A key priority for infectious disease research is to clarify how pathogen genetic variation, modulated by host immunity, transmission bottlenecks, and epidemic dynamics, determines the wide variety ...of pathogen phylogenies observed at scales that range from individual host to population. We call the melding of immunodynamics, epidemiology, and evolutionary biology required to achieve this synthesis pathogen "phylodynamics." We introduce a phylodynamic framework for the dissection of dynamic forces that determine the diversity of epidemiological and phylogenetic patterns observed in RNA viruses of vertebrates. A central pillar of this model is the Evolutionary Infectivity Profile, which captures the relationship between immune selection and pathogen transmission.
The factors determining differential HIV disease outcome among individuals expressing protective HLA alleles such as HLA-B*27:05 and HLA-B*57:01 remain unknown. We here analyse two HIV-infected ...subjects expressing both HLA-B*27:05 and HLA-B*57:01. One subject maintained low-to-undetectable viral loads for more than a decade of follow up. The other progressed to AIDS in < 3 years.
The rapid progressor was the recipient within a known transmission pair, enabling virus sequences to be tracked from transmission. Progression was associated with a 12% Gag sequence change and 26% Nef sequence change at the amino acid level within 2 years. Although next generation sequencing from early timepoints indicated that multiple CD8+ cytotoxic T lymphocyte (CTL) escape mutants were being selected prior to superinfection, < 4% of the amino acid changes arising from superinfection could be ascribed to CTL escape. Analysis of an HLA-B*27:05/B*57:01 non-progressor, in contrast, demonstrated minimal virus sequence diversification (1.1% Gag amino acid sequence change over 10 years), and dominant HIV-specific CTL responses previously shown to be effective in control of viraemia were maintained. Clonal sequencing demonstrated that escape variants were generated within the non-progressor, but in many cases were not selected. In the rapid progressor, progression occurred despite substantial reductions in viral replicative capacity (VRC), and non-progression in the elite controller despite relatively high VRC.
These data are consistent with previous studies demonstrating rapid progression in association with superinfection and that rapid disease progression can occur despite the relatively the low VRC that is typically observed in the setting of multiple CTL escape mutants.
Recent studies have suggested greater HIV cure potential among infected children than adults. A major obstacle to HIV eradication in adults is that the viral reservoir is largely comprised of ...HIV-specific cytotoxic T lymphocyte (CTL) escape variants. We here evaluate the potential for CTL in HIV-infected slow-progressor children to play an effective role in "shock-and-kill" cure strategies. Two distinct subgroups of children were identified on the basis of viral load. Unexpectedly, in both groups, as in adults, HIV-specific CTL drove the selection of escape variants across a range of epitopes within the first weeks of infection. However, in HIV-infected children, but not adults, de novo autologous variant-specific CTL responses were generated, enabling the pediatric immune system to "corner" the virus. Thus, even when escape variants are selected in early infection, the capacity in children to generate variant-specific anti-HIV CTL responses maintains the potential for CTL to contribute to effective shock-and-kill cure strategies in pediatric HIV infection.
The spin structure function of the neutron is traditionally determined by measuring the spin asymmetry of inclusive electron deep inelastic scattering (DIS) off polarized 3He nuclei. In such ...experiments, nuclear corrections are significant and must be treated carefully in the interpretation of experimental data. Here we study the feasibility of suppressing model dependencies by tagging both spectator protons in the process of DIS off neutrons in 3He at the forthcoming Electron-Ion Collider (EIC). This allows for a reconstruction of the momentum of the struck neutron to ensure it was nearly at rest in the initial state, thereby reducing sensitivity to nuclear corrections and suppressing contributions from electron DIS off protons in 3He. Using realistic accelerator and detector configurations, we demonstrate that the EIC can probe the neutron spin structure from xB of 0.003 to 0.651. We find that the double spectator tagging method results in reduced uncertainties by a factor of 2 on the extracted neutron spin asymmetries over all kinematics and by a factor of 10 in the low-xB region, thereby providing valuable insight into the spin and flavor structure of nucleons.
The extraction of the relative abundances of short-range correlated (SRC) nucleon pairs from inclusive electron scattering is studied using the generalized contact formalism (GCF) with several ...nuclear interaction models. GCF calculations can reproduce the observed scaling of the cross-section ratios for nuclei relative to deuterium at high xB and large Q2, a2=(σA/A)/(σd/2). In the nonrelativistic instant-form formulation, the calculation is very sensitive to the model parameters and only reproduces the data using parameters that are inconsistent with ab initio many-body calculations. Using a light-cone GCF formulation significantly decreases this sensitivity and improves the agreement with ab initio calculations. The ratio of similar mass isotopes, such as 40Ca and 48Ca, should be sensitive to the nuclear asymmetry dependence of SRCs, but is found to also be sensitive to low-energy nuclear structure. Thus the empirical association of SRC pair abundances with the measured a2 values is only accurate to about 20%. Finally, improving this will require cross-section calculations that reproduce the data while properly accounting for both nuclear structure and relativistic effects.
We report on the results of the first search for the production of axion-like particles (ALPs) via Primakoff production on nuclear targets, γA→aA, in the “SRC-CT” experiment using the GlueX detector ...at Jefferson Lab. This search uses an integrated luminosity of 100 pb⋅−1nucleon on a 12C target with a real photon beam of energies 6<Eγ<10.8 GeV, and explores the mass region of 200<ma<450 MeV via the decay a→γγ. This mass range is between the π0 and η meson masses, which enables the use of the measured η meson production rate to obtain absolute bounds on the ALP production with reduced sensitivity to experimental luminosity and detection efficiency. We find no evidence for an ALP, consistent with previous searches in the quoted mass range, and present limits on the effective photon coupling scale of O(1TeV−1). We further find that the ALP production limit we obtain is hindered by the peaking structure of the non-target-related dominant background the in GlueX spectrometer, which we treat by using data on 4He to estimate and subtract it. We comment on how this search can be improved in a future higher-statistics dedicated measurement.
HIV can be partially contained by host immunity and understanding the basis of this may inform vaccine design. The importance of B-cell function in long-term control is poorly understood. One method ...of investigating this is in vivo cellular depletion. In this study, we take advantage of a unique opportunity to investigate the role of B cells in an HIV-infected patient. The HIV-1(+) patient studied here was not taking antiretroviral drugs and was treated for pre-existing low-grade lymphoplasmacytoid lymphoma by depletion of CD20+ B cells using rituximab. We demonstrate that B-cell depletion results in a decline in autologous neutralizing antibody (NAb) responses and a 1.7 log(10) rise in HIV-1 plasma viral load (pVL). The recovery of NAbs results in a decline in pVL. The HIV-1 sequences diversify and NAb-resistant mutants are subsequently selected. These data suggest that B-cell function can contribute to the long-term control of pVL, and that NAbs may be more important in controlling chronic HIV-1 infection than previously suspected.
B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. ...We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.
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•IgD interacts with basophils through the CD44-binding protein galectin-9•IgD ligation by antigen elicits basophil release of Th2 cell-associated cytokines•IgD-activated basophils enhance B cell production of IgG1 and IgE•IgD interferes with IgE-mediated basophil degranulation
The function of IgD has been mysterious. Shan et al. find that IgD recognized food antigens and targeted basophils through galectin-9. IgD ligation by antigen induced basophil secretion of IL-4, IL-5, and IL-13, which amplified Th2 cell-mediated IgG1 and IgE production by B cells. IgD also constrained IgE-mediated basophil degranulation.
Measurements of short-range correlations in exclusive 4He(e,e′pN) reactions are analyzed using the Generalized Contact Formalism (GCF). We consider both instant-form and light-cone formulations with ...both the AV18 and local N2LO(1.0) nucleon-nucleon (NN) potentials. We find that kinematic distributions, such as the reconstructed pair opening angle, recoil neutron momentum distribution, and pair center of mass motion, as well as the measured missing energy, missing mass distributions, are all well reproduced by GCF calculations. The missing momentum dependence of the measured 4He(e,e′pN)/4He(e,e′p) cross-section ratios, sensitive to nature of the NN interaction at short-distacnes, are also well reproduced by GCF calculations using either interaction and formulation. This gives credence to the GCF scale-separated factorized description of the short-distance many-body nuclear wave-function.
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