Research Initiatives on AIDS and HIV in the Division of the National Toxicology Program

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 body weight, cognitive function, cardiac function, immune response, and bone growth and 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 developmental exposure to HIV therapeutics in the absence of the HIV virus or viral proteins. Using experimental rodent models, effects on offspring exposed to the drugs via the dam during gestation and lactation were examined. The initial research focused on outcomes related to reproductive, developmental, cardiovascular, and nervous system outcomes with exposure to a select cART, allowing for comparison across studies and organ systems. 1) Developmental and Reproductive Studies cART is indicated throughout pregnancy to avoid transmission of HIV from mother to fetus, and for a few weeks after birth to mitigate any potential viremia transmitted at birth. To determine if these exposures impact the offspring, developmental and reproductive 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 For cardiovascular outcomes, 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 (electrocardiograms, ECGs, and echocardiograms, ECHO), biochemical and genomics parameters were assessed at PND21, PND120 and when animals reached 1 year old. Current data only include the first two time-points, and indicate that treatment of adults during these 5 months do not lead to significant changes in heart function or biochemical/molecular parameters. Conversely, preliminary data suggest exposed pups show decreased cardiac function at PND21 and PND120. At these times, mitochondrial DNA (mtDNA) levels are decreased, mitochondrial structure is altered as is the transcriptional profile. Data from the 12-month-old animals will inform the extent of the protracted effects associated with the developmental exposure. 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.