Early antiretroviral therapy in SIV-infected rhesus macaques reveals a multiphasic, saturable dynamic accumulation of the rebound competent viral reservoir.

The rebound competent viral reservoir (RCVR)-virus that persists during antiretroviral treatment (ART) and can reignite systemic infection when treatment is stopped-is the primary barrier to eradicating HIV. We used time to initiation of ART during primary infection of rhesus macaques (RMs) after intravenous challenge with barcoded SIVmac239 as a means to elucidate the dynamics of RCVR establishment in groups of RMs by creating a multi-log range of pre-ART viral loads and then assessed viral time-to-rebound and reactivation rates resulting from the discontinuation of ART after one year. RMs started on ART on days 3, 4, 5, 6, 7, 9 or 12 post-infection showed a nearly 10-fold difference in pre-ART viral measurements for successive ART-initiation timepoints. Only 1 of 8 RMs initiating ART on days 3 and 4 rebounded after ART interruption despite measurable pre-ART plasma viremia. Rebounding plasma from the 1 rebounding RM contained only a single barcode lineage detected at day 50 post-ART. All RMs starting ART on days 5 and 6 rebounded between 14- and 50-days post-ART with 1-2 rebounding variants each. RMs starting ART on days 7, 9, and 12 had similar time-to-measurable plasma rebound kinetics despite multiple log differences in pre-ART plasma viral load (pVL), with all RMs rebounding between 7- and 16-days post-ART with 3-28 rebounding lineages. Calculated reactivation rates per pre-ART pVL were highest for RMs starting ART on days 5, 6, and 7 after which the rate of accumulation of the RCVR markedly decreased for RMs treated on days 9 and 12, consistent with multiphasic establishment and near saturation of the RCVR within 2 weeks post infection. Taken together, these data highlight the heterogeneity of the RCVR between RMs, the stochastic establishment of the very early RCVR, and the saturability of the RCVR prior to peak viral infection.

Mathematical Modeling of Tumor and Cancer Stem Cells Treated with CAR-T Therapy and Inhibition of TGF-[Formula: see text].

The stem cell hypothesis suggests that there is a small group of malignant cells, the cancer stem cells, that initiate the development of tumors, encourage its growth, and may even be the cause of metastases. Traditional treatments, such as chemotherapy and radiation, primarily target the tumor cells leaving the stem cells to potentially cause a recurrence. Chimeric antigen receptor (CAR) T-cell therapy is a form of immunotherapy where the immune cells are genetically modified to fight the tumor cells. Traditionally, the CAR T-cell therapy has been used to treat blood cancers and only recently has shown promising results against solid tumors. We create an ordinary differential equations model which allows for the infusion of trained CAR-T cells to specifically attack the cancer stem cells that are present in the solid tumor microenvironment. Additionally, we incorporate the influence of TGF-[Formula: see text] which inhibits the CAR-T cells and thus promotes the growth of the tumor. We verify the model by comparing it to available data and then examine combinations of CAR-T cell treatment targeting both non-stem and stem cancer cells and a treatment that reduces the effectiveness of TGF-[Formula: see text] to determine the scenarios that eliminate the tumor.

Double-mirror catadioptric sensors with ultrawide field of view and no distortion.

We compute a family of double-mirror catadioptric sensors with ultrawide field of view and no distortion. The two concentric mirrors are rotationally symmetric, and the inside mirror is a revolved conic section. The mapping between the object and the image planes was linear, hence the lack of distortion. The equations describing the outer mirror were determined by the projection induced by the inside mirror and the rectifying property of the sensor. Solving the resulting nonlinear ordinary differential equations yielded the cross section of the secondary mirror. The sensors we present require no further digital processing.

Equitable mirrors.

Mirror surfaces used in catadioptric sensors are often designed so as to minimize one particular kind of image distortion. In this article we explore some finer properties of equi-areal mirrors, those that feature no area distortion, and we propose novel ways to measure compound forms of distortion. Specifically, we develop new mirror surfaces with large fields of view that simultaneously minimize angular and areal distortion with respect to different cost functions.

Adeno-associated viral delivery of Env-specific antibodies prevents SIV rebound after discontinuing antiretroviral therapy.

An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two rhesus macaque antibodies to the SIV envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIVmac239M after discontinuing suppressive ART. Following AAV administration, sustained antibody expression with minimal anti-drug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within two weeks in all of the control animals but remained below the threshold of detection in plasma (<15 copies/mL) for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals with delayed rebound exhibited restricted barcode diversity and antibody escape. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.

Modeling the stem cell hypothesis: Investigating the effects of cancer stem cells and TGF-ß on tumor growth.

We propose a mathematical model to describe the interaction of cancer stem cells, tumor cells, and the immune system in order to better understand tumor growth in the presence of cancer stem cells. We consider the system in two scenarios: with no-treatment and with a chemotherapy treatment regimen. We develop a system of differential equations, fit the parameters to experimental data, and perform sensitivity and stability analysis. The model simulations show that the tumor cells grow as predicted with no-treatment and that with chemotherapy, which targets only the tumor cells, the cancer will eventually relapse. As chemotherapy does not target the cancer stem cells, we conclude that the tumor cells recover due to the presence of cancer stem cells.