. Problem. There are distinct sex-based differences that affect the natural history of HIV infection and HIV- specific immune responses. These differences are partially driven by sex hormones (estrogens in particular) and might influence the size, distribution and transcriptional activity of the HIV reservoirs. Globally, women account for over half of all people living with HIV but represent only 11% of participants in HIV cure research resulting in a significant knowledge gap between the biology of HIV in men and women. Even less is known about how this effect changes when women are entering menopause and hormonal levels starts to decline. What we know now. ? Women have lower levels of HIV DNA in peripheral blood mononuclear cells (PBMCs) than men. ? Various in vitro studies reported sex-based differences on HIV infection and replication in target cells. ? Women have different HIV-specific immune responses than men. ? These differences are partially driven by estradiol that inhibits HIV replication in PBMCs through estrogen receptor dependent mechanisms. A recent ex vivo study (by Jon Karn et al) provided strong evidence that estrogen inhibits HIV transcriptional activity in a sex-specific manner. Proposed Solution. We will request longitudinal stored samples from 30 HIV-infected women aged 40-55 at enrollment (not taking hormonal therapy) and 30 men (similar age) on antiretroviral therapy (ART) with suppressed HIV RNA for >48 weeks. This age range was selected to maximize variability in hormonal levels (across study participants and longitudinally) and because younger women are more likely to take hormonal therapy. Our goal. We will characterize extensively the HIV reservoir and generate immunological data at each time- point. We will use these data to determine the effect of sex hormones and receptor expression (in particular estradiol) on the HIV reservoir size and transcriptional activity over 3+ years of follow-up while on ART. We will compare these data with a similar group of men. How will we advance the field. To date, the majority of HIV cure research has used male participants and therefore a significant knowledge gap exists between men and women. We do not know if the same immune- modulatory interventions will be effective in promoting HIV RNA transcription in men and women and how declining sex hormones will impact their efficacy. In particular, agents that are designed for ?kick and kill? strategies may be especially impacted by estradiol-mediated mechanisms. A better understanding of these differences will assist in the design of future cure approaches that can be applied across sexes.

Public Health Relevance

There are distinct sex-based differences that affect the natural history and immune pathogenesis of HIV infection. These factors likely impact the establishment, distribution and transcriptional activity of the HIV reservoir. Our study is designed to determine the effect of declining sex hormones and receptor expression on the HIV reservoir size and transcriptional activity in women aged 40-55 years during suppressive antiretroviral therapy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD094646-02
Application #
9568360
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Russo, Denise
Project Start
2017-09-20
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Gianella, Sara; Sonya Haw, J; Blumenthal, Jill et al. (2018) The Importance of Human Immunodeficiency Virus Research for Transgender and Gender-Nonbinary Individuals. Clin Infect Dis 66:1460-1466
Dubé, Karine; Luter, Stuart; Lesnar, Breanne et al. (2018) Use of 'eradication' in HIV cure-related research: a public health debate. BMC Public Health 18:245
Chaillon, Antoine; Gianella, Sara; Lada, Steven M et al. (2018) Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc. J Virol 92:
Burlacu, Ruxandra; Umlauf, Anya; Luca, Anca et al. (2018) Sex-based differences in neurocognitive functioning in HIV-infected young adults. AIDS 32:217-225
Letendre, Scott; Bharti, Ajay; Perez-Valero, Ignacio et al. (2018) Higher Anti-Cytomegalovirus Immunoglobulin G Concentrations Are Associated With Worse Neurocognitive Performance During Suppressive Antiretroviral Therapy. Clin Infect Dis 67:770-777
Lin, Timothy C; Gianella, Sara; Tenenbaum, Tara et al. (2018) A Simple Symptom Score for Acute Human Immunodeficiency Virus Infection in a San Diego Community-Based Screening Program. Clin Infect Dis 67:105-111
Christensen-Quick, Aaron; Vanpouille, Christophe; Lisco, Andrea et al. (2017) Cytomegalovirus and HIV Persistence: Pouring Gas on the Fire. AIDS Res Hum Retroviruses 33:S23-S30

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