Project 1: Brain
Neuro Hypothalamic pituitary adrenal axis.
PIs: Gretchen Neigh and Vasiliki Michopoulos
Sex hormones are influential in setting the tone of immune responses and estradiol exhibits a particularly strong influence that varies across the life cycle in women.
Although largely anti-inflammatory and protective, estradiol can have divergent effects. In addition, the influence and availability of estradiol changes with aging, most notably with the menopause transition. Furthermore, exposure to stressors can impact the functions of sex hormones, including estradiol.
Women living with HIV (WLH) may be more vulnerable to the effects of stress and trauma exposure on hormone function and precipitated changes may manifest as enhanced inflammatory signaling. This project will further our understanding of the biology of aging, and specifically the prognosis of WLH, and characterize the link between immunosenescence and endocrinesenescence.
Our research activities are defining estrogen deficiency at both the systemic and receptor level and evaluating the extent to which global variation in these parameters predicts pro-inflammatory pathways in WLH. We are conducting clinical interviews to assess trauma exposure and trauma-related hyperarousal to examine how these factors interact with HIV to exacerbate estrogen deficiency and inflammation. Furthermore, are characterizing the influence of trauma exposure and estrogen receptor function on inflammation at the molecular level in WLH.
Overall, the data generated from this project will provide critical information about the influence of estradiol signaling on inflammation in WLH and provide mechanistic insight more broadly into the influence of estradiol receptor function on inflammation. Because trauma exposure and its related adverse mental health outcomes (i.e. posttraumatic stress disorder; PTSD) are poorly controlled in WLH, and PTSD has dangerous implications for HIV pathogenesis and transmission, it is of critical importance to identify the effects of trauma and PTSD comorbidity with HIV in order to titrate the most effective treatment approaches for this complex comorbidity.
Project 2: Bone
The Collision of HIV/ART- and Estrogen Deficiency-Bone Loss
PIs: Neale Weitzmann and Igho Ofotokun
HIV-infection causes bone loss that is paradoxically worsened by antiretroviral therapy (ART) leading to significantly increased fracture rates in men and women. However, recent studies show that fracture incidence is further exacerbated in HIV-infected women after menopause, suggesting a collision between HIV/ART and estrogen deficiency, aggravating skeletal deterioration.
While the magnitude of bone loss may vary, all ART drug classes cause bone loss and we have hypothesized that this is an indirect downstream effect of ART, driven by immune-reconstitution and inflammatory events associated with the rekindling of adaptive immunity following T cell reconstitution.
We have demonstrated that an animal model of T cell reconstitution does indeed cause significant inflammatory bone loss that closely mimics key features of ART-induced skeletal deterioration. In this model, adaptive immune cells including lymphocytes and macrophages secrete the key osteoclastogenic cytokines Receptor activator of NF-kB ligand (RANKL) and TNF which drives up basal bone resorption leading to bone loss.
Interestingly, postmenopausal osteoporosis, the archetypal bone disease of women, results from estrogen decline after menopause that is also driven in part, by an inflammatory state characterized by B and T cell production of RANKL and TNF by adaptive immune cells.
Although the etiologies are different, because bone loss in estrogen deficiency and in HIV/ART, both involve activation of adaptive immunity leading to the development of chronic inflammatory states, we hypothesize that a collision between inflammatory bone loss associated with HIV/ART may synergize with the inflammatory bone loss associated with estrogen deficiency. Such events may account for exacerbated fracture in postmenopausal HIV-infected women and may portend a looming epidemic of fracture in the rapidly aging female HIV community.
Project 2 of this SCORE grant is studying whether HIV/ART- and estrogen deficiency-induced inflammatory events collide to additively or synergistically augment inflammation and bone loss. We are employing animal models of ART- and estrogen deficiency-induced inflammatory bone loss, and translational clinical studies in human HIV+ and HIV- women to quantify the combined effects of HIV/ART and estrogen decline on bone structure and turnover in relation to adaptive immune function and osteoclastogenesis.
Our hypotheses, if validated, will significantly inform current understanding of the collision between HIV/ART-induced skeletal decline with that of estrogen deficiency bone loss and the underlying HIV-induced and estrogen deficiency induced immunological defects leading to bone loss. It will also establish whether these defects are additive or synergistic, or even diminished. This will have broad implications for the future of HIV care, especially as the population ages.
Project 3: Heart
Cardiovascular Risk in Women with HIV
PI: Arshed Quyyumi
Although heightened cardiovascular disease (CVD) risk in HIV is partly attributable to an increased burden of CVD traditional risk factors and to antiretroviral therapy-mediated effects, persistent inflammation and immune dysregulation may also play a role.
Women have a greater burden of CVD risk factors, including inflammation, despite having less obstructive coronary artery disease (CAD), but nevertheless have worsening clinical outcomes. Among HIV+ women, CVD risk is further compounded by estrogen deficiency and early menopause.
Coronary computed tomographic angiography (CCTA) can not only detect the presence and volume of plaque, but assess high risk plaque (HRP) characteristics. Vascular functional and structural measures including carotid intima-media thickness (CIMT), carotid plaque, and brachial artery endothelial function are predictive of future MI and stroke.
In HIV+ subjects, CIMT is thicker and carotid plaque 1.5-fold more prevalent compared to controls. Magnetic resonance imaging (MRI) of the carotid arteries provides a state-of-the-art, accurate and reproducible measure of carotid arterial wall thickness, plaque and its high risk characteristics, and permits reliable measures of disease progression.
Circulating bone marrow-derived progenitor cells (PCs) are actively involved in cardiovascular homeostasis and mediate cardiovascular repair and regeneration. We have shown that a reduction in the number and migratory activity of PCs is associated with higher CVD risk and mortality. Moreover, women have lower numbers of circulating PCs compared to men, and levels of PCs correlate with estrogen status. In HIV+ subjects PC counts are lower, providing evidence for reduced regenerative capacity.
Our overall objective in Project 3 is to define the contribution of HIV infection in women to both injurious factors (inflammation, HIV status) and to endogenous reparative/regenerative processes in the setting of estrogen deficiency. We are also examining their combined impact on the presence and progression of sub-clinical coronary and carotid artery atherosclerosis, as measured by CCTA and carotid MRI.
In this project we are analyzing the impact of HIV-related changes in regenerative capacity, endothelial function and arterial stiffness on prevalent coronary and carotid arterial disease.