Research Initiatives on AIDS and HIV in the Division of Translational Toxicology

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

HIV infections remain a worldwide concern, requiring life-long therapies with high compliance to effectively manage the level of active virus. In the past 30 years, antiretroviral therapies (ART) have aided in the management of the acquired immune deficiency syndrome (AIDS) resulting from HIV, changing the disease from a fatal infection in the early 90s to a chronically managed condition in the mid-2000s. Initial medicines used to treat HIV consisted of nucleotide reverse transcriptase inhibitors (NRTIs), which aimed at blocking viral replication. These drugs had severe side effects due to off-target mitochondrial toxicity and over the years have been replaced, to some extent, by administration of less toxic drugs that are now provided in combination (cART). Despite this, new generation NRTIs remain a staple of cART. These combination drug therapies have also been used prophylactically to minimize risk of maternal transfer to the child and to non-infected partners. While beneficial, the various combination therapies are not without potential health-related concerns. Prominent issues have been raised with regards to metabolism and increased bodyweight, cognitive function, cardiac function, immune response, and bone growth. It has therefore become imperative to understand the long-term health effects associated with chronic cART exposure. This is relevant for patients that start treatment as adults but also for pediatric populations that are exposed during susceptible developmental windows. Given the severity of the disease, therapeutic intervention to regulate viral load is necessary, however, it also limits the ability to identify and characterize the adverse effects of the drugs and interactions with viral load. This research initiative focuses on the effects of exposure to HIV therapeutics in the absence of the HIV virus or viral proteins both in adults as well as in embryo/fetus during pregnancy and early post-natal period. Using experimental rodent models, effects on offspring exposed to the drugs via the dam during gestation and lactation as well as the effects on the dams were examined. The initial studies focused on outcomes with of exposure to two selected cART as they related the reproductive, the cardiovascular and the nervous systems in addition to potential developmental effects on the offspring This approach allowed for comparisons of effects not only across studies but between different organ systems and timings of exposure. 1) Developmental and Reproductive Studies: studies were employed to evaluate potential liabilities associated with gestational and lactational exposure to a select HIV combination therapy. In this effort, pregnant rats were treated from gestational day 6 (GD6) until postnatal day 28 (PND28), with pups indirectly exposed in utero and via lactation. After weaning, pups were evaluated over a 15-week period for clinical observations, body weight, food consumption, developmental and reproductive indices, and clinical- and histo-pathology parameters. In addition, assessment of maternal-fetal and offspring exposure levels were measured. The in-life portion of the study is complete and data evaluations are ongoing. 2) Cardiovascular Studies: Dams were treated continuously from GD6 until PND120; pups were exposed indirectly via the dam and then aged to 4 and 12 months without any drug exposure. Functional cardiovascular (electrocardiogram or ECGs, and echocardiograms or ECHO), biochemical and genomics parameters were assessed at PND21, PND120 and when animals reached 1 year old. Data suggest ECG effects in both dams and offspring, with the effects on the latter being pronounced at 12 months of age. Interestingly, offspring also showed effects on ECHO, indicating changes in contractility, that were significant in males but not in females. Genomics data has also identified sex differences in transcriptional profiles of the offspring as they age. The next phase of these studies will involve understanding the mechanisms underlying the ECG and ECHO effects and the differential response observed in males and females. 3) Neurological Studies: Using the same perinatal exposure regimen, the offspring have been examined over a 1.5-year period for general endpoints associated with motor and sensory functions, response to pharmacological challenge, and stress related responses. Additional assessments of response to an inflammatory challenge and the effects of cART exposure in the aged animal are under study to determine potential senescence and evidence of accelerated inflammaging in the nervous system.