. 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. Unfortunately, cis- gender women represent only 11% of all participants recruited to HIV cure research and there is a significant knowledge gap between the biology of HIV cure in men and women. Even less is known about the effect of exogenous sex hormones on the viral reservoir and immune response in HIV-infected transgender women. What we know now. One study including >500 HIV-infected participants on antiretroviral therapy (ART) found that women have on average significantly lower levels of HIV DNA in peripheral mononuclear blood cells (PBMC) than men. Various in vitro studies reported sex-based differences on HIV infection and replication in target cells. These differences are partially driven by estrogens that inhibit HIV transcription, through estrogen receptor-dependent mechanisms. Our proposed solution. We will prospectively enroll 15 HIV-infected transgender women (?male-to-female?) on ART with suppressed HIV RNA for >12 months, who plan to start estradiol-based hormonal therapy (HT). We will follow this cohort for 12 months. We will collect longitudinal blood samples before and after initiation of HT. We are uniquely positioned to recruit this ?hard-to-reach? population thanks to our collaboration with ?The Night Clinic? in San Diego, which is following >400 unique transgender women, 40% of whom are HIV-positive. Our goal. We will characterised 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 12 months of follow-up while on suppressive ART. Historical data from a similar cohort of HIV-infected men (matched by baseline HIV DNA levels, age, CD4+ cells, time on ART and duration of HIV infection) will be used as a comparison. How will we advance the field. Transgender women are disproportionately impacted by HIV in the United States and worldwide and face overwhelming disparities. There is urgent need to include transgender women in the HIV cure agenda, and to adapt curative approaches to meet the unique needs of this specific population. Investigating the effect of estradiol-based HT on the HIV reservoir size and transcriptional activity in transgender women will provide the unique opportunity to the isolate the effect of estradiol on HIV transcription.

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 sex hormones and receptor expression on the HIV reservoir size and transcriptional activity during suppressive antiretroviral therapy in transgender women starting estradiol-based hormonal therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI134295-01
Application #
9410682
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Lawrence, Diane M
Project Start
2017-06-26
Project End
2019-05-31
Budget Start
2017-06-26
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
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
Dubé, Karine; Gianella, Sara; Concha-Garcia, Susan et al. (2018) Ethical considerations for HIV cure-related research at the end of life. BMC Med Ethics 19:83
Gianella, Sara; Marconi, Vincent C; Berzins, Baiba et al. (2018) Genital HIV-1 Shedding With Dolutegravir (DTG) Plus Lamivudine (3TC) Dual Therapy. J Acquir Immune Defic Syndr 79:e112-e114
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
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
Promer, Katherine; Karris, Maile Y (2018) Current Treatment Options for HIV Elite Controllers: a Review. Curr Treat Options Infect Dis 10:302-309
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
Gianella, Sara; Chaillon, Antoine; Mutlu, Ece A et al. (2017) Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals. AIDS 31:2059-2067
Gianella, Sara; Chaillon, Antoine; Mutlu, Ece A et al. (2017) Effect of CMV and EBV replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals. AIDS :