Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure

Antiretroviral therapy regimens durably suppress HIV replication, but do not cure infection. This is partially attributable to the persistence of long-lived pools of resting CD4+ T-cells harboring latent replication-competent virus. Substantial clinical and pre-clinical research is currently being directed at purging this viral reservoir by combining pharmacological latency reversal with immune effectors, such as HIV-specific CD8+ T-cells, capable of eliminating reactivated targets—the so-called “shock-and-kill” approach. However, several studies indicate that the latency-reversing agents (LRAs) may affect CD8+ T-cell function. The current review aims to frame recent advances, and ongoing challenges, in implementing “shock-and-kill” strategies from the perspective of effectively harnessing CD8+ T-cells. We review and contextualize findings indicating that LRAs often have unintended impacts on CD8+ T-cell function, both detrimental and beneficial. We identify and attempt to bridge the gap between viral reactivation, as measured by the detection of RNA or protein, and bona fide presentation of viral antigens to CD8+ T-cells. Finally, we highlight factors on the effector (CD8+) and target (CD4+) cell sides that contribute to whether or not infected-cell recognition results in killing/elimination. These perspectives may contribute to an integrated view of “shock-and-kill,” with implications for therapeutic development

High eccentricity planets from the Anglo-Australian Planet Search

We report Doppler measurements of the stars HD187085 and HD20782 which indicate two high eccentricity low-mass companions to the stars. We find HD187085 has a Jupiter-mass companion with a ~1000d orbit. Our formal `best fit' solution suggests an eccentricity of 0.47, however, it does not sample the periastron passage of the companion and we find that orbital solutions with eccentricities between 0.1 and 0.8 give only slightly poorer fits (based on RMS and chi^2) and are thus plausible. Observations made during periastron passage in 2007 June should allow for the reliable determination of the orbital eccentricity for the companion to HD187085. Our dataset for HD20782 does sample periastron and so the orbit for its companion can be more reliably determined. We find the companion to HD20782 has M sin i=1.77+/-0.22M_JUP, an orbital period of 595.86+/-0.03d and an orbit with an eccentricity of 0.92+/-0.03. The detection of such high-eccentricity (and relatively low velocity amplitude) exoplanets appears to be facilitated by the long-term precision of the Anglo-Australian Planet Search. Looking at exoplanet detections as a whole, we find that those with higher eccentricity seem to have relatively higher velocity amplitudes indicating higher mass planets and/or an observational bias against the detection of high eccentricity systems.Comment: to appear in MNRA

Tissue memory CD4+ T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection.

The primary reservoir for HIV is within memory CD4+ T cells residing within tissues, yet the features that make some of these cells more susceptible than others to infection by HIV is not well understood. Recent studies demonstrated that CCR5-tropic HIV-1 efficiently enters tissue-derived memory CD4+ T cells expressing CD127, the alpha chain of the IL7 receptor, but rarely completes the replication cycle. We now demonstrate that the inability of HIV to replicate in these CD127-expressing cells is not due to post-entry restriction by SAMHD1. Rather, relative to other memory T cell subsets, these cells are highly prone to undergoing latent infection with HIV, as revealed by the high levels of integrated HIV DNA in these cells. Host gene expression profiling revealed that CD127-expressing memory CD4+ T cells are phenotypically distinct from other tissue memory CD4+ T cells, and are defined by a quiescent state with diminished NFκB, NFAT, and Ox40 signaling. However, latently-infected CD127+ cells harbored unspliced HIV transcripts and stimulation of these cells with anti-CD3/CD28 reversed latency. These findings identify a novel subset of memory CD4+ T cells found in tissue and not in blood that are preferentially targeted for latent infection by HIV, and may serve as an important reservoir to target for HIV eradication efforts

Detection of Planetary and Stellar Companions to Neighboring Stars via a Combination of Radial Velocity and Direct Imaging Techniques

13 pages, 6 figures, 4 tables, accepted for publication in the Astronomical Journal (submitted 25 Feb 2019; accepted 28 April 2019). Machine readable tables and Posteriors from the RadVel fits are available here: http://stephenkane.net/rvfits.tarThe sensitivities of radial velocity (RV) surveys for exoplanet detection are extending to increasingly longer orbital periods, where companions with periods of several years are now being regularly discovered. Companions with orbital periods that exceed the duration of the survey manifest in the data as an incomplete orbit or linear trend, a feature that can either present as the sole detectable companion to the host star, or as an additional signal overlain on the signatures of previously discovered companion(s). A diagnostic that can confirm or constrain scenarios in which the trend is caused by an unseen stellar rather than planetary companion is the use of high-contrast imaging observations. Here, we present RV data from the Anglo-Australian Planet Search (AAPS) for 20 stars that show evidence of orbiting companions. Of these, six companions have resolved orbits, with three that lie in the planetary regime. Two of these (HD 92987b and HD 221420b) are new discoveries. Follow-up observations using the Differential Speckle Survey Instrument (DSSI) on the Gemini South telescope revealed that 5 of the 20 monitored companions are likely stellar in nature. We use the sensitivity of the AAPS and DSSI data to place constraints on the mass of the companions for the remaining systems. Our analysis shows that a planetary-mass companion provides the most likely self-consistent explanation of the data for many of the remaining systems.Peer reviewedFinal Accepted Versio

On the Double Planet System Around HD 83443

The Geneva group has reported two Saturn-mass planets orbiting HD 83443 (K0V) with periods of 2.98 and 29.8 d. The two planets have raised interest in their dynamics because of the possible 10:1 orbital resonance and the strong gravitational interactions. We report precise Doppler measurements of HD 83443 obtained with the Keck/HIRES and the AAT/UCLES spectrometers. These measurements strongly confirm the inner planet with period of 2.985 d, with orbital parameters in very good agreement with those of the Geneva group. However these Doppler measurements show no evidence of the outer planet, at thresholds of 1/4 (3 m/s) of the reported velocity amplitude of 13.8 m/s. Thus, the existence of the outer planet is in question. Indeed, the current Doppler measurements reveal no evidence of any second planet with periods less than a year.Comment: 26 pages incl. 3 tables and 8 figures; uses AASTE

The regenerating skeletal muscle niche drives satellite cell return to quiescence

Skeletal muscle stem cells, or satellite cells (SCs), are essential to regenerate and maintain muscle. Quiescent SCs reside in an asymmetric niche between the basal lamina and myofiber membrane. To repair muscle, SCs activate, proliferate, and differentiate, fusing to repair myofibers or reacquiring quiescence to replenish the SC niche. Little is known about when SCs reacquire quiescence during regeneration or the cellular processes that direct SC fate decisions. We find that most SCs reacquire quiescence 5&ndash;10 days after muscle injury, following differentiation and fusion of most cells to regenerate myofibers. Single-cell sequencing of myogenic cells in regenerating muscle identifies SCs reacquiring quiescence and reveals that noncell autonomous signaling networks influence SC fate decisions during regeneration. SC transplantation experiments confirm that the regenerating environment influences SC fate. We define a window for SC repopulation of the niche, emphasizing the temporal contribution of the regenerative muscle environment on SC fate. &nbsp;</p

Two extra-solar planets from the Anglo-Australian Planet Search

We report the detection of two new extra-solar planets from the Anglo-Australian Planet Search around the stars HD142 and HD23079. The planet orbiting HD142 has an orbital period of just under one year, while that orbiting HD23079 has a period of just under two years. HD142 falls into the class of "eccentric" gas giants. HD23079 lies in the recently uncovered class of "epsilon Ret-like" planets - extra-solar gas giant planets with near-circular orbits outside 0.1 a.u. The recent discovery of several more members of this class provides new impetus for the extension of existing planet searches to longer periods, in the search for Jupiter-like planets in Jupiter-like orbits.Comment: 6 pages, 4 figures and 3 tables include

A Super-Earth and Two Neptunes Orbiting the Nearby Sun-like Star 61 Virginis

We present precision radial velocity data that reveal a multiple exoplanet system orbiting the bright nearby G5V star 61 Virginis. Our 4.6 years of combined Keck/HIRES and Anglo-Australian Telescope precision radial velocities indicate the hitherto unknown presence of at least three planets orbiting this well-studied star. These planets are all on low-eccentricity orbits with periods of 4.2, 38.0, and 124.0 days, and projected masses (Msin i) of 5.1, 18.2, and 24.0 M_⊕, respectively. Test integrations of systems consistent with the radial velocity data suggest that the configuration is dynamically stable. Depending on the effectiveness of tidal dissipation within the inner planet, the inner two planets may have evolved into an eccentricity fixed-point configuration in which the apsidal lines of all three planets corotate. This conjecture can be tested with additional observations. We present a 16-year time series of photometric observations of 61 Virginis, which comprise 1194 individual measurements, and indicate that it has excellent photometric stability. No significant photometric variations at the periods of the proposed planets have been detected. This new system is the first known example of a G-type Sun-like star hosting a Super-Earth mass planet. It joins HD 75732 (55 Cnc), HD 69830, GJ 581, HD 40307, and GJ 876 in a growing group of exoplanet systems that have multiple planets orbiting with periods less than an Earth-year. The ubiquity of such systems portends that space-based transit-search missions such as Kepler and CoRoT will find many multi-transiting systems