Broadening the use of antiretroviral therapy: the case for feline leukemia virus

Antiretroviral drugs have saved and extended the lives of millions of individuals infected with HIV. The major classes of anti-HIV drugs include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry/fusion inhibitors. While antiretroviral drug regimens are not commonly used to treat other types of retroviral infections, there are instances where there is a perceived need for re-evaluation of the benefits of antiretroviral therapy. One case in point is that of feline leukemia virus (FeLV), an infection of companion felines. While vaccines exist to prevent FeLV infection and spread, they have not eliminated FeLV infection. For FeLV-infected felines and their human companions, antiretroviral therapy would be desirable and of practical importance if good options were available. Here, we discuss FeLV biology and current treatment options, and propose that there is a need for antiretroviral treatment options for FeLV infection. The comparative use and analysis of antiretroviral therapy can provide new insights into the mechanism of antiretroviral drug action

Mathematical modeling of escape of HIV from cytotoxic T lymphocyte responses

Human immunodeficiency virus (HIV-1 or simply HIV) induces a persistent infection, which in the absence of treatment leads to AIDS and death in almost all infected individuals. HIV infection elicits a vigorous immune response starting about 2-3 weeks post infection that can lower the amount of virus in the body, but which cannot eradicate the virus. How HIV establishes a chronic infection in the face of a strong immune response remains poorly understood. It has been shown that HIV is able to rapidly change its proteins via mutation to evade recognition by virus-specific cytotoxic T lymphocytes (CTLs). Typically, an HIV-infected patient will generate 4-12 CTL responses specific for parts of viral proteins called epitopes. Such CTL responses lead to strong selective pressure to change the viral sequences encoding these epitopes so as to avoid CTL recognition. Here we review experimental data on HIV evolution in response to CTL pressure, mathematical models developed to explain this evolution, and highlight problems associated with the data and previous modeling efforts. We show that estimates of the strength of the epitope-specific CTL response depend on the method used to fit models to experimental data and on the assumptions made regarding how mutants are generated during infection. We illustrate that allowing CTL responses to decay over time may improve the fit to experimental data and provides higher estimates of the killing efficacy of HIV-specific CTLs. We also propose a novel method for simultaneously estimating the killing efficacy of multiple CTL populations specific for different epitopes of HIV using stochastic simulations. Lastly, we show that current estimates of the efficacy at which HIV-specific CTLs clear virus-infected cells can be improved by more frequent sampling of viral sequences and by combining data on sequence evolution with experimentally measured CTL dynamics

New Insights into HTLV-1 Particle Structure, Assembly, and Gag-Gag Interactions in Living Cells

Human T-cell leukemia virus type 1 (HTLV-1) has a reputation for being extremely difficult to study in cell culture. The challenges in propagating HTLV-1 has prevented a rigorous analysis of how these viruses replicate in cells, including the detailed steps involved in virus assembly. The details for how retrovirus particle assembly occurs are poorly understood, even for other more tractable retroviral systems. Recent studies on HTLV-1 using state-of-the-art cryo-electron microscopy and fluorescence-based biophysical approaches explored questions related to HTLV-1 particle size, Gag stoichiometry in virions, and Gag-Gag interactions in living cells. These results provided new and exciting insights into fundamental aspects of HTLV-1 particle assembly—which are distinct from those of other retroviruses, including HIV-1. The application of these and other novel biophysical approaches promise to provide exciting new insights into HTLV-1 replication

Evidence of Andreev bound states as a hallmark of the FFLO phase in κ\kappa-(BEDT-TTF)2_2Cu(NCS)2_2

Superconductivity is a quantum phenomena arising, in its simplest form, from pairing of fermions with opposite spin into a state with zero net momentum. Whether superconductivity can occur in fermionic systems with unequal number of two species distinguished by spin, atomic hyperfine states, flavor, presents an important open question in condensed matter, cold atoms, and quantum chromodynamics, physics. In the former case the imbalance between spin-up and spin-down electrons forming the Cooper pairs is indyced by the magnetic field. Nearly fifty years ago Fulde, Ferrell, Larkin and Ovchinnikov (FFLO) proposed that such imbalanced system can lead to exotic superconductivity in which pairs acquire finite momentum. The finite pair momentum leads to spatially inhomogeneous state consisting of of a periodic alternation of "normal" and "superconducting" regions. Here, we report nuclear magnetic resonance (NMR) measurements providing microscopic evidence for the existence of this new superconducting state through the observation of spin-polarized quasiparticles forming so-called Andreev bound states.Comment: 6 pages, 5 fig

Impurity Effect on the In-plane Penetration Depth of the Organic Superconductors κ\kappa-(BEDT-TTF)2X_2X (XX = Cu(NCS)2_2 and Cu[N(CN)2_2]Br)

We report the in-plane penetration depth $\lambda_{\parallel}$ of single crystals $\kappa$-(BEDT-TTF)$_2X$ ($X=$ Cu(NCS)$_2$ and Cu[N(CN)$_2$]Br) by means of the reversible magnetization measurements under the control of cooling-rate. In $X$ = Cu(NCS)$_2$, $\lambda_{\parallel}(0)$ as an extrapolation toward $T$ = 0 K does not change by the cooling-rate within the experimental accuracy, while $T_{\textrm{c}}$ is slightly reduced. On the other hand, in $X$ = Cu[N(CN)$_2$]Br, $\lambda_{\parallel}(0)$ indicates a distinct increase by cooling faster. The different behavior of $\lambda_{\parallel}(0)$ on cooling-rate between the two salts is quantitatively explained in terms of the local-clean approximation (London model), considering that the former salt belongs to the very clean system and the later the moderate clean one. The good agreement with this model demonstrates that disorders of ethylene-group in BEDT-TTF introduced by cooling faster increase the electron(quasiparticle)-scattering, resulting in shorter mean free path.Comment: 8 pages, 9 figure

Biophysical analysis of HTLV-1 particles reveals novel insights into particle morphology and Gag stoichiometry

<p>Abstract</p> <p>Background</p> <p>Human T-lymphotropic virus type 1 (HTLV-1) is an important human retrovirus that is a cause of adult T-cell leukemia/lymphoma. While an important human pathogen, the details regarding virus replication cycle, including the nature of HTLV-1 particles, remain largely unknown due to the difficulties in propagating the virus in tissue culture. In this study, we created a codon-optimized HTLV-1 Gag fused to an <it>EYFP </it>reporter as a model system to quantitatively analyze HTLV-1 particles released from producer cells.</p> <p>Results</p> <p>The codon-optimized Gag led to a dramatic and highly robust level of Gag expression as well as virus-like particle (VLP) production. The robust level of particle production overcomes previous technical difficulties with authentic particles and allowed for detailed analysis of particle architecture using two novel methodologies. We quantitatively measured the diameter and morphology of HTLV-1 VLPs in their native, hydrated state using cryo-transmission electron microscopy (cryo-TEM). Furthermore, we were able to determine HTLV-1 Gag stoichiometry as well as particle size with the novel biophysical technique of fluorescence fluctuation spectroscopy (FFS). The average HTLV-1 particle diameter determined by cryo-TEM and FFS was 71 ± 20 nm and 75 ± 4 nm, respectively. These values are significantly smaller than previous estimates made of HTLV-1 particles by negative staining TEM. Furthermore, cryo-TEM reveals that the majority of HTLV-1 VLPs lacks an ordered structure of the Gag lattice, suggesting that the HTLV-1 Gag shell is very likely to be organized differently compared to that observed with HIV-1 Gag in immature particles. This conclusion is supported by our observation that the average copy number of HTLV-1 Gag per particle is estimated to be 510 based on FFS, which is significantly lower than that found for HIV-1 immature virions.</p> <p>Conclusions</p> <p>In summary, our studies represent the first quantitative biophysical analysis of HTLV-1-like particles and reveal novel insights into particle morphology and Gag stochiometry.</p

Superconductivity in a layered cobalt oxyhydrate Na0.31_{0.31}CoO2⋅_{2}\cdot1.3H2_{2}O

We report the electrical, magnetic and thermal measurements on a layered cobalt oxyhydrate Na$_{0.31}$CoO$_{2}\cdot$1.3H$_{2}$O. Bulk superconductivity at 4.3 K has been confirmed, however, the measured superconducting fraction is relatively low probably due to the sample's intrinsic two-dimensional characteristic. The compound exhibits weak-coupled and extreme type-II superconductivity with the average energy gap $\Delta_{a}(0)$ and the Ginzburg-Landau parameter $\kappa$ of $\sim$ 0.50 meV and $\sim$ 140, respectively. The normalized electronic specific heat data in the superconducting state well fit the $T^{3}$ dependence, suggesting point nodes for the superconducting gap structure.Comment: 4 pages, 3 figure

Diurnal secretion of growth hormone, cortisol, and dehydroepiandrosterone in pre- and perimenopausal women with active rheumatoid arthritis: a pilot case-control study

Rheumatoid arthritis (RA) is associated with neuroendocrine and immunologic dysfunction leading to rheumatoid cachexia. Although excess proinflammatory cytokines can decrease somatotropic axis activity, little is known about the effects of RA on growth hormone/insulin-like growth factor-1 (GH/IGF-I) axis function. We tested the hypothesis that patients with active RA exhibit decreased GH/IGF-I axis activity. To do so, we conducted a pilot case-control study at a clinical research center in 7 pre- and perimenopausal women with active RA and 10 age- and body mass index-matched healthy women. Participants underwent blood sampling every 20 minutes for 24 hours (8 a.m. to 8 a.m.), and sera were assayed for GH, cortisol, and dehydroepiandrosterone (DHEA). Sera obtained after overnight fasting were assayed for IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, C-reactive protein (CRP), interleukin-6 (IL-6), glucose, insulin, and lipids. Body composition and bone mineral density were evaluated by DEXA (dual emission x-ray absorptiometry) scans. In patients with RA, mean disease duration was 7.6 ± 6.8 years, and erythrocyte sedimentation rate, CRP, and IL-6 were elevated. GH half-life was shorter than in control subjects (p = 0.0037), with no other significant group differences in GH deconvolution parameters or approximate entropy scores. IGF-I (p = 0.05) and IGFBP-3 (p = 0.058) were lower, whereas IGFBP-1 tended to be higher (p = 0.066), in patients with RA, with nonsignificantly increased 24-hour total GH production rates. There were no significant group differences in cortisol or DHEA secretion. Lean body mass was lower in patients with RA (p = 0.019), particularly in the legs (p = 0.01). Women with active RA exhibit a trend toward GH insensitivity and relatively diminished diurnal cortisol and DHEA secretion for their state of inflammation. Whether these changes contribute to rheumatoid cachexia remains to be determined