Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we ...measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (T
), stem-cell- (T
), central- (T
), transitional- (T
), and effector-memory (T
). HIV decreases in T
and T
but not in less-differentiated subsets. Cell turnover is ~10 times faster than HIV clearance in memory subsets, implying that cellular proliferation consistently creates HIV DNA. The optimal mathematical model for these integrated data sets posits HIV DNA also passages between CD4 cell subsets via cellular differentiation. Estimates are heterogeneous, but in an average participant's year ~10 (in T
and T
) and ~10
(in T
, T
, T
) proviruses are generated by proliferation while ~10
proviruses passage via cell differentiation (per million CD4). In simulations, therapies blocking proliferation and/or enhancing differentiation could reduce HIV DNA by 1-2 logs over 3 years. In summary, HIV exploits cellular proliferation and differentiation to persist during ART but clears faster in more proliferative/differentiated CD4 cell subsets and the same physiological mechanisms sustaining HIV might be temporarily modified to reduce it.
Magnetic nanoparticles are useful biological probes as well as therapeutic agents. Several approaches have been used to model nanoparticle magnetization dynamics for both Brownian as well as Neel ...rotation. Magnetizations are often of interest and can be compared with experimental results. Here we summarize these approaches, including the Stoner-Wohlfarth approach and stochastic approaches including thermal fluctuations. Non-equilibrium-related temperature effects can be described by a distribution function approach (Fokker-Planck equation) or a stochastic differential equation (Langevin equation). Approximate models in several regimes can be derived from these general approaches to simplify implementation.
Proliferation of CD4+ T cells harboring HIV-1 proviruses is a major contributor to viral persistence in people on antiretroviral therapy (ART). To determine whether differential rates of clonal ...proliferation or HIV-1-specific cytotoxic T lymphocyte (CTL) pressure shape the provirus landscape, we performed an intact proviral DNA assay (IPDA) and obtained 661 near-full-length provirus sequences from 8 individuals with suppressed viral loads on ART at time points 7 years apart. We observed slow decay of intact proviruses but no changes in the proportions of various types of defective proviruses. The proportion of intact proviruses in expanded clones was similar to that of defective proviruses in clones. Intact proviruses observed in clones did not have more escaped CTL epitopes than intact proviruses observed as singlets. Concordantly, total proviruses at later time points or observed in clones were not enriched in escaped or unrecognized epitopes. Three individuals with natural control of HIV-1 infection (controllers) on ART, included because controllers have strong HIV-1-specific CTL responses, had a smaller proportion of intact proviruses but a distribution of defective provirus types and escaped or unrecognized epitopes similar to that of the other individuals. This work suggests that CTL selection does not significantly check clonal proliferation of infected cells or greatly alter the provirus landscape in people on ART.
The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial ...data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT
) biomarker-which quantifies the neutralization potency of antibodies in an individual's serum against an HIV-1 isolate-can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT
of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT
<200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT
biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.
Modern HIV research depends crucially on both viral sequencing and population measurements. To directly link mechanistic biological processes and evolutionary dynamics during HIV infection, we ...developed multiple within-host phylodynamic models of HIV primary infection for comparative validation against viral load and evolutionary dynamics data. The optimal model of primary infection required no positive selection, suggesting that the host adaptive immune system reduces viral load but surprisingly does not drive observed viral evolution. Rather, the fitness (infectivity) of mutant variants is drawn from an exponential distribution in which most variants are slightly less infectious than their parents (nearly neutral evolution). This distribution was not largely different from either in vivo fitness distributions recorded beyond primary infection or in vitro distributions that are observed without adaptive immunity, suggesting the intrinsic viral fitness distribution may drive evolution. Simulated phylogenetic trees also agree with independent data and illuminate how phylogenetic inference must consider viral and immune-cell population dynamics to gain accurate mechanistic insights.
Invasive species introductions in high latitudes are accelerating and elevating the need to address questions of their effects on Subarctic and Arctic ecosystems. As a driver of ecosystem function, ...submerged aquatic vegetation is one of the most deleterious biological invasions to aquatic food webs. The aquatic plant
Elodea
spp. has potential to be a widespread invader to Arctic and Subarctic ecosystems and is already established in 19 waterbodies in Alaska, USA.
Elodea
spp. has been found to alter ecosystem processes through multiple pathways; yet little is known about the impact of
Elodea
spp. on fish life history. A primary concern is the effect of
Elodea
spp. on juvenile Pacific salmon (
Oncorhynchus
spp.), because this invading plant can form dense stands in littoral zones, potentially impacting important freshwater rearing habitats used by juvenile fish for foraging and refuge from predators. We used a field experiment to test the effect of
Elodea
spp. on juvenile coho salmon (
O. kisutch
) growth in an infested lake near Cordova, Alaska, USA. We found that
Elodea
spp. stands result in reduced growth and a lower trophic position for juvenile coho salmon over the summer compared to habitats dominated by a native assemblage of aquatic plants. While infested sites were not associated with significant changes in water condition or primary productivity compared to sites dominated by native vegetation, zooplankton densities were reduced, and
Elodea
spp. height and vegetation richness increased macroinvertebrate densities. Combined, these results indicate that
Elodea
spp. may alter the flow of energy to juvenile salmon by restructuring space and affecting prey resources for rearing fish. Furthermore, these results suggest that widespread establishment of
Elodea
spp. may alter the quality of habitat for juvenile salmon and, by affecting juvenile fish growth, could lead to population-level impacts on salmon returns.
In the era of antiretroviral therapy (ART), HIV-1 infection is no longer tantamount to early death. Yet the benefits of treatment are available only to those who can access, afford, and tolerate ...taking daily pills. True cure is challenged by HIV latency, the ability of chromosomally integrated virus to persist within memory CD4
T cells in a non-replicative state and activate when ART is discontinued. Using a mathematical model of HIV dynamics, we demonstrate that treatment strategies offering modest but continual enhancement of reservoir clearance rates result in faster cure than abrupt, one-time reductions in reservoir size. We frame this concept in terms of compounding interest: small changes in interest rate drastically improve returns over time. On ART, latent cell proliferation rates are orders of magnitude larger than activation and new infection rates. Contingent on subtypes of cells that may make up the reservoir and their respective proliferation rates, our model predicts that coupling clinically available, anti-proliferative therapies with ART could result in functional cure within 2-10 years rather than several decades on ART alone.
Functionalized magnetic nanoparticles (mNPs) have shown promise in biosensing and other biomedical applications. Here we use functionalized mNPs to develop a highly sensitive, versatile sensing ...strategy required in practical biological assays and potentially in vivo analysis. We demonstrate a new sensing scheme based on magnetic spectroscopy of nanoparticle Brownian motion (MSB) to quantitatively detect molecular targets. MSB uses the harmonics of oscillating mNPs as a metric for the freedom of rotational motion, thus reflecting the bound state of the mNP. The harmonics can be detected in vivo from nanogram quantities of iron within 5s. Using a streptavidin–biotin binding system, we show that the detection limit of the current MSB technique is lower than 150pM (0.075pmole), which is much more sensitive than previously reported techniques based on mNP detection. Using mNPs conjugated with two anti-thrombin DNA aptamers, we show that thrombin can be detected with high sensitivity (4nM or 2pmole). A DNA–DNA interaction was also investigated. The results demonstrated that sequence selective DNA detection can be achieved with 100pM (0.05pmole) sensitivity. The results of using MSB to sense these interactions, show that the MSB based sensing technique can achieve rapid measurement (within 10s), and is suitable for detecting and quantifying a wide range of biomarkers or analytes. It has the potential to be applied in variety of biomedical applications or diagnostic analyses.
•The freedom of rotational motion of mNP can be measured by MSB within seconds.•The MSB signal of mNP decreased with increasing analyte concentration.•We optimized the sensing scheme using streptavidin/biotin as the model system.•MSB can detect protein and DNA with high specificity and sensitivity.•MSB is a versatile technique, suitable for both in vitro and in vivo detection.
For a solar flare occurring on 2010 November 3, we present observations using several SDO/AIA extreme-ultraviolet (EUV) passbands of an erupting flux rope followed by inflows sweeping into a current ...sheet region. The inflows are soon followed by outflows appearing to originate from near the termination point of the inflowing motion-an observation in line with standard magnetic reconnection models. We measure average inflow plane-of-sky speeds to range from ~ 150 to 690 km s super(-1) with the initial, high-temperature inflows being the fastest. Using the inflow speeds and a range of Alfven speeds, we estimate the Alfvenic Mach number which appears to decrease with time. We also provide inflow and outflow times with respect to RHESSI count rates and find that the fast, high-temperature inflows occur simultaneously with a peak in the RHESSI thermal light curve. Five candidate inflow-outflow pairs are identified with no more than a minute delay between detections. The inflow speeds of these pairs are measured to be ~ 10 super(2) km s super(-1) with outflow speeds ranging from ~ 10 super(2) to 10 super(3) km s super(-1)-indicating acceleration during the reconnection process. The fastest of these outflows are in the form of apparently traveling density enhancements along the legs of the loops rather than the loop apexes themselves. These flows could possibly either be accelerated plasma, shocks, or waves prompted by reconnection. The measurements presented here show an order of magnitude difference between the retraction speeds of the loops and the speed of the density enhancements within the loops-presumably exiting the reconnection site.
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