Reservoir Expansion Research Articles

Prevalence of transmitted HIV-1 drug resistance among treatment-naive individuals in China, 2000-2016.

Human immunodeficiency virus (HIV) with transmitted drug-resistance (TDR) limits the therapeutic options available for treatment-naive HIV patients. This study aimed to further our understanding of the prevalence and transmission characteristics of HIV with TDR for the application of first-line antiretroviral regimens. A total of 6578 HIV-1 protease/reverse-transcriptase sequences from treatment-naive individuals in China between 2000 and 2016 were obtained from the Los Alamos HIV Sequence Database and were analyzed for TDR. Transmission networks were constructed to determine genetic relationships. The spreading routes of large TDR clusters were identified using a Bayesian phylogeographic framework. TDR mutations were detected in 274 (4.51%) individuals, with 1.40% associated with resistance to nucleoside reverse transcriptase inhibitors, 1.52% to non-nucleoside reverse transcriptase inhibitors, and 1.87% to protease inhibitors. The most frequent mutation was M46L (58, 0.89%), followed by K103N (36, 0.55%), M46I (36, 0.55%), and M184V (26, 0.40%). The prevalence of total TDR initially decreased between 2000 and 2010 (OR = 0.83, 95% CI 0.73-0.95) and then increased thereafter (OR = 1.50, 95% CI 1.13-1.97). The proportion of sequences in a cluster (clustering rate) among HIV isolates with TDR sequences was lower than that of sequences without TDR (40.5% vs. 48.8%, P = 0.023) and increased from 27.3% in 2005-2006 to 63.6% in 2015-2016 (P < 0.001). While most TDR mutations were associated with reduced relative transmission fitness, mutation M46I was associated with higher relative transmission fitness than the wild-type strain. This study identified a low-level prevalence of TDR HIV in China during the last two decades. However, the increasing TDR HIV rate since 2010, the persistent circulation of drug resistance mutations, and the expansion of self-sustaining drug resistance reservoirs may compromise the efficacy of antiretroviral therapy programs.

Overtopping process and structural safety analyses of the earth-rock fill dam with a concrete core wall by using numerical simulations

Earth-rock fill dams are the most widely used dam type all over the world, and flood overtopping is the key reason causing dam burst. However, since an earth-rock fill dam with a concrete core wall is a modified new dam type, overtopping studies on these dams are rather deficient. The overtopping process and structural safety analyses of this new dam type have been studied in this paper by using a CFD-FEM coupled method based on the three-dimensional model of the Fangtianba reservoir expansion project. The scouring characteristics of the earth-rock fill dam, the variation trend of the downstream scouring depth, and the deformation as well as stress of the core wall have been obtained. Overtopping burst failure of the earth-rock fill dam with a concrete core wall is greatly affected by the downstream scouring depth, and tensile stress will occur on the upstream side of the core wall near the scour hole. When the downstream scouring depth is small and its growth is slow but stable, the tensile stress cannot exceed the allowable value in the early period of overtopping, and the concrete core wall may be able to support the dam body for a period of time, which might delay the occurrence of destructive collapse and overall burst. However, a sudden collapse may occur in the later period of overtopping; thus, reinforcement and emergency measures should be taken in time before the overall dam bursts.

Hemodynamic function of the right ventricular-pulmonary vascular-left atrial unit: normal responses to exercise in healthy adults

With each heartbeat, the right ventricle (RV) inputs blood into the pulmonary vascular (PV) compartment, which conducts blood through the lungs at low pressure and concurrently fills the left atrium (LA) for output to the systemic circulation. This overall hemodynamic function of the integrated RV-PV-LA unit is determined by complex interactions between the components that vary over the cardiac cycle but are often assessed in terms of mean pressure and flow. Exercise challenges these hemodynamic interactions as cardiac filling increases, stroke volume augments, and cycle length decreases, with PV pressures ultimately increasing in association with cardiac output. Recent cardiopulmonary exercise hemodynamic studies have enriched the available data from healthy adults, yielded insight into the underlying mechanisms that modify the PV pressure-flow relationship, and better delineated the normal limits of healthy responses to exercise. This review will examine hemodynamic function of the RV-PV-LA unit using the two-element Windkessel model for the pulmonary circulation. It will focus on acute PV and LA responses that accommodate increased RV output during exercise, including PV recruitment and distension and LA reservoir expansion, and the integrated mean pressure-flow response to exercise in healthy adults. Finally, it will consider how these responses may be impacted by age-related remodeling and modified by sex-related cardiopulmonary differences. Studying the determinants and recognizing the normal limits of PV pressure-flow relations during exercise will improve our understanding of cardiopulmonary mechanisms that facilitate or limit exercise.

A landscape hydrology approach to inform sustainable water resource management under a changing environment. A case study for the Kaleya River Catchment, Zambia

Study regionKaleya River Catchment in southern Zambia. Study focusThe ability of a landscape hydrology approach to detect controls on water availability in a fragmented landscape to inform interventions under a changing environment was investigated. Simple and measurable climatic and landscape pattern attributes were analysed using change detection, trend analysis and backward variable elimination with Partial Least Squares Regression (PLSR) to identify controls on seasonal river flows and how landscape components could be enhanced to augment natural river flows. New hydrological insights for the regionLandscape pattern showed increasing fragmentation, expansion of irrigated cropland and reservoirs and loss of forestland. Significant increasing trends (p < 0.05) were observed for reference evapotranspiration (ETo), one-day maximum rainfall, coefficient of variation (CV) of rainfall, maximum dry spell length, and start of rains but not annual rainfall. Increased CV of rainfall, rainfall intensity and ETo were the main climatic stressors on river flows. Increased Percentage of Landscape (PLAND) of irrigated cropland, PLAND of reservoirs, Patch Density (PD) and Largest Patch Index (LPI) of reservoirs were the main landscape pattern stressors. Only the LPI of forestland positively explained seasonal river flows. Water resource interventions in the region must adapt more to changing seasonal rainfall characteristics than to annual rainfall totals. Additionally, regeneration of larger forest patches could improve river flows. The approach can be applied in other regions.

Global characterization factors for terrestrial biodiversity impacts of future land inundation in Life Cycle Assessment

Life Cycle Assessment (LCA) is a tool for analyzing and comparing environmental impacts of products throughout their life cycles, facilitating shifts towards more environmentally friendly products. However, LCA does currently not address terrestrial biodiversity impacts related to the conversion of terrestrial habitat into aquatic habitat. This conversion can occur because of sea level rise, establishment of new land-based aquaculture, as well as reservoir expansion or creation. Here, we focus on land occupation and terrestrial biodiversity impacts, while transformation impacts, and habitat gain for aquatic species were beyond the scope of the study. To be able to estimate the regional and global terrestrial biodiversity impacts of future land occupation from terrestrial to aquatic habitat in LCA, we developed new characterization factors (CFs) for 781 terrestrial ecoregions, 5 land cover/use types, and 4 taxonomic groups. The basis for the development of the proposed CFs is the model concept of the currently recommended method for quantifying land use impacts on biodiversity in LCA by the Life Cycle Initiative hosted by United Nations Environmental Program. The global CFs vary between 7.44 E−20 PDF/m2 and 6.25 E−09 PDF/m2, showing that a highly variable terrestrial biodiversity impact of land inundation between land cover/use types, taxonomic groups and ecoregions exists.

High-fat diet exacerbates SIV pathogenesis and accelerates disease progression.

Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases.

Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro

BackgroundSince HIV-associated neurocognitive disorders (HANDs) occur in up to half of HIV-positive individuals, even with combined antiretroviral therapy (cART), adjunctive therapies are needed. Chronic CNS inflammation contributes to HAND and HIV encephalitis (HIVE). Baricitinib is a JAK 1/2 inhibitor approved in the USA, EU, and Japan for rheumatoid arthritis, demonstrating potent inhibition of IL-6, D-dimer, CRP, TNF-α, IFN-α/β, and other pro-inflammatory cytokines.MethodsOur modified murine HAND model was used to evaluate the ability of baricitinib to cross the blood-brain barrier (BBB) and modulate monocyte/macrophage-driven HAND. Severity of HAND was measured by assessing cognitive performance of low- and high-dose baricitinib treated versus untreated HAND mice. The severity of brain neuroinflammation was evaluated in these mouse groups after flow cytometric analyses. We also assessed the ability of baricitinib to block events in myeloid and lymphoid cells in vitro that may undergird the persistence of HIV in the central nervous system (CNS) in primary human macrophages (Mϕ) and lymphocytes including HIV replication, HIV-induced activation, reservoir expansion, and reservoir maintenance.ResultsIn vivo, both doses of 10 and 50 mg/kg qd baricitinib crossed the BBB and reversed behavioral abnormalities conferred by HIV infection. Moreover, baricitinib significantly reduced HIV-induced neuroinflammation marked by glial activation: activated microglia (MHCII+/CD45+) and astrogliosis (GFAP). Baricitinib also significantly reduced the percentage of p24+ human macrophages in mouse brains (p < 0.05 versus HAND mice; t test). In vitro, baricitinib significantly reduced markers of persistence, reservoir size, and reseeding in Mϕ.ConclusionThese results show that blocking the JAK/STAT pathway reverses cognitive deficits and curtails inflammatory markers in HAND in mice. Our group recently reported safety and tolerability of ruxolitinib in HIV-infected individuals (Marconi et al., Safety, tolerability and immunologic activity of ruxolitinib added to suppressive ART, 2019), underscoring potential safety and utility of JAK inhibitors for additional human trials. The data reported herein coupled with our recent human trial with JAK inhibitors provide compelling preclinical data and impetus for considering a trial of baricitinib in HAND individuals treated with cART to reverse cognitive deficits and key events driving viral persistence.

A Three-Dimensional Analytical Solution for Reservoir Expansion, Surface Uplift and Caprock Stress Due to Pressurized Reservoirs

An analytical solution is presented for the displacement, strain and stress of a three-dimensional poro-elastic model with three layers, where the three layers are an underburden, a reservoir with a given fluid pressure, and an overburden. The fluid pressure in the reservoir is assumed symmetrical around the z-axis and represented by a Fourier cosine series. The poro-elastic solution is expressed as a superposition of the solutions for each term in the Fourier series. It is shown that the bulk strain in the reservoir layer is proportional to the fluid pressure and that the bulk strain in the underburden and overburden is zero. Using these properties of the bulk strain, a solution is derived for the three-layer model where the fluid flow and mechanics are fully coupled. A particular aim of the model is to study the surface uplift from a given reservoir pressure. The expansion of the reservoir and the uplift of the surface are studied in terms of the wavelengths in the Fourier representation of the pressure. It is shown that the surface uplift can be written in a similar form to the 1D vertical expansion of the reservoir layer, but where the fluid pressure is based on the Fourier series. It is shown that the amplitudes with average wavelengths longer than 2pi times the thickness of the reservoir give expansion of the reservoir, but average wavelengths much shorter than this limit do not. Similarly, amplitudes with average wavelengths much longer than 2pi times the thickness of the overburden produce surface uplift, but wavelengths much shorter do not. The stress in the overburden, which is generated by the reservoir fluid pressure, is also analysed in terms of the wavelengths. A case is given where the analytical uplift is compared with the results of a numerical simulation and the agreement is excellent.

Is Water Pricing Policy Adequate to Reduce Water Demand for Drought Mitigation in Korea?

Korea experienced an unexpected drought in the southern Seoul metropolitan area from 2015 to 2017. After that, the Korean government has been drafting various policies to mitigate the effects of drought. However, these are primarily long-term drought policies, such as reservoir expansion. A comprehensive water demand reduction policy, which considers both short-term and long-term droughts, is also required. To confirm the effectiveness of the water pricing policy in Korea, we estimated the water demand reduction volume during droughts by assuming the drought and water pricing policy. We used two models for simulation: the severe drought area prediction (SDAP) model and the SD (system dynamics) model. The results showed the water demand reduction by price would not be significantly effective in Korea. We indicated that the effectiveness of policies could differ in each situation so that appropriate policies are needed for each country. This discussion could provide policy implications for other countries being at risk of droughts as well as the Korean government. Furthermore, we discussed non-price water policies that could be implemented in combination with the pricing policy in cases where the water pricing policy does not effectively reduce water demand.

F-106 Ebola and lassa fever: Lessons learned, continuing challenges

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Cellular HIV Reservoirs and Viral Rebound from the Lymphoid Compartments of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine (EFdA)-Suppressed Humanized Mice.

Although antiretroviral therapy (ART) greatly suppresses HIV replication, lymphoid tissues remain a sanctuary site where the virus may replicate. Tracking the earliest steps of HIV spread from these cellular reservoirs after drug cessation is pivotal for elucidating how infection can be prevented. In this study, we developed an in vivo model of HIV persistence in which viral replication in the lymphoid compartments of humanized mice was inhibited by the HIV reverse transcriptase inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) to very low levels, which recapitulated ART-suppression in HIV-infected individuals. Using a combination of RNAscope in situ hybridization (ISH) and immunohistochemistry (IHC), we quantitatively investigated the distribution of HIV in the lymphoid tissues of humanized mice during active infection, EFdA suppression, and after drug cessation. The lymphoid compartments of EFdA-suppressed humanized mice harbored very rare transcription/translation-competent HIV reservoirs that enable viral rebound. Our data provided the visualization and direct measurement of the early steps of HIV reservoir expansion within anatomically intact lymphoid tissues soon after EFdA cessation and suggest a strategy to enhance therapeutic approaches aimed at eliminating the HIV reservoir.

Impact of Treatment Interruption on HIV Reservoirs and Lymphocyte Subsets in Individuals Who Initiated Antiretroviral Therapy During the Early Phase of Infection.

Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)-infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.

Effect of Obesity on Left Atrial Strain in Persons Aged 35–55 Years (The Asklepios Study)

Obesity increases the risk of heart failure and atrial fibrillation. Left atrial (LA) dysfunction is increasingly recognized as a mediator of cardiovascular disease. Early effects of obesity on LA function have not been examined in large population samples. We quantified LA strain and strain rate (SR) through speckle tracking echocardiography in 1,531 middle-aged community-based participants enrolled in the Asklepios study. We compared LA function between individuals with body mass index (BMI) < 25 kg/m2 (n = 779), 25 to 29.9 kg/m2 (n = 618) and ≥ 30 kg/m2 (n = 134). Significant differences in reservoir longitudinal LA strain (BMI < 25 kg/m2 = 35.3%, BMI 25-29.9 kg/m2 = 33.1%, and BMI ≥ 30 kg/m2 = 30.9%; p < 0.00001) strain rate ([SR] BMI < 25 kg/m2 = 151; BMI 25 to 29.9 kg/m2 = 141; and BMI ≥ 30 kg/m2 = 135 %/s; p <0.00001) and expansion index (BMI < 25 kg/m2 = 1.6, BMI 25 to 29.9 kg/m2 = 1.4, and BMI ≥ 30 kg/m2 = 1.4; p <0.00001) were seen, indicating reduced reservoir function with increasing BMI. Obesity was also associated with impaired LA conduit function, including conduit longitudinal LA strain (BMI < 25 kg/m2 = 21.6%, BMI 25 to 29.9 kg/m2 = 18.9%, and BMI ≥ 30 kg/m2 = 16.7%; p <0.00001), SR (BMI < 25 kg/m2 = -189, BMI 25 to 29.9 kg/m2 = 166, and BMI ≥ 30 kg/m2 = 150 %/s; p <0.0001) and passive LA emptying fraction (BMI < 25 kg/m2 = 40.5, BMI 25 to 29.9 kg/m2 = 36.5, and BMI ≥ 30 kg/m2 = 36%, p <0.00001). These differences persisted after adjustment for age, gender and other potential confounders. In contrast to reservoir and conduit function, obesity was associated with increased booster pump function (active LA emptying fraction: BMI < 25 kg/m2 = 19.4%, BMI 25 to 29.9 kg/m2 = 20.5%, and BMI ≥ 30 kg/m2 = 21.5%; p <0.00001). In middle-aged adults, obesity is associated with impaired reservoir and conduit LA function and higher booster function, which may be compensatory. Loss of booster LA function, either because of more advanced LA dysfunction or atrial fibrillation, may play an important role in precipitating heart failure in obese individuals.

MTOR signaling mediates effects of common gamma-chain cytokines on T cell proliferation and exhaustion: implications for HIV-1 persistence and cure research.

: Chronic elevation of plasma cytokines is a key feature of HIV infection. The physiological consequences of this response to infection and its role in HIV persistence are not fully understood. Here, we show that common gamma chain (γc)-cytokines induce both proliferation and expression of T cell exhaustion markers in a mammalian target of rapamycin (mTOR)-dependent fashion, suggesting a possible therapeutic target that, if inhibited, could diminish HIV reservoir expansion, persistence, and resistance to immune surveillance.

Water shortages worsened by reservoir effects

The expansion of reservoirs to cope with droughts and water shortages is hotly debated in many places around the world. We argue that there are two counterintuitive dynamics that should be considered in this debate: supply–demand cycles and reservoir effects. Supply–demand cycles describe instances where increasing water supply enables higher water demand, which can quickly offset the initial benefits of reservoirs. Reservoir effects refer to cases where over-reliance on reservoirs increases vulnerability, and therefore increases the potential damage caused by droughts. Here we illustrate these counterintuitive dynamics with global and local examples, and discuss policy and research implications. Reservoirs are frequently posited as a method of increasing water supplies, especially in arid areas. However, they may be inducing and enabling demands for water through increased population and economic activity, and these demands can surpass even the supply that the reservoir can provide and counterintuitively make the areas more vulnerable to drought conditions.

Quantifying the potential for reservoirs to secure future surface water yields in the world’s largest river basins

Surface water reservoirs provide us with reliable water supply, hydropower generation, flood control and recreation services. Yet reservoirs also cause flow fragmentation in rivers and lead to flooding of upstream areas, thereby displacing existing land-use activities and ecosystems. Anticipated population growth and development coupled with climate change in many regions of the globe suggests a critical need to assess the potential for future reservoir capacity to help balance rising water demands with long-term water availability. Here, we assess the potential of large-scale reservoirs to provide reliable surface water yields while also considering environmental flows within 235 of the world’s largest river basins. Maps of existing cropland and habitat conservation zones are integrated with spatially-explicit population and urbanization projections from the Shared Socioeconomic Pathways to identify regions unsuitable for increasing water supply by exploiting new reservoir storage. Results show that even when maximizing the global reservoir storage to its potential limit (∼4.3–4.8 times the current capacity), firm yields would only increase by about 50% over current levels. However, there exist large disparities across different basins. The majority of river basins in North America are found to gain relatively little firm yield by increasing storage capacity, whereas basins in Southeast Asia display greater potential for expansion as well as proportional gains in firm yield under multiple uncertainties. Parts of Europe, the United States and South America show relatively low reliability of maintaining current firm yields under future climate change, whereas most of Asia and higher latitude regions display comparatively high reliability. Findings from this study highlight the importance of incorporating different factors, including human development, land-use activities, and climate change, over a time span of multiple decades and across a range of different scenarios when quantifying available surface water yields and the potential for reservoir expansion.

Assessing the impacts of dams and levees on the hydrologic record of the Middle and Lower Mississippi River, USA

The impacts of dams and levees on the long-term (>130 years) discharge record was assessed along a ~1200 km segment of the Mississippi River between St. Louis, Missouri, and Vicksburg, Mississippi. To aid in our evaluation of dam impacts, we used data from the U.S. National Inventory of Dams to calculate the rate of reservoir expansion at five long-term hydrologic monitoring stations along the study segment. We divided the hydrologic record at each station into three periods: (1) a pre-rapid reservoir expansion period; (2) a rapid reservoir expansion period; and (3) a post-rapid reservoir expansion period. We then used three approaches to assess changes in the hydrologic record at each station. Indicators of hydrologic alteration (IHA) and flow duration hydrographs were used to quantify changes in flow conditions between the pre- and post-rapid reservoir expansion periods. Auto-regressive interrupted time series analysis (ARITS) was used to assess trends in maximum annual discharge, mean annual discharge, minimum annual discharge, and standard deviation of daily discharges within a given water year. A one-dimensional HEC-RAS hydraulic model was used to assess the impact of levees on flood flows. Our results revealed that minimum annual discharges and low-flow IHA parameters showed the most significant changes. Additionally, increasing trends in minimum annual discharge during the rapid reservoir expansion period were found at three out of the five hydrologic monitoring stations. These IHA and ARITS results support previous findings consistent with the observation that reservoirs generally have the greatest impacts on low-flow conditions. River segment scale hydraulic modeling revealed levees can modestly increase peak flood discharges, while basin-scale hydrologic modeling assessments by the U.S. Army Corps of Engineers showed that tributary reservoirs reduced peak discharges by a similar magnitude (2 to 30%). This finding suggests that the effects of dams and levees on peak flood discharges are in part offsetting one another along the modeled river segments and likely other substantially leveed segments of the Mississippi River.

Changes of deep Pacific overturning circulation and carbonate chemistry during middle Miocene East Antarctic ice sheet expansion

East Antarctic ice sheet expansion (EAIE) at ∼13.9 Ma in the middle Miocene represents a major climatic event during the long-term Cenozoic cooling, but ocean circulation and carbon cycle changes during this event remain unclear. Here, we present new fish teeth isotope (εNd) and benthic foraminiferal B/Ca records from the South China Sea (SCS), newly integrated meridional Pacific benthic foraminiferal δ18O and δ13C records and simulated results from a biogeochemical box model to explore the responses of deep Pacific Ocean circulation and carbon cycle across EAIE. The εNd and meridional benthic δ13C records reveal a more isolated Pacific Deep Water (PDW) and a sluggish Pacific meridional overturning circulation during the post-EAIE with respect to the pre-EAIE owing to weakened southern-sourced deep water formation. The deep-water [CO2−3] and calcium carbonate mass accumulation rate in the SCS display markedly similar increases followed by recoveries to the pre-EAIE level during EAIE, which were probably caused by a shelf–basin shift of CaCO3 deposition and strengthened weathering due to a sea level fall within EAIE. The model results show that the ∼1‰ positive δ13C excursion during EAIE could be attributed to increased weathering of high-δ13C shelf carbonates and a terrestrial carbon reservoir expansion. The drawdown of atmospheric CO2 over the middle Miocene were probably caused by combined effects of increased shelf carbonate weathering, expanded land biosphere carbon storage and a sluggish deep Pacific meridional overturning circulation.

Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.

Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15)-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15) ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies.

Cytomegalovirus and HIV Persistence: Pouring Gas on the Fire.

The inherent stability of a small population of T cells that are latently infected with HIV despite antiretroviral therapy (ART) remains a stubborn obstacle to an HIV cure. By exploiting the memory compartment of our immune system, HIV maintains persistence in a small subset of quiescent cells with varying phenotypes, thus evading immune surveillance and clinical detection. Understanding the molecular and immunological mechanisms that maintain the latent reservoir will be critical to the success of HIV eradication strategies. Human cytomegalovirus (CMV), another chronic viral infection, frequently co-occurs with HIV and occupies an oversized proportion of memory T cell responses. CMV and HIV have both evolved complex strategies to manipulate our immune system for their own advantage. Given the increasingly clear links between CMV replication, chronic immune activation, and increased HIV reservoirs, we present a closer examination of the interplay between these two chronic coinfections. Here we review the effects of CMV on the immune system and show how they may affect persistence of the latent HIV reservoir during ART. The studies described herein suggest that hijacking of cytokine and chemokine signaling, manipulation of cell development pathways, and transactivation of HIV expression by CMV might be pouring gas on the fire of HIV persistence. Future interventional studies are required to formally determine the extent to which CMV is causally associated with inflammation and HIV reservoir expansion.