Optimizing thymic recovery in HIV patients through multidrug therapies

A control-theoretic approach to the problem of designing `low-side-effects´ therapies for HIV patients based on highly active drugs is substantiated here. The evolution of side-effects during treatment is modelled by an extra differential equation coupled to the dynamics of virions, healthy T-cells, and infected ones.  The new equation reflects the dependence of collateral damages on the amount of each dose administered to the patient, and on the evolution of the viral load detected by periodical blood analyses.  The cost objective accounts for recommended bounds on healthy cells and virions, and also penalizes the appearance of collateral malignancies caused by the medication.  The problem is solved by a hybrid Dynamic Programming scheme that adhere to discrete-time observation and control actions, but maintaining the continuous-time setup for predicting states and side-effects.  The resulting optimal strategies employ less drugs than those prescribed by previous optimization studies, but maintaining high doses at the beginning and the end of each period of six months.  If an inverse discount rate is applied to favor early actions, and under a mild penalization of the final viral load, then the optimal doses are found to be high at the beginning and decrease afterwards, causing a desirable stabilization of the main variables.Fil: Costanza, Vicente. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); ArgentinaFil: Rivadeneira Paz, Pablo Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe. Instituto de Desarrollo Tecnológico Para la Industria Química (i); ArgentinaFil: Biafore, Federico Leonardo. Universidad Favaloro; ArgentinaFil: D'attellis, C. E.. Universidad Nacional de San Martín. Escuela de Ciencia y Tecnología; Argentina. Universidad Favaloro; Argentin

Thymic Rejuvenation: Are We There Yet?

Vaccination is an appealing form of immunotherapy for frail senior patients. However, several studies have shown that in contrast to younger adults, older patients do not effectively respond to vaccines. This phenomenon is greatly attributed to immunosenescence, a hallmark of aging defined by a general decline in immunity caused by thymic involution. Historically, the study of thymic involution brought to attention several factors and components involved in thymopoiesis, as contributors to the phenomena. Depicting the underlying cause(s) of the dramatic changes in the production and properties of the naïve T-cell pool in the event of acute thymic injury or due to inovulation can therefore, help focus the efforts on the best strategy to reverse or overcome these hurdles. Here, we discuss some of the well-studied approaches for rejuvenating the thymus, and introduce interleukin-(IL) 21 as the most recent thymo-stimulatory agent in the field

Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles

Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1's ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV's evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy's unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents

In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation.

Regulatory T cells (Tregs) have been shown to be critical in the balance between autoimmunity and tolerance and have been implicated in several human autoimmune diseases. However, the small number of Tregs in peripheral blood limits their therapeutic potential. Therefore, we developed a protocol that would allow for the expansion of Tregs while retaining their suppressive activity. We isolated CD4+CD25 hi cells from human peripheral blood and expanded them in vitro in the presence of anti-CD3 and anti-CD28 magnetic Xcyte Dynabeads and high concentrations of exogenous Interleukin (IL)-2. Tregs were effectively expanded up to 200-fold while maintaining surface expression of CD25 and other markers of Tregs: CD62L, HLA-DR, CCR6, and FOXP3. The expanded Tregs suppressed proliferation and cytokine secretion of responder PBMCs in co-cultures stimulated with anti-CD3 or alloantigen. Treg expansion is a critical first step before consideration of Tregs as a therapeutic intervention in patients with autoimmune or graft-versus-host disease

Immunotherapeutic restoration in HIV-infected individuals

While the development of combined active antiretroviral therapy (cART) has dramatically improved life expectancies and quality of life in HIV-infected individuals, long-term clinical problems, such as metabolic complications, remain important constraints of life-long cART. Complete immune restoration using only cART is normally unattainable even in cases of sufficient plasma viral suppression. The need for immunologic adjuncts that complement cART remains, because while cART alone may result in the complete recovery of peripheral net CD4+ T lymphocytes, it may not affect the reservoir of HIV-infected cells. Here, we review current immunotherapies for HIV infection, with a particular emphasis on recent advances in cytokine therapies, therapeutic immunization, monoclonal antibodies, immune-modulating drugs, nanotechnology-based approaches and radioimmunotherapy.ope

Therapeutic advancements in the management of HIV/AIDS

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.A infeção pelo vírus da imunodeficiência humana tornou-se numa epidemia global que está a entrar na sua quarta década. Estima-se que, desde a descoberta deste vírus, 79,3 milhões (55,9- 110 milhões) de pessoas foram infetadas e que dessas, 36,3 milhões (27,2 milhões-47,8 milhões) perderam as suas vidas. Podemos dividir este retrovírus em dois tipos: tipo 1 e tipo 2. Ambas as espécies pertencem ao grupo dos Lentivirus, que por sua vez pertencem à família e subfamília Retroviridae e Orthoretrovirinae, respetivamente. Ambos possuem a mesma estrutura genética básica, o mesmo mecanismo de replicação intracelular, via de transmissão e progressão da doença; no entanto, eles pertencem a linhagens diferentes, ou seja, representam transmissões entre espécies distintas (zoonose). A síndrome da imunodeficiência humana adquirida é o estadio final da progressão viral e, se não for tratada, acaba com a morte do doente. Com um melhor entendimento da replicação viral e dos mecanismos utilizados para evadir a imunidade do nosso organismo, os alvos para interromper a produção viral também se tornaram mais claros. Atualmente, existe um arsenal de mais de 30 fármacos antirretrovirais, que possuem oito mecanismos de ação distintos. O vírus que antes era visto como uma sentença de morte para todos que o contraíam, é agora é uma doença crónica que pode ser controlada com terapia existente. Esta dissertação está dividida em 4 partes: origem e descoberta do HIV; mecanismo de replicação viral; Terapia antirretroviral; avanços na manutenção da terapêutica do HIV. O objetivo principal do trabalho é entender como uma zoonose com origem em África conseguiu espalhar-se pelo mundo e até hoje permanece sem cura. Será também abordada a progressão da terapêutica disponível e dos medicamentos aprovados ao longo dos anos, desde os primeiros medicamentos que causavam efeitos secundários graves e que eram facilmente suscetíveis à resistência viral devido à ocorrência de mutações no início dos anos 90 até 2021, onde é utilizada uma terapêutica dupla ou tripla, sem que exista toxicidade para o doente e com uma excelente relação benefício-risco. Também serão abordados fármacos e vacinas em ensaios clínicos para o tratamento deste retrovírus, que poderão vir a ser aprovados num futuro a médio/longo prazo.The human immunodeficiency virus has become a global epidemic that is now entering his fourth decade. It is estimated that since the discovery of this virus, 79.3 million (55.9 million 110 million) people have become infected and 36.3 million (27.2 million-47.8 million) have lost their lives. We can divide this retrovirus into two main types: 1 and 2. Both species belong to the Lentivirus group, that belongs to the Retroviridae Orthoretrovirinae family and subfamily, respectively. Both types share the same basic gene arrangement, equal intracellular replication mechanism, transmission pathway and disease progression however they belong to different lineages and furthermore represent distinctive cross-species transmissions (zoonosis). The acquired human immunodeficiency syndrome is the final stage of viral progression and it ends up in death if not treated. With the better understanding of viral replication and their mechanisms to evade immunity, the targets to stop viral production also became clearer. Nowadays, we are in possession of an armory of more than 30 antiretroviral agents, acting through eight different mechanisms. The virus that once was a death sentence for everyone who caught it, is now a chronic disease that can be managed by the existing therapy. This dissertation is divided in 4 parts: origin and discovery of HIV; mechanism of viral replication; antiretroviral therapy; advancements in the management of HIV. The main purpose of the work is to understand how a zoonosis originated in Africa was able to spread throughout the world and until this day remains with no cure. It will also approach the progression of the approved drugs throughout the years, from the 1-2 medicines that caused brutal side effects and were easily prone to resistance mutations in the beginning of the 90s to 2021, where 2-3 medicines are simultaneously used in almost non-toxic, with little to no side effects in the treatment of this retrovirus, along with possible drugs that could be approved in a medium-long term

Antimicrobial host defence peptides: functions and clinical potential

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally occurring peptides that can combat infections through their direct microbicidal properties and/or by influencing the host's immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been used to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies