Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells.

Latently human immunodeficiency virus (HIV)-infected cells are transcriptionally quiescent and invisible to clearance by the immune system. To demonstrate that the latency reversing agent vorinostat (VOR) induces a window of vulnerability in the latent HIV reservoir, defined as the triggering of viral antigen production sufficient in quantity and duration to allow for recognition and clearance of persisting infection, we developed a latency clearance assay (LCA). The LCA is a quantitative viral outgrowth assay (QVOA) that includes the addition of immune effectors capable of clearing cells expressing viral antigen. Here we show a reduction in the recovery of replication-competent virus from VOR exposed resting CD4 T cells following addition of immune effectors for a discrete period. TAKE HOME MESSAGE: VOR exposure leads to sufficient production of viral protein on the cell surface, creating a window of vulnerability within this latent reservoir in antiretroviral therapy (ART)-suppressed HIV-infected individuals that allows the clearance of latently infected cells by an array of effector mechanisms.

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency.

BACKGROUND: The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency. METHODS: In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell-associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals. RESULTS: Serial VOR exposures separated by 72 hours most often resulted in an increase in cell-associated HIV RNA within circulating resting CD4+ T cells. VOR was well tolerated by all participants. However, despite serial reversal of latency over 1 month of VOR dosing, we did not observe a measurable decrease (>0.3 log10) in the frequency of latent infection within resting CD4+ T cells. CONCLUSIONS: These findings outline parameters for the experimental use of VOR to clear latent infection. Latency reversal can be achieved by VOR safely and repeatedly, but effective depletion of persistent HIV infection will require additional advances. In addition to improvements in latency reversal, these advances may include the sustained induction of potent antiviral immune responses capable of recognizing and clearing the rare cells in which HIV latency has been reversed. TRIAL REGISTRATION: Clinicaltrials.gov NCT01319383. FUNDING: NIH grants U01 AI095052, AI50410, and P30 CA016086 and National Center for Advancing Translational Sciences grant KL2 TR001109.

Field Flight Dynamics of Hummingbirds during Territory Encroachment and Defense.

Hummingbirds are known to defend food resources such as nectar sources from encroachment by competitors (including conspecifics). These competitive intraspecific interactions provide an opportunity to quantify the biomechanics of hummingbird flight performance during ecologically relevant natural behavior. We recorded the three-dimensional flight trajectories of Ruby-throated Hummingbirds defending, being chased from and freely departing from a feeder. These trajectories allowed us to compare natural flight performance to earlier laboratory measurements of maximum flight speed, aerodynamic force generation and power estimates. During field observation, hummingbirds rarely approached the maximal flight speeds previously reported from wind tunnel tests and never did so during level flight. However, the accelerations and rates of change in kinetic and potential energy we recorded indicate that these hummingbirds likely operated near the maximum of their flight force and metabolic power capabilities during these competitive interactions. Furthermore, although birds departing from the feeder while chased did so faster than freely-departing birds, these speed gains were accomplished by modulating kinetic and potential energy gains (or losses) rather than increasing overall power output, essentially trading altitude for speed during their evasive maneuver. Finally, the trajectories of defending birds were directed toward the position of the encroaching bird rather than the feeder.