Monosialodihexosylganglioside (GM3)-presenting lipid-coated polymer nanoparticles (NPs) that recapitulate the sequestration of human immunodeficiency virus-1 (HIV-1) particles in CD169+ virus-containing compartments (VCCs) of macrophages were developed as carriers for delivery and sustained release of a combination of two antiretrovirals (ARVs), rilpivirine (RPV) and cabotegravir (CAB). RPV and CAB were co-loaded into GM3-presenting lipid-coated polylactic acid (PLA) and poly­(lactic-co-glycolic acid) (PLGA) NPs without loss in potency of the drugs. GM3-presenting PLA NPs demonstrated the most favorable release properties and achieved inhibition of HIV-1 infection of primary human macrophages for up to 35 days. Intracellular localization of GM3-presenting PLA NPs in VCCs correlated with retention of intracellular ARV concentrations and sustained inhibition of HIV-1 infection. This work elucidates the design criteria of lipid-coated polymer NPs to utilize CD169+ macrophages as cellular drug depots for eradicating the viral reservoir sites or to achieve long-acting prophylaxis against HIV-1 infection.

Vpr is a 14 kDa accessory protein conserved amongst extant primate lentiviruses that is required for virus replication in vivo . Although many functions have been attributed to Vpr, its primary role, and the function under selective pressure in vivo , remains elusive. The minimal importance of Vpr in infection of activated CD4+ T cells in vitro suggests that its major importance lies in overcoming restriction to virus replication in non-cycling myeloid cell populations, such as macrophages and dendritic cells. HIV-1 replication is attenuated in the absence of Vpr in myeloid cells such as monocyte-derived dendritic cells (MDDCs) and macrophages, and is correlated with the ability of Vpr to overcome a post-integration transcriptional defect in these cells. Intriguingly, recent identification of the human hub silencing (HUSH) complex as a target for DCAF CRL4 -mediated degradation by numerous ancestral SIV Vpr alleles, and the Vpr paralog Vpx, signifies the potential function of HIV-1 Vpr to alter yet-to-be identified chromatin remodeling complexes and prevent host-mediated transcriptional repression of both invading viral genomes and pro-inflammatory responses. Myeloid cells constitute an important bridge between innate and adaptive immune responses to invading pathogens. Here, we seek to illustrate the numerous means by which Vpr manipulates the myeloid cellular environment and facilitates virus replication, myeloid cell-dependent HIV transmission, and systemic virus dissemination.

Palladium-catalyzed allylic aminations have been widely studied due to their synthetic utility 1 and the increasing availability of highly enantioselective versions. 2 We recently reported that reversible nucleophilic addition can lower the observed enantioselectivity of allylic amination reactions with a wide range of prototypical chiral ligands. 3 Amatore, Jutand, et al. 4a have found that nucleophilic addition of amines was reversible with the bidentate ligand dppb but irreversible with the monodentate ligand PPh 3. Based on our interest in chiral ligand design and specific studies with PHOX ligands, 5,6 we wanted to investigate the key ligand, solvent, and base additive factors governing the reversibility of nucleophilic addition of amines.

Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed “shock and kill”. This strategy has shown limited clinical effectiveness thus far, potentially due to limitations of the few therapeutics currently available. We have identified a novel class of benzazole compounds effective at inducing HIV-1 expression in several cellular models. These compounds do not act via histone deacetylase inhibition or T cell activation, and show specificity in activating HIV-1 in vitro. Initial exploration of structure-activity relationships and pharmaceutical properties indicates that these compounds represent a potential scaffold for development of more potent HIV-1 latency reversing agents.

Herein, lipid‐coated mesoporous silica nanoparticles (LMSNs) are investigated as biomimetic delivery vehicle for two antiretroviral (ARV) compounds, rilpivirine (RPV), and cabotegravir (CAB). Monosialodihexosylganglioside (GM3) is incorporated into the membrane to facilitate LMSN binding to CD169 (Siglec‐1)‐expressing myeloid cells, that are predominantly expressed in secondary lymphoid tissues in vivo. It is demonstrated that in addition to providing CD169‐binding functionalities, the lipid membrane around the silica core provides stealth properties that dampen the inflammatory cytokine response to ARVs‐loaded LMSN in human monocyte‐derived macrophages. Quantification of RPV and CAB releases from nanoparticles, and assessment of antiviral potency to human immunodeficiency virus 1 (HIV‐1) infection in vitro reveals that RPV and CAB co‐formulated into LMSN retain optimal antiviral potency for 90 days, even upon storage at room temperature, making LMSN an attractive nanoplatform, immune to cold chain requirements. These findings suggest that GM3–LMSN equip the mesoporous silica nanoparticle (MSN) core with lipid‐derived properties for surface passivation and lipid‐mediated binding that are of high interest for achieving an effective delivery of ARVs to tissue reservoirs of HIV‐1 replication.