transport and fate. Wide-spread application of fluorescent tracers has been limited by the prohibitive costs of research-grade equipment and logistical constraints of sampling, due to the need for high spatial resolutions and access to remote locations over long timescales. Recently, low-cost alternatives to research-grade equipment have been found to produce comparable data at a small fraction of the price for commercial equipment. Here, we prototyped and benchmarked performance of a variety of fluorometer components against commercial units, including performance as a function of tracer concentration, turbidity, and temperature, all of which are known to impact fluorometer performance. While component performance was found to be comparable to the commercial units tested, the best configuration tested obtained a functional resolution of 0.1 ppb, a working concentration range of 0.1 to >300 ppb, and a cost of USD 59.13.

What makes pharmacists successful? An investigation of personal characteristics.

OBJECTIVES: The primary objective of this study was to identify characteristics of pharmacists that contribute to their success. DESIGN: A working definition of success in pharmacy practice was derived from a scoping literature review and is based on the premise that successful pharmacists practice to full scope within the context of their practice setting. Semistructured individual interviews were conducted with selected pharmacists. Potential candidates were nominated by leading pharmacists in the field with the use of our prespecified definition of success. Lists from the nominators were compared, and pharmacists who appeared on more than 1 list were invited to participate. The interview tool was developed with the use of previous research on success in health care professions. SETTING AND PARTICIPANTS: Participants were 10 practicing pharmacists in a variety of locations (5 urban/5 rural) and practice settings (5 hospital/4 community/1 ambulatory care). OUTCOME MEASURES: Themes related to successful pharmacists practicing to full scope. RESULTS: Pharmacists meeting our definition of success were engaged in assessment and care planning, other expanded scope activities, and interpersonal activities and collaboration. The 10 interviewed pharmacists described motivation, critical thinking, emotional intelligence, core competencies, and work-life balance as significant contributors to their success. CONCLUSION: Several characteristics were identified as potentially related to success. These characteristics may be useful in pharmacists identifying areas for personal growth and development.

An analysis of conservation practice adoption studies in agricultural human-natural systems.

Farmers' conservation decisions are central to addressing regional environmental challenges, such as biodiversity loss, water quality impairment, or climate change. However, three decades of substantial investment in agri-environmental programs has not yielded widespread adoption or improved environmental outcomes. It remains difficult to explain why farmers adopt despite an extensive body of research on the topic. One possible reason for this is that researchers are limiting the types of metrics they are analyzing to explain farmer decisions. We systematically and critically evaluated the social science adoption literature to address three important gaps: (1) How are adoption studies measuring adoption effectiveness? (2) How do studies integrate individual farmer perspectives into broader institutional (i.e., social and governance) contexts? (3) What are the most prevalent metrics that adoption research uses to characterize the human-natural system? We coded 174 studies and found that only 10% connect adoption decisions to conservation outcomes or undertake longitudinal research, while the dominant approach in adoption research excludes the institutional contexts in which farmers are situated. The most prevalent metrics focus on farmer demographics, financial and technical capacity to adopt, and economic motivations. The lack of attention to both conservation outcomes and longitudinal studies limits researchers' ability to analyze the effectiveness of CP adoption. To advance our understanding of adoption, we recommend that future research measure conservation outcomes and track how knowledge about adoption effectiveness feeds back into farmer perceptions and social norms towards adoption. Research should also consistently measure how agri-environmental programs mediate the social acceptability of adoption. Lastly, institutional metrics that can be widely incorporated into coupled human-natural systems research will advance synthesis efforts to better explain why farmers adoption conservation practices.

Optimizing Sampling Strategies for Riverine Nitrate Using High-Frequency Data in Agricultural Watersheds.

Understanding linked hydrologic and biogeochemical processes such as nitrate loading to agricultural streams requires that the sampling bias and precision of monitoring strategies be known. An existing spatially distributed, high-frequency nitrate monitoring network covering ∼40% of Iowa provided direct observations of in situ nitrate concentrations at a temporal resolution of 15 min. Systematic subsampling of nitrate records allowed for quantification of uncertainties (bias and precision) associated with estimates of various nitrate parameters, including: mean nitrate concentration, proportion of samples exceeding the nitrate drinking water standard (DWS), peak (>90th quantile) nitrate concentration, and nitrate flux. We subsampled continuous records for 47 site-year combinations mimicking common, but labor-intensive, water-sampling regimes (e.g., time-interval, stage-triggered, and dynamic-discharge storm sampling). Our results suggest that time-interval sampling most efficiently characterized all nitrate parameters, except at coarse frequencies for nitrate flux. Stage-triggered storm sampling most precisely captured nitrate flux when less than 0.19% of possible 15 min observations for a site-year were used. The time-interval strategy had the greatest return on sampling investment by most precisely and accurately quantifying nitrate parameters per sampling effort. These uncertainty estimates can aid in designing sampling strategies focused on nitrate monitoring in the tile-drained Midwest or similar agricultural regions.

Enhanced vadose zone nitrogen removal by poplar during dormancy.

A pilot-scale, engineered poplar tree vadose zone system was utilized to determine effluent nitrate (NO3(-)) and ammonium concentrations resulting from intermittent dosing of a synthetic wastewater onto sandy soils at 4.5°C. The synthetic wastewater replicated that of an industrial food processor that irrigates onto sandy soils even during dormancy which can leave groundwater vulnerable to NO3(-) contamination. Data from a 21-day experiment was used to assess various Hydrus model parameterizations that simulated the impact of dormant roots. Bromide tracer data indicated that roots impacted the hydraulic properties of the packed sand by increasing effective dispersion, water content and residence time. The simulated effluent NO3(-) concentration on day 21 was 1.2 mg-N L(-1) in the rooted treatments compared to a measured value of 1.0 ± 0.72 mg-N L(-1). For the non-rooted treatment, the simulated NO3(-) concentration was 4.7 mg-N L(-1) compared to 5.1 ± 3.5 mg-N L(-1) measured on day 21. The model predicted a substantial "root benefit" toward protecting groundwater through increased denitrification in rooted treatments during a 21-day simulation with 8% of dosed nitrogen converted to N2 compared to 3.3% converted in the non-rooted test cells. Simulations at the 90-day timescale provided similar results, indicating increased denitrification in rooted treatments.

Antecedent moisture controls on stream nitrate flux in an agricultural watershed.

Evaluating nitrate-N fluxes from agricultural landscapes is inherently complex due to the wide range of intrinsic and dynamic controlling variables. In this study, we investigate the influence of contrasting antecedent moisture conditions on nitrate-N flux magnitude and dynamics in a single agricultural watershed on intra-annual and rainfall-event temporal scales. High temporal resolution discharge and nitrate concentration data were collected to evaluate nitrate-N flux magnitude associated with wet (2009) and dry (2012) conditions. Analysis of individual rainfall events revealed a marked and consistent difference in nitrate-N flux response attributed to wet/dry cycles. Large-magnitude dilutions (up to 10 mg N L) persisted during the wet antecedent conditions (2009), consistent with a dominant baseflow contribution and excess groundwater release in relation to precipitation volume (discharge > > precipitation). Smaller-magnitude concentrations (<7 mg N L) were observed during the drought conditions of 2012, consistent with a quickflow-dominated response to rain events and infiltration/storage of precipitation resulting in discharge < precipitation. Nitrate-N loads and yields from the watershed were much higher (up to an order of magnitude) in the wet year vs. the dry year. Our results suggest that the response of nitrate-N loading to rain events is highly dependent on intra-annual antecedent moisture conditions and subsurface hydrologic connectivity, which together dictate the dominant hydrologic pathways for stream recharge. Additionally, the results of our study indicate that continued pronounced wet/dry cycles may become more dominant as the short-term driver of future nitrate-N exports.

p38 mitogen-activated protein kinase (MAPK) promotes cholesterol ester accumulation in macrophages through inhibition of macroautophagy.

p38 MAPK has been strongly implicated in the development of atherosclerosis, but its role in cholesterol ester accumulation in macrophages and formation of foam cells, an early step in the development of atherosclerosis, has not been investigated. We addressed this issue and made some brand new observations. First, elevated intracellular cholesterol level induced by the exposure to LDL-activated p38 MAPK and activation of p38 MAPK with anisomycin increased the ratio of cholesterol esters over free cholesterol, whereas inhibition of p38 MAPK with SB203580 or siRNA reduced the LDL loading-induced intracellular accumulation of free cholesterol and cholesterol esters in macrophages. Second, exposure to LDL cholesterol inhibited autophagy in macrophages, and inhibition of autophagy with 3-methyladenine increased intracellular accumulation of cholesterol (free cholesterol and cholesterol esters), whereas activation of autophagy with rapamycin decreased intracellular accumulation of free cholesterol and cholesterol esters induced by the exposure to LDL cholesterol. Third, LDL cholesterol loading-induced inhibition of autophagy was prevented by blockade of p38 MAPK with SB203580 or siRNA. Neutral cholesterol ester hydrolase was co-localized with autophagosomes. Finally, LDL cholesterol loading and p38 activation suppressed expression of the key autophagy gene, ulk1, in macrophages. Together, our results provide brand new insight about cholesterol ester accumulation in macrophages and foam cell formation.

Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1.

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.

The latency-reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific T cells.

IL-15 is under clinical investigation toward the goal of curing HIV infection because of its abilities to reverse HIV latency and enhance immune effector function. However, increased potency through combination with other agents may be needed. 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhances IL-15-mediated latency reversal and NK cell function by increasing STAT5 activation. We hypothesized that HODHBt would also synergize with IL-15, via STAT5, to directly enhance HIV-specific cytotoxic T cell responses. We showed that ex vivo IL-15 + HODHBt treatment markedly enhanced HIV-specific granzyme B-releasing T cell responses in PBMCs from antiretroviral therapy-suppressed (ART-suppressed) donors. We also observed upregulation of antigen processing and presentation in CD4+ T cells and increased surface MHC-I. In ex vivo PBMCs, IL-15 + HODHBt was sufficient to reduce intact proviruses in 1 of 3 ART-suppressed donors. Our findings reveal the potential for second-generation IL-15 studies incorporating HODHBt-like therapeutics. Iterative studies layering on additional latency reversal or other agents are needed to achieve consistent ex vivo reservoir reductions.

Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1.

Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.

The Index of Attitudes Toward Homosexuals: Factor Analysis in a National Sample of Oncology Clinicians.

The Index of Attitudes toward Homosexuals (IAH) was published by Hudson and Ricketts in 1980 as a unidimensional index to measure affective responses to homosexuals. Siebert et al. identified two factors in a sample of predominantly female social science students: Cognitive/Social Distance (α = .91) and Affective/Attraction-Advances (α = .79). The present study sought to conduct a factor analysis to confirm the factor structure of the IAH in a national sample of oncology clinicians (n = 406). Exploratory factor analysis conducted on a random subset of 40% of survey respondents (n = 163) indicated three factors, termed: Avoidance (α = .92), Approach (α = .75) and Acceptance (α = .80). Confirmatory factor analysis conducted on the remaining 60% of respondents (n = 243) confirmed the three-factor structure (final Chi-square/DF = 1.988, RMSEA = 0.064, Bentler CFI = 0.949). Given the diversity, size, and strength of the sampling frame, future research using the IAH in clinical settings can obtain more precise findings by analyzing data according to these three factors.

Abundance of Nef and p-Tau217 in Brains of Individuals Diagnosed with HIV-Associated Neurocognitive Disorders Correlate with Disease Severance.

HIV-associated neurocognitive disorders (HAND) is a term used to describe a variety of neurological impairments observed in HIV-infected individuals. The pathogenic mechanisms of HAND and of its connection to HIV infection remain unknown, but one of the considered hypotheses suggests that HIV infection accelerates the development of Alzheimer's disease. Previous studies suggested that HIV-1 Nef may contribute to HAND by inhibiting cholesterol efflux, increasing the abundance of lipid rafts, and affecting their functionality. Our comparative analysis of postmortem brain samples demonstrated a trend toward the decreased abundance of cholesterol transporter ABCA1 in samples from HIV-infected ART-treated individuals relative to samples from uninfected controls, and a reverse correlation between ABCA1 and flotillin 1, a marker for lipid rafts, in all analyzed samples. The brain samples from HIV-infected individuals, both with and without HAND, were characterized by the increased abundance of p-Tau217 peptide, which correlated with the abundance of flotillin 1. HIV-1 Nef was analyzed in samples from HAND-affected individuals by Western blot with 4 different antibodies and by LC-MS/MS, producing a Nef-positivity score. A significant correlation was found between this score and the abundance of flotillin 1, the abundance of p-Tau217, and the severity of HAND. These results highlight the contribution of Nef and Nef-dependent impairment of cholesterol efflux to HAND pathogenesis and support a connection between the pathogenesis of HAND and Alzheimer's disease.

No evidence that circulating HIV-specific immune responses contribute to persistent inflammation and immune activation in persons on long-term ART.

OBJECTIVE: People with HIV (PWH) have persistently elevated levels of inflammation and immune activation despite suppressive antiretroviral therapy (ART), with specific biomarkers showing associations with non-AIDS-defining morbidities and mortality. We investigated the potential role of the HIV-specific adaptive immune response, which also persists under ART, in driving levels of these clinically relevant biomarkers. DESIGN: Cohort-based study. METHODS: HIV-specific IFN-γ-producing T-cell responses and antibody concentrations were measured in blood at study entry in the ACTG A5321 cohort, following a median of 7 years of suppressive ART. HIV persistence measures including cell-associated (CA)-DNA, CA-RNA, and plasma HIV RNA (single-copy assay) were also assessed at study entry. Plasma inflammatory biomarkers and T-cell activation and cycling were measured at a pre-ART time point and at study entry. RESULTS: Neither the magnitudes of HIV-specific T-cell responses nor HIV antibody levels were correlated with levels of the inflammatory or immune activation biomarkers, including hs-CRP, IL-6, neopterin, sCD14, sCD163, TNF-α, %CD38 + HLA-DR + CD8 + and CD4 + cells, and %Ki67 + CD8 + and CD4 + cells - including after adjustment for pre-ART biomarker level. Plasma HIV RNA levels were modestly correlated with CD8 + T-cell activation ( r  = 0.25, P  = 0.027), but other HIV persistence parameters were not associated with these biomarkers. In mediation analysis, relationships between HIV persistence parameters and inflammatory biomarkers were not influenced by either HIV-specific T-cell responses or antibody levels. CONCLUSION: Adaptive HIV-specific immune responses do not appear to contribute to the elevated inflammatory and immune activation profile in persons on long-term ART.

Assessing placement bias of the global river gauge network.

Knowing where and when rivers flow is paramount to managing freshwater ecosystems. Yet stream gauging stations are distributed sparsely across rivers globally and may not capture the diversity of fluvial network properties and anthropogenic influences. Here we evaluate the placement bias of a global stream gauge dataset on its representation of socioecological, hydrologic, climatic and physiographic diversity of rivers. We find that gauges are located disproportionally in large, perennial rivers draining more human-occupied watersheds. Gauges are sparsely distributed in protected areas and rivers characterized by non-perennial flow regimes, both of which are critical to freshwater conservation and water security concerns. Disparities between the geography of the global gauging network and the broad diversity of streams and rivers weakens our ability to understand critical hydrologic processes and make informed water-management and policy decisions. Our findings underscore the need to address current gauge placement biases by investing in and prioritizing the installation of new gauging stations, embracing alternative water-monitoring strategies, advancing innovation in hydrologic modelling, and increasing accessibility of local and regional gauging data to support human responses to water challenges, both today and in the future.

Administration of broadly neutralizing anti-HIV-1 antibodies at ART initiation maintains long-term CD8+ T cell immunity.

In simian-human immunodeficiency virus (SHIV)-infected non-human primates, broadly neutralizing antibodies (bNAbs) against the virus appear to stimulate T cell immunity. To determine whether this phenomenon also occurs in humans we measured HIV-1-specific cellular immunity longitudinally in individuals with HIV-1 starting antiviral therapy (ART) with or without adjunctive bNAb 3BNC117 treatment. Using the activation-induced marker (AIM) assay and interferon-γ release, we observe that frequencies of Pol- and Gag-specific CD8+ T cells, as well as Gag-induced interferon-γ responses, are significantly higher among individuals that received adjunctive 3BNC117 compared to ART-alone at 3 and 12 months after starting ART. The observed changes in cellular immunity were directly correlated to pre-treatment 3BNC117-sensitivity. Notably, increased HIV-1-specific immunity is associated with partial or complete ART-free virologic control during treatment interruption for up to 4 years. Our findings suggest that bNAb treatment at the time of ART initiation maintains HIV-1-specific CD8+ T cell responses that are associated with ART-free virologic control.