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Inhibitors of bromodomain and extraterminal domain (BET) proteins are possible anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here we show that BET proteins should not be inactivated therapeutically because theyare critical antiviral factors at the post-entry level. Depletion of BRD3 or BRD4 in cells overexpressing ACE2 exacerbates SARS-CoV-2 infection; the same is observed when cells with endogenous ACE2 expression are treated with BET inhibitors during infection and not before. Viral replication and mortality are also enhanced in BET inhibitor-treated mice overexpressing ACE2. BET inactivation suppresses interferon productioninduced by SARS-CoV-2, a process phenocopied by the envelope (E)protein previously identified as a possible "histone mimetic." E protein, in an acetylated form, directly binds the second bromodomain ofBRD4. Our data support a model where SARS-CoV-2 E protein evolved to antagonize interferon responsesvia BET protein inhibition; this neutralization should not be further enhanced with BET inhibitor treatment.

Quiescence is a hallmark of CD4+ T cells latently infected with human immunodeficiency virus 1 (HIV-1). While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. As a key regulator of T-cell quiescence, FOXO1 promotes latency and suppresses productive HIV infection. We report that, in resting T cells, FOXO1 inhibition impaired autophagy and induced endoplasmic reticulum (ER) stress, thereby activating two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Both factors associate with HIV chromatin and are necessary for HIV reactivation. Indeed, inhibition of protein kinase R-like ER kinase, an ER stress sensor that can mediate the induction of ATF4, and calcineurin, a calcium-dependent regulator of NFAT, synergistically suppressed HIV reactivation induced by FOXO1 inhibition. Thus, our studies uncover a link of FOXO1, ER stress and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.

The introduction of antiretroviral therapy (ART) in the 1990s has turned the once fatal condition of HIV-1/AIDS into a chronic illness. However, it has failed to fully eradicate the virus, which remains in a latent state in a small number of CD4+ T cells in individuals on ART. One promising therapeutic strategy called “shock and kill” utilizes small-molecule latency-reversing agents (LRAs) to “shock” the virus out of latency, resulting in the “killing” of previously latent, now virus-producing cells by way of viral cytopathic effects or immune cytolytic mechanisms. While many LRAs are able to reverse viral latency of in vitro models of HIV-1 latency, most have little to no effect in resting CD4+ T cells from HIV+ patients. In PNAS, Timmons et al. (1) demonstrate that latency reversal for many LRAs depends on heat shock factor 1 (HSF1), a mediator of the stress response known to induce HIV-1 transcription. Their work not only sheds light on latency-reversing mechanisms but also explains the discrepancies in LRA activity between HIV-1 latency models based on immortalized vs. primary cells. The central bottleneck in studying HIV-1 latency is the lack of methods to home in on the elusive population of latently infected cells in HIV+ patients. Consequently, surrogate models in immortalized immune cell lines were developed to allow for mechanistic studies of HIV-1 latency. Their known proviral sequence, uniform integration site, and convenient scalability make cell lines, such as Jurkat-Latent (J-Lats), a pillar of molecular latency studies (2, 3). However, they do have limitations, which also extend to in vitro primary T cell models, in recapitulating latent infection in vivo (4). It remains the gold standard to validate any results obtained in J-Lats or primary T cell models in resting T cells from HIV+ patients on ART. Nevertheless, … [↵][1]1To whom correspondence may be addressed. Email: mott{at}gladstone.ucsf.edu. [1]: #xref-corresp-1-1

Estrogen receptor-positive (ER+) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.