Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

Massive research efforts are now underway to develop a cure for HIV infection, allowing patients to discontinue lifelong combination antiretroviral therapy (ART). New latency-reversing agents (LRAs) may be able to purge the persistent reservoir of latent virus in resting memory CD4+ T cells, but the degree of reservoir reduction needed for cure remains unknown. Here we use a stochastic model of infection dynamics to estimate the efficacy of LRA needed to prevent viral rebound after ART interruption. We incorporate clinical data to estimate population-level parameter distributions and outcomes. Our findings suggest that approximately 2,000-fold reductions are required to permit a majority of patients to interrupt ART for one year without rebound and that rebound may occur suddenly after multiple years. Greater than 10,000-fold reductions may be required to prevent rebound altogether. Our results predict large variation in rebound times following LRA therapy, which will complicate clinical management. This model provides benchmarks for moving LRAs from the lab to the clinic and can aid in the design and interpretation of clinical trials. These results also apply to other interventions to reduce the latent reservoir and can explain the observed return of viremia after months of apparent cure in recent bone marrow transplant recipients and an immediately-treated neonate.Comment: 8 pages main text (4 figures). In PNAS Early Edition http://www.pnas.org/content/early/2014/08/05/1406663111. Ancillary files: SI, 24 pages SI (7 figures). File .htm opens a browser-based application to calculate rebound times (see SI). Or, the .cdf file can be run with Mathematica. The most up-to-date version of the code is available at http://www.danielrosenbloom.com/reboundtimes

Audit of Antenatal Testing of Sexually Transmissible Infections and Blood Borne Viruses at Western Australian Hospitals

In August 2007, the Western Australian Department of Health (DOH) released updated recommendations for testing of sexually transmissible infections (STI) and blood-borne viruses (BBV) in antenates. Prior to this, the Royal Australian & New Zealand College of Obstetricians & Gynaecologists (RANZCOG) antenatal testing recommendations had been accepted practice in most antenatal settings. The RANZCOG recommends that testing for HIV, syphilis, hepatitis B and C be offered at the first antenatal visit. The DOH recommends that in addition, chlamydia testing be offered. We conducted a baseline audit of antenatal STI/BBV testing in women who delivered at selected public hospitals before the DOH recommendations. We examined the medical records of 200 women who had delivered before 1st July 2007 from each of the sevenWAhospitals included in the audit. STI and BBV testing information and demographic data were collected. Of the 1,409 women included, 1,205 (86%) were non-Aboriginal and 200 (14%) were Aboriginal. High proportions of women had been tested for HIV (76%), syphilis (86%), hepatitis C (87%) and hepatitis B (88%). Overall, 72% of women had undergone STI/BBV testing in accordance with RANZCOG recommendations. However, chlamydia testing was evident in only 18% of records. STI/BBV prevalence ranged from 3.9% (CI 1.5– 6.3%) for chlamydia, to 1.7% (CI 1–2.4%) for hepatitis C, 0.7% (CI 0.3–1.2) for hepatitis B and 0.6% (CI 0.2–1) for syphilis. Prior to the DOH recommendations, nearly three-quarters of antenates had undergone STI/BBV testing in accordance with RANZCOG recommendations, but less than one fifth had been tested for chlamydia. The DOH recommendations will be further promoted with the assistance of hospitals and other stakeholders. A future audit will be conducted to determine the proportion of women tested according to the DOH recommendations. The hand book from this conference is available for download Published in 2008 by the Australasian Society for HIV Medicine Inc © Australasian Society for HIV Medicine Inc 2008 ISBN: 978-1-920773-59-

Optimization of HAART with genetic algorithms and agent-based models of HIV infection

Motivation: Highly Active AntiRetroviral Therapies (HAART) can prolong life significantly to people infected by HIV since, although unable to eradicate the virus, they are quite effective in maintaining control of the infection. However, since HAART have several undesirable side effects, it is considered useful to suspend the therapy according to a suitable schedule of Structured Therapeutic Interruptions (STI).In the present article we describe an application of genetic algorithms (GA) aimed at finding the optimal schedule for a HAART simulated with an agent-based model (ABM) of the immune system that reproduces the most significant features of the response of an organism to the HIV-1 infection.Results: The genetic algorithm helps in finding an optimal therapeutic schedule that maximizes immune restoration, minimizes the viral count and, through appropriate interruptions of the therapy, minimizes the dose of drug administered to the simulated patient.To validate the efficacy of the therapy that the genetic algorithm indicates as optimal, we ran simulations of opportunistic diseases and found that the selected therapy shows the best survival curve among the different simulated control groups.Availability: A version of the C-ImmSim simulator is available at http://www.iac.cnr.it/~filippo/c-ImmSim.htmlContact: [email protected]

Role of delay differential equations in modelling low level HIV viral load

Over the past 30 years, HIV has infected over 60 million people, with almost half succumbing to AIDS-related illnesses.While antiretroviral therapy, used to significantly reduce within-host HIV replication, was available within 10 years of the discovery of HIV/AIDS, it is only within the last 10 years that it has become truly effective and universally accessible. However, there are problems with this therapy, not least that it must be administered indefinitely , but is expensive and highly toxic. Furthermore, as therapy reaches more resource-limited regions, continual access can not be guaranteed, resulting in therapy interruptions. This, coupled with a significant cost reduction by systematically interrupting therapy, means a set of models which can account for both treatment events need to be developed, as numerous models exist for therapy introduction, but those for therapy removal are limited. Thus a set of delay differential models are designed, which account for previously overlooked important features of intracellular delay and HIV latency. Incorporation of these features requires additional model components, leading to a rapid increase in complexity. To combat this complexity issue, dimensional analysis is introduced, as a novel method of identifying key components to model function, thus allowing significant reduction in parameter space. Based on these developed models, a number of existing and potential treatment interruption regimes are investigated, with a best practice regime suggested

The viral diversity in the EPIC4 cohort and the evolution of the size of the HIV-1 cellular reservoir in perinatally infected children and adolescents under cART

Le VIH-1 reste incurable dû à sa diversité génétique et sa capacité à se cacher dans des réservoirs cellulaires. Certaines études ont révélé que le clade du VIH peut influencer l’issue de l’infection. D'autres études chez l'adulte et l'enfant ont montré que l'initiation précoce d'un traitement antirétroviral combiné (TARc) peut limiter la taille du réservoir et conduire à une suppression virale soutenue (SVS) après interruption du traitement. Ici, nous allons génotyper le clade de 64 participants et allons examiner l’influence de l'âge, du maintien de la SVS et de l'initiation précoce du TARc sur la dynamique du réservoir chez 67 enfants et adolescents verticalement infectés (cohorte EPIC4). Une analyse phylogénétique basée sur le gène gag du VIH-1 a démontré que la majorité était infectée par le clade C, puis A, B, CRF01_AE, CRF02_AG et G. La prévalence des sous-types non-B (77 %) est cohérente avec les tendances courantes et l'origine ethnique des participants. L'ADN viral a été mesuré dans les cellules mononuclées du sang périphérique. L'ARN induit par un analogue de prostratin a été mesuré dans des cellules T CD4+. Nous avons démontré la corrélation positive entre les deux techniques. La taille du réservoir était similaire entre enfants et adolescents et est restée stable aux différents temps de mesures. Les participants avec SVS présentaient les niveaux médians d'ARN et d'ADN les plus bas. Une longue durée de la TARc et l’initiation précoce du traitement chez ceux qui ont maintenu une SVS étaient associées à un réservoir plus petit. La présence de « blips » a influencé la trajectoire et la taille du réservoir.HIV-1 infection remains incurable due to the genetic diversity of the virus and its ability to hide out of reach in cellular reservoirs. Some studies revealed that HIV clades may differently influence the outcome of HIV. Other studies in adults and children have shown that early initiation of combination antiretroviral therapy (cART) can limit the size of the reservoir and can lead to sustained viral suppression (SVS) after treatment interruption. Here we genotyped the HIV-1 subtype in 64 participants and examined how the dynamics of the viral reservoir in 67 children and adolescents with vertically acquired HIV infection was influenced by age, maintenance of SVS, and early initiation of cART (EPIC4 cohort). Following a phylogenetic analysis based on HIV-1 gag gene, we discovered the majority were infected with clade C, then A, B, CRF01_AE, CRF02_AG and G. The high prevalence of non-B subtypes (77%) is consistent with current trends and the ethnic origin of study participants. Viral DNA was measured in peripheral blood mononuclear cells, and RNA induced with an prostratin analog was measured in CD4+ T cells. We demonstrated the positive correlation between these two assays. The size of the reservoir was similar between children and adolescents and remained stable at different time-points. Participants with SVS presented the lowest median HIV-1 RNA and DNA levels. Longer duration of effective treatment and early initiation of treatment in participants who maintained SVS were associated with a smaller reservoir. The presence of « blips » influenced the trajectory of reservoir size over time

HIV/AIDS Study. Bibliographic review of the virus and mathematical models.

The human immunodeficiency virus is a global pandemic that causes thousands of deaths a year. It is caused by two lentivirus that can already either type 1 or 2 (HIV-1, HIV-2) and are spread by blood or bodily fluids. HIV infection has an incubation period of 8 to 10 years and is characterized by attacking CD4 cells in the immune system. Today, the World Health Organization (WHO) estimates that more than 37 million people live with HIV worldwide, of which only half have access to antiretroviral therapy. The main function of the therapy is to reduce the rate at which HIV replicates in the body by using combinations of drugs. Nowadays, the HIV virus continues to have a major impact on the world due to its rapid spread and the significant number of cases in certain areas, specifically sub-Saharan Africa. While in most countries the growth rate tends to fall, in the case of sub-Saharan Africa it is still growing. The use of HIV treatments and vaccines have helped in the non-development of the virus, yet the problem still remains. That is why other tools have been used in recent years to prevent and analyze the problem of the epidemic, such as the use of mathematical models. These can help us understand the evolution of HIV in the world as is the HIV clinical course. In this work, a bibliographic review of the current knowledge about HIV is proposed, as well as the mathematical models that have been used in its study. This work is the starting point of a new line of research of the Computational Biology and Complex Systems Group of the Polytechnical University of Catalonia.El virus de la inmunodeficiencia humana es una pandemia a nivel mundial que causa miles de muertes al año. Esta causada por dos lentivirus, ya pueden ser del tipo 1 o 2 (VIH-1, VIH-2) y se contagia mediante la sangre o fluidos corporales. La infección por VIH tiene un periodo de incubación de 8 a 10 años y se caracteriza por atacar a las células CD4 del sistema inmunitario. Hoy en día, la Organización Mundial de la Salud (OMS) calcula que más de 37 millones de personas viven con el VIH en todo el mundo. De los cuales, solo la mitad tiene acceso a la terapia antirretroviral. La función principal de la terapia es reducir la velocidad a la que el VIH hace copias de sí mismo en el organismo mediante el uso de combinaciones de medicamentos. Hoy en día, el virus del VIH sigue teniendo una gran repercusión en el mundo debido a su rápida propagación y a la notable cantidad de casos en ciertas zonas como es el caso del África Subsahariana. Mientras en la mayoría de los países el índice de crecimiento tiende a bajar, en el caso de África subsahariana sigue en crecimiento. El uso de tratamientos y vacunas para el VIH han ayudado al no desarrollo del virus, aun así, el problema sigue vigente. Es por ello, que en los últimos años se han usado otras herramientas para prevenir y analizar el problema de la epidemia, como es el caso del uso de modelos matemáticos. Estos, nos pueden hacer entender la evolución del VIH en el mundo como es también el curso clínico del VIH. En este trabajo se plantea una revisión bibliográfica del conocimiento actual sobre el VIH, así como de los modelos matemáticos que se han utilizado en su estudio. Este trabajo es el punto de partida de una nueva línea de investigación del Grupo de Biología Computacional i Sistemas Complejos de la Universidad Politécnica de Cataluña.El virus d'Immunodeficiència humana és una pandèmia global que provoca milers de morts a l'any. És causada per dos lentivirus, poden ser tipus 1 o 2 (VIH-1, HIV-2) i es propaga per sang o fluids corporals. La infecció pel VIH té un període d'incubació de 8 a 10 anys i es caracteritza per atacar a les cèl·lules de CD4 en el sistema immunitari. Avui en dia, l'organització mundial de la salut (OMS) estima que més de 37 milions de persones viuen amb el VIH a tot el món, de les quals només la meitat tenen accés a la teràpia antiretroviral. La funció principal de la teràpia és reduir la velocitat a la qual el VIH fa còpies de si mateix en el cos mitjançant l'ús de combinacions de fàrmacs. Avui en dia, el virus del VIH continua tenint un impacte important en el món a causa de la seva ràpida propagació i el nombre significatiu de casos en certes àrees com l'Àfrica subsahariana. Mentre que en la majoria dels països la taxa de creixement tendeix a disminuir, en el cas de l'Àfrica subsahariana, encara està en creixement. L'ús dels tractaments del VIH i les vacunes han ajudat al no-desenvolupament del virus, però, el problema es manté. És per això que s'han utilitzat altres eines en els últims anys per prevenir i analitzar el problema de l'epidèmia, com ara l'ús de models matemàtics. Aquests ens poden fer entendre l'evolució del VIH al món com també el curs clínic del VIH. En aquest treball es planteja una revisió bibliogràfica del coneixement actual sobre el VIH, així com dels models matemàtics que s'han utilitzat en el seu estudi. Aquest treball és el punt de partida d'una nova línia de recerca del Grup de Biologia Computacional i Sistemes Complexos de la Universitat Politècnica de Catalunya

Rebound Relationships: An Investigation Of Hiv-1 Rebound Dynamics And Host Immune Responses During Analytical Treatment Interruption

In HIV-infected patients, combination antiretroviral therapy (cART) during HIV-1 infection potently suppresses viral replication and slows progression to AIDS. Upon cessation of cART, however, systemic infection is rapidly re-established due to the long-lived pool of latently infected cells, or HIV reservoir, that is seeded early in infection and persists despite years of cART in patients. This long-lived reservoir is the target of novel curative strategies. In order to determine in vivo efficacy of these interventions, closely monitored analytical treatment interruption (ATI) is required. Previously conducted ATI trials have provided important baseline information regarding the kinetics and diversity of viruses emerging from latency. As future HIV curative clinical trials move towards prolonged periods of ATI, studies assessing the effect of ATI on host virus-immune dynamics will provide an important baseline that will further our understanding of trial outcomes. In this thesis, I conducted single genome sequencing (SGS) of HIV-1 env and neutralization assays using autologous antibodies to characterize the viral and immune dynamics of rebound in two clinical trials: a longitudinal ATI study in the absence of any intervention, and a brief ATI study involving administration of the broadly neutralizing antibody VRC01. Our data, consistent with previous studies, demonstrated that viral rebound occurs within four weeks of ATI and is established by multiple latently infected cells in the majority of HIV-infected participants. Analyses of plasma containing VRC01 and/or autologous antibodies show that latent reservoir viruses can experience an antibody-mediated neutralization sieve effect, thus preventing the persistence of antibody-sensitive viruses. Additionally, SGS of latent viruses before and after brief ATI show that the size and composition of the peripheral latent viral reservoir is not significantly altered during ATI, demonstrating that short-term ATI is safe. Taken together, these data highlight the complex virus-host dynamics during ATI, and further suggest that passively infused or host-derived neutralizing antibodies can exert selective pressure, altering the evolution of HIV in its host

Reconciling conflicting clinical studies of ANTIOXIDANT SUPPLEMENTATION AS HIV THERAPY: A MATHEMATICAL APPROACH

Small highly reactive molecules called reactive oxygen species (ROS) play a crucial role in cell signalling and infection control. However, high levels of ROS can cause significant damage to cell structure and function. Studies have shown that infection with the human immunodeficiency virus (HIV) results in increased ROS concentrations, which can in turn lead to faster progression of HIV infection, and cause CD4+ T-cell apoptosis. To counteract these effects, clinical studies have explored the possibility of raising antioxidant levels, with mixed results. In this thesis, a mathematical model is used to explore this potential therapy, both analytically and numerically. For the numerical work, we use clinical data from both HIV-negative and HIV-positive injection drug users (IDUs) to estimate model parameters; these groups have lower baseline concentrations of antioxidants than non-IDU controls. Our model suggests that increases in CD4+ T cell concentrations can result from moderate levels of daily antioxidant supplementation, while excessive supplementation has the potential to cause periods of immunosuppression. We discuss implications for HIV therapy in IDUs and other populations which may have low baseline concentrations of antioxidants

Finding a cure for HIV: will it ever be achievable?

Combination antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity. However, HIV still cannot be cured. With the absence of an effective prophylactic or therapeutic vaccine, increasing numbers of infected people, emerging new toxicities secondary to cART and the need for life-long treatment, there is now a real urgency to find a cure for HIV