DESCRIPTION (provided by applicant): The overall aims of this five-year career development award are to 1.) enable the candidate's career development as an independent clinical researcher through advanced didactic coursework, structured mentoring and conduct/analysis of a clinical research study; and 2.) better define vitamin D status as a mediator of HIV-related cardiovascular disease (CVD) as well as to determine if vitamin D status changes the effect of rosuvastatin on HIV-related CVD risk. Adults living with HIV are at higher risk than the general population for CVD. Vitamin D deficiency is common in HIV, and appears to play a critical role in systemic inflammation and CVD in the general population, but is not well studied in HIV. Strategies to modify the risk of CVD in HIV present an opportunity for primary disease prevention-an important public health alternative to the treatment of established disease and closely aligned with the mission of NHLBI "to promote the prevention and treatment of heart disease and enhance the health of all individuals so that they can live longer and more fulfilling lives." The candidate will conduct two separate, but complimentary studies one ambispective, cohort study and one randomized clinical trial that will be embedded into two already funded, ongoing studies. The specific aims of the candidates proposal are: 1.) to evaluate the effect over time of vitamin D status on carotid intima media thickness (cIMT) progression and proinflammatory biomarkers in HIV- infected adults before and after initiating antiretroviral therapy (ART) and in age-, sex- and race-matched HIV- uninfected adults; 2.) to evaluate the impact over time of rosuvastatin on vitamin D levels in HIV-infected adults on stable ART; and 3.) to determine if vitamin D status modifies the effect of rosuvastatin on surrogate markers of CVD, proinflammatory biomarkers and cholesterol levels in HIV-infected adults on stable ART. Endpoints will include established surrogate markers of CVD, i.e., cIMT measured by ultrasound, coronary artery calcium score measured by CT scanning, flow mediated dilation of the brachial artery measured by ultrasound, and several important biomarkers of inflammation, endothelial activation, coagulation and oxidation. Statistical analyses will include multiple linea regression and mixed effects modeling. The candidate will be mentored by a multidisciplinary team led by Dr. Grace McComsey, an internationally-recognized clinical researcher in HIV- related metabolic complications, including cardiovascular disease. The candidate has shown a dedication to a career in clinical research through receipt of a Master's in Epidemiology and profile of research projects to date focused in the area of HIV-related CVD and targets to ameliorate this risk. This Career Development Award will provide the foundation for the candidate to pursue an independent research career dedicated to better understanding the pathophysiology of and targets to reduce subsequent morbidity and mortality associated with HIV-related CVD.

Project Narrative - People living with HIV are now suffering from several complications of HIV and its treatment including heart disease. Vitamin D deficiency is common in HIV and has been linked to cardiovascular disease in the general population but has not been well studied in HIV. A better understanding of the association between vitamin D deficiency and cardiovascular disease risk in HIV will provide insight for future clinical trials specifically targeting vitamin D deficiency with the goal of reducing morbidity and mortality due to heart disease in HIV. __SpecificAimsTextDelimiter__ 10. Specific Aims: HIV-infected adults are at higher risk than the general population for cardiovascular disease (CVD).(1- 3) Strategies to modify this co-morbidity present an opportunity for primary disease prevention-an important public health alternative to the treatment of established disease. Vitamin D deficiency is common in HIV(4-10), and appears to play a critical role in systemic inflammation(11-16) and CVD(17-20) in the general population. Therefore, optimizing vitamin D levels in the HIV population may present a good opportunity to attenuate the increased CVD risk and inflammation-related co-morbidities in a simple and cost-effective manner. Much investigation is ongoing examining vitamin D deficiency and its considerable negative impact across different patient groups. Proposed mechanisms for the contribution of vitamin D to CVD pathogenesis include its effects on inflammation(11, 12, 14-16) and on vasculature through modulation of myocardial and vascular smooth muscle cell growth.(21, 22) The impact of vitamin D deficiency in HIV may be compounded further as the etiology of HIV-related CVD is thought to be related to inflammation and detrimental endothelial effects associated with HIV itself.(23-30) We have recently reported that HIV-infected adults with the lowest 25 hydroxyvitamin D (25(OH)D) levels are 10 times more likely to have the highest carotid intima media thickness (cIMT), a well-established marker for subclinical CVD.(31) However, before guidelines can be formulated and instituted for widespread testing for vitamin D deficiency and subsequent treatment, prospective, longitudinal studies determining the effects of vitamin D deficiency on CVD risk in HIV are necessary. In the general population, rosuvastatin, an HMG-CoA reductase inhibitor, has been shown to be effective in primary CVD prevention in adults with normal lipid levels (LDL-cholesterol <130 mg/L) and elevated high-sensitivity C-reactive protein (hsCRP), a marker of systemic inflammation.(32) Although this effect is likely due to the anti-inflammatory properties of statins, a potential mediator for this effect is the effect of statins on vitamin D levels. Indeed, rosuvastatin and other statins have been shown to increase vitamin D levels in HIV- uninfected populations.(33-39) 7-dehydrocholesterol (7-DHC) is the direct precursor of both cholesterol and vitamin D, and it is thus possible that statins exert an effect on both cholesterol and vitamin D metabolism.(40) No study to date has evaluated the CVD risk reduction that statins provide in HIV and the role of vitamin D changes on the CVD protective effects. As the HIV population ages and statins are being investigated as immunomodulatory agents, it will be important to understand how statins might affect vitamin D metabolism. Furthermore, if increased vitamin D level contributes to the risk reduction seen with statins, vitamin D supplementation would provide a safe, cost-effective way to optimize the preventative effect of statins. Three Specific Aims will be investigated using two separate, but complimentary studies that will be embedded into two already funded, ongoing studies (PI, Dr. McComsey, lead mentor). Regardless of the results, these studies will enhance our understanding of the relationship between vitamin D status and CVD risk in HIV-infected individuals. [Firt wehypoheize ha low2(OH)Dlevelsill beindependently socitedwihgreterprogresionofcITand higherproinflmmtory biomrkersinboth H-inVfecedand -uninfectedaduls withthe effec greterinmagniudeinthose with HVinfeciThoins.]hypothesis will be tested in an ongoing prospective cohort study of cIMT progression in HIV-infected adults before and after initiating antiretroviral therapy (ART) and age-, sex- and race- matched HIV-uninfected controls. Specific Aim 1: To evaluate the effect over time of vitamin D [sats] on cIMT progression and proinflammatory biomarkers in HIV-infected adults before and after initiating ART and in age-, sex- and race-matched HIV-uninfected adults. Endpoints include changes over 48 and 96 weeks in: 1) cIMT; 2) levels of proinflammatory cytokines (soluble tumor necrosis factor-¿ receptors-I and -II (sTNFR-I and -II), interleukin-6 (IL6), D-Dimer and hsCRP); 3) cellular adhesion molecules (soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1)); 4) the oxidation marker (F2- isoprostanes). Secondly, using an ongoing NIH-funded, double-blinded, randomized clinical trial of rosuvastatin in HIV-infected adults on ART with LDL-cholesterol <130 mg/L, we hypothesize that rosuvastatin treatment will be associated with increases in vitamin D levels and that higher vitamin D levels will be independently associated with improved surrogate measures of CVD and biomarkers in the statin group and overall. Specific Aim 2: To evaluate impact over time of rosuvastatin on vitamin D levels in HIV-infected adults on stable ART. The endpoints of this aim include changes over 48 and 96 weeks in 25(OH)D levels. Specific Aim 3: To determine if vitamin D status changes the effect of rosuvastatin on surrogate markers of CVD, proinflammatory biomarkers and cholesterol levels in HIV-infected adults on stable ART in a blinded, randomized clinical trial. Endpoints include changes over 48 and 96 weeks in: 1) cIMT; 2) Coronary artery calcium score; 3) flow mediated dilation of the brachial artery (to 48 weeks only); 4) levels of proinflammatory cytokines (sTNFR-I and -II, IL6, D-Dimer and hsCRP); 5) cellular adhesion molecules (sVCAM-1 and sICAM-1); 6) oxidation marker (F2-isoprostanes); 7) cholesterol levels; 8) insulin resistance.