HIV persists despite HAART, and discontinuation of HAART typically leads to high virus level rebound. A priority therefore is to identify and ultimately destroy these latently-infected virus reservoirs. To accomplish this, it becomes important to specifically identify the cells and tissue sites that harbor HIV during latency and HAART. Our long-term goal is to inhibit or prevent virus rebound after discontinuation of HAART. The purpose of this R21/R33 proposal is to verify the contributions of CD4+ T cells and macrophages as reservoir cells in SIV- infected, HAART-treated rhesus macaques. Our central hypothesis is that tissue macrophages (in addition to CD4+ T cells) serve as major virus (SIV) reservoirs that develop initially in short-lived macrophages and transi- tion to longer-lived macrophages in deep tissues.
The aims of phase I (R21) are:
Aim 1. To determine the contribution of CD4+ T cells to the SIV reservoir in SIV-infected macaques undergoing effective HAART. Our working hypothesis is that in vivo depletion of CD4 cells (via anti-CD4 antibody) in SIV-infected macaques undergoing effective HAART will directly demonstrate the proportion of CD4 T cells (vs macrophages) that contribute to the SIV reservoir.
Aim 2. To determine the contribution of monocytes/macrophages to the reservoir in SIV-infected macaques undergoing effective HAART. Our working hypothesis is that the in vivo depletion of monocyte /macrophages (via liposome-alendronate) of the SIV-infected macaques undergoing effective HAART will also demonstrate a contribution of macrophages (vs CD4+ T cells) to the SIV reservoir. These studies focus on lung as a model to closely examine T cell and macrophage reservoirs in """"""""deep"""""""" tis- sues. This sets the foundation for the corroborating studies of phase II (R33) to now examine viral reservoirs after discontinuation of HAART (i.e. to determine if viral rebound is prevented by having depleted the viral reservoirs or where viral reservoirs remain if virus rebound occurs).
Aim 3. To determine if in vivo depletion of CD4 and/or monocyte/macrophages prevents virus rebound after discontinuation of HAART. Our working hypothesis is that both CD4+ T cells and macrophages con- tribute to SIV reservoirs and that elimination of either or both cell populations followed by discontinuation of HAART will lead to maintenance of low or absent viral load. Conversely, if virus rebound occurs, we will define the remaining or alternate sites of the virus reservoirs that need to be targeted. The overall results will move work forward to developing rational intervention strategies to inhibit progression or cure AIDS in humans.

Public Health Relevance

There are 33 million individuals living with the human immunodeficiency virus (HIV) that causes Acquired Immunodeficiency Disease Syndrome (AIDS). The use of highly active antiretroviral therapy (HAART) for HIV infection has been one of the key scientific achievements to slow down AIDS disease progression, but discontinuation of HAART due to toxicity from long-term use allows the virus to rebound. The goal of this study is to use an animal model of AIDS disease to determine specifically the cell(s) and/or tissues(s) that act as viral reservoirs so that these cells can be removed to cure HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI110163-01
Application #
8656273
Study Section
Special Emphasis Panel (ZAI1-JRR-A (S4))
Program Officer
Sanders, Brigitte E
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$222,698
Indirect Cost
$90,924
Name
Tulane University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
He, Ziyuan; Allers, Carolina; Sugimoto, Chie et al. (2018) Rapid Turnover and High Production Rate of Myeloid Cells in Adult Rhesus Macaques with Compensations during Aging. J Immunol 200:4059-4067
Merino, Kristen M; Allers, Carolina; Didier, Elizabeth S et al. (2017) Role of Monocyte/Macrophages during HIV/SIV Infection in Adult and Pediatric Acquired Immune Deficiency Syndrome. Front Immunol 8:1693
Fujino, Masayuki; Sato, Hirotaka; Okamura, Tomotaka et al. (2017) Simian Immunodeficiency Virus Targeting of CXCR3+ CD4+ T Cells in Secondary Lymphoid Organs Is Associated with Robust CXCL10 Expression in Monocyte/Macrophage Subsets. J Virol 91:
Filipowicz, Adam R; McGary, Christopher M; Holder, Gerard E et al. (2016) Proliferation of Perivascular Macrophages Contributes to the Development of Encephalitic Lesions in HIV-Infected Humans and in SIV-Infected Macaques. Sci Rep 6:32900
Didier, E S; MacLean, A G; Mohan, M et al. (2016) Contributions of Nonhuman Primates to Research on Aging. Vet Pathol 53:277-90
Kim, Woong-Ki; McGary, Christopher M; Holder, Gerard E et al. (2015) Increased Expression of CD169 on Blood Monocytes and Its Regulation by Virus and CD8 T Cells in Macaque Models of HIV Infection and AIDS. AIDS Res Hum Retroviruses 31:696-706
Sugimoto, Chie; Hasegawa, Atsuhiko; Saito, Yohei et al. (2015) Differentiation Kinetics of Blood Monocytes and Dendritic Cells in Macaques: Insights to Understanding Human Myeloid Cell Development. J Immunol 195:1774-81
Cai, Yanhui; Sugimoto, Chie; Liu, David Xianhong et al. (2015) Increased monocyte turnover is associated with interstitial macrophage accumulation and pulmonary tissue damage in SIV-infected rhesus macaques. J Leukoc Biol 97:1147-53
Cai, Yanhui; Sugimoto, Chie; Arainga, Mariluz et al. (2015) Preferential Destruction of Interstitial Macrophages over Alveolar Macrophages as a Cause of Pulmonary Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques. J Immunol 195:4884-91
Holder, Gerard E; McGary, Christopher M; Johnson, Edward M et al. (2014) Expression of the mannose receptor CD206 in HIV and SIV encephalitis: a phenotypic switch of brain perivascular macrophages with virus infection. J Neuroimmune Pharmacol 9:716-26