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Background: CAB LA dosed at 2-month intervals demonstrated viro-logic efficacy in maintaining HIV-1 suppression as part of a dual regimen with rilpivirine LA and is undergoing Phase 3 evaluation as a single agent for HIV-1 pre-exposure prophylaxis (PrEP). CAB pharma-cokinetics (PK) in plasma and mucosal tissues associated with sexual HIV-1 transmission were evaluated following single CAB LA IM injection. Methods: Participants received 4 weeks of daily oral CAB 30 mg, followed by 14 to 42 day washout and a single ultrasound-guided gluteal IM injection of CAB LA 600 mg (3 mL). PK samples were collected after oral dosing and through 12 weeks post-injection in plasma, rectal tissue (RT), cervical tissue (CT), vaginal tissue (VT), cervicovaginal fluid (CF), and rectal fluid (RF). CAB concentrations were determined by HPLC-MS/MS. PK parameters were estimated using noncompartmental analysis. Pearson correlations of time-matched tissue and plasma concentration pairs were determined. Results: Nineteen participants (10F, 9M) enrolled with mean age 33 years, weight 79.4 kg, and BMI 27.2 kg/[m.sup.2]. Two participants withdrew before injections, one did not undergo tissue sampling, and one was hospitalized for unrelated serotonin syndrome. Median CAB concentration-time profiles are presented by matrix (Figure 1). Median CAB tissue:plasma ratio was 9% to 10% in RT (r = 0.96), 14% to 18% in CT (r = 0.94), 14% to 16% in VT (r = 0.92), 8% to 13% in CF (r = 0.65), 32% to 45% in RF (r = 0.19). Geometric mean (CVb%) plasma half-life was 19.1 (81.4%) days. Conclusions: Plasma CAB PK was consistent with prior studies, and CAB concentrations in tissue and fluid were proportional to plasma over time. Correlations with plasma concentrations were stronger for tissue (RT, CT, VT) than for luminal fluid (CF and RF). Tissue concentrations were 1/6th (CT, VT) to 1/10th (RT) of plasma concentrations. With sufficient distribution into mucosal tissues associated with sexual HIV-1 transmission, CAB tissue:plasma ratios may serve as important measurements in evaluating CAB LA as an effective PrEP agent., OA04.03 E. Weld (1); J. Sadik Shaik (2); S. Edick (3); E. Fuchs (4); S. Riddler (3); M. Marzinke (1); R. D'Amico (5); K. Bakshi (2); Y. Lou (6); C.W. [...]

Rear-wheel steering has seen new popularity in recent years. Many explanations of rear-wheel steering systems use the concept of a 'virtual wheel base' to explain in-phase or out-of-phase steering. This paper introduces a novel reference model that realises this metaphor. A reference model is created where its wheelbase can be changed arbitrarily, making the resulting system intuitive and simpler to design and tune. This augments the properties of the reference model whose signals are used for a feedback control system. The real vehicle tracks these signals using active front and rear-wheel steering. This system can be implemented in a vehicle using steer-by-wire or an autonomous vehicle for control. A MIMO controller is derived and results show that the system operates as intended. Finally, a control law is proposed to change the virtual wheelbase using the road curvature. It is shown that it has advantages over conventional rear-wheel steering control. [ABSTRACT FROM AUTHOR]

Background: Pre-clinical and clinical antibody-dependent cellular cytotoxic (ADCC) responses correlating with protection from HIV-1 infection provide the rationale to leverage them for treatment purposes. We evaluated ADCC mediated by 62 monoclonal antibodies (mAbs) combinations to identify those effective against latent reservoir viruses (LRVs) isolated from ART-suppressed HIV+ donors using Latency Reversing Agents (LRA)-exposed resting latently infected CD4+ T cells. Methods: HIV-1 envelope-specific CD4-binding site CH557, C1/C2 A32, V1/V2 PG9, V3 PGT121, gp120-gp41 interface PGT151 and MPER DH511.2K3 mAbs were tested at a concentration < 1 [micro]g/mL for their ability to mediate ADCC individually and in combinations. Target cells were either primary CD4+ T cells infected in vitro with a panel of 10 clade B LRVs or ART-suppressed HIV+ donor cells exposed to LRAs. We used an Infected Cell Elimination assay and a novel ex vivo modified viral outgrowth assay (Latent Clearance Assay) in presence of autologous primary NK cells, respectively. Results: We observed that within 2 hours of incubation at < 1 [micro]g/mL, 3 mAbs combinations mediated significantly higher killing (p < 0.005) compared to single or paired mAbs. Addition of more than 3 mAbs did not further increase specific killing. A32+ DH511.2K3+ PGT121 was the best combination with a mean of 33.1% ADCC activity. Three LRVs were resistance to neutralization by PGT121, one of which (P800) was also resistant to PG9 and DH511.2K3. The resistance was caused by the escape mutations within HIV-1 Env of these LRVs. These results were confirmed by the loss of the binding of PGT121 and/or DH511.2K3 to cells infected with these LRVs. After 24 hours of incubation, we observed remarkably increased ADCC activity against 4 LRVs tested with the A32+ DH511.2K3+ PGT121 combination, and demonstrated elimination of cells infected with 3-bNAbs-resistant P800 LRV Further, the A32+ DH511.2K3+ PGT121 combination efficiently cleared ex vivo latently infected LRA-treated resting CD4+ T cells from P800 donor by autologous NK cells during a 25-day culture. Conclusions: MAbs combinations targeted the diverse HIV-1 Env epitopes on the surface of infected cells, upon reactivation of the latent infection, more efficiently than individual mAbs. The results strongly indicate the importance of mAb combinations to achieve the broadest activity against HIV-1 infected cells in future cure strategies., OA14.01 M. Tuyishime (1); C. Garrido (2); S. Jha (1); M. Moeser (2); D. Mielke (1); C. LaBranche (1); D. Montefiori (1); B.F. Haynes (3); S. Joseph (4); D. Margolis [...]