R01AG071441

Effect of Estrogen Replacement on Postmenopausal ART-Associated Comorbidity and Viral Latency - Project Summary

Current antiretroviral therapy (ART) regimens have rendered HIV/AIDS a manageable chronic condition rather than a fatal disease, and people living with HIV (PLWH) that initiate ART soon after infection can achieve almost normal life expectancy. This leads to an aging population of PLWH that are increasingly subject to a collection of age-associated diseases, including obesity, diabetes, and cardiovascular disease.

In spite of effective control of viremia, HIV-induced inflammation is incompletely resolved following ART initiation, and this chronic inflammation leads to a variety of comorbidities, including increased risk for the same age-related diseases. Women living with HIV (WLWH) now comprise the majority of the global HIV/AIDS population and represent the preponderance of new cases. However, women are still underrepresented in clinical studies in spite of significant sex differences in multiple aspects of HIV pathology.

As a consequence of the increased survival of PLWH, more WLWH will now undergo menopause and be subject to a disease burden that reflects age, ART-associated chronic inflammation, and, in addition, any adverse consequences of postmenopausal estrogen deficiency. The likely effects of estrogen deficiency will involve changes in systemic metabolic status, white adipose tissue (WAT) function and control of glucose and lipid metabolism, and suppression of the circulating and tissue latent reservoirs based on the recent discovery that estrogen receptor-A is a negative regulator of the HIV reservoir.

We hypothesize that estrogen replacement will reduce the scope and severity of ART-associated metabolic comorbidities and facilitate ART suppression of latent reservoirs in WLWH. We propose to address this hypothesis using a unique nonhuman primate model of female rhesus macaques infected with a novel barcoded strain of simian immunodeficiency virus (SIV), then treated with a current ART regimen until full suppression, followed by ovariectomy and subsequent estrogen deficiency or estrogen replacement by silastic implants.

This hypothesis will be addressed through pursuit of the following specific aims:

Specific Aim 1. Determine the effect of E2 replacement on metabolism and WAT function in a nonhuman primate (NHP) model of postmenopausal WLWH. Female rhesus macaques will be infected with SIV, treated with ART until full suppression, and then ovariectomized with subsequent replacement with premenstrual levels of estrogen or placebo vehicle. Glucose and lipid metabolic parameters and levels of circulating adipocytokines and WAT immune cell profiles and WAT function will be assessed longitudinally throughout the study.

Specific Aim 2. Determine the effect of E2 replacement on peripheral, secondary lymphoid, and WAT SIV latent reservoirs. The size, complexity, and clonality of the plasma, cell-associated and inducible, replication-competent reservoirs will be assessed following modulation of estrogen status using multiple quantitation approaches.

Oregon Health & Science University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Portland, Oregon 972393011 United States

Single Zip Code

Multidisciplinary Studies of HIV/AIDS and Aging (R01 Clinical Trial Optional) (PAR-18-189)

Amendment Since initial award the total obligations have increased 376% from $824,709 to $3,922,003.