HIV persistence in the optimally-treated patient is sustained by the maintenance of transcriptionally-silent proviral genomes within cell populations that are long-lived or that turn over slowly, and/or by ongoing low-level viral replication leading to de novo infection of target cells. It is a central theme of this Collaboratory that such persistence/latency of HIV is maintained by tissue-based interactions between CD4[+] T cells and myeloid cells through one or more mechanisms, including: (1) efficient cell-to-cell transfer of HIV;(2) regulatory signals that result in CD4[+] T cell dysfunction and impairment of the antiviral response;(3) myeloid signaling to CD4[+] T cells that results in maintenance of transcriptional silencing;and (4) inflammatory signals which result in CD4[+] T cell activation and increased risk of either de novo infection or reactivation of latently infected cells and replenishment of long-lived infected cells. Additionally, HIV infection may induce factors that promote survival of infected cells and, hence, of a long-lived viral reservoir. To determine which of these mechanisms are operative, we will first systemically interrogate the tissue spaces of the optimally treated host, so that the location and size of the latent and actively replicating reservoir can be determined. Given the availability of therapeutic agents that impact upon these mechanisms, we will then test definitively to what extent they might contribute to virus persistence/latency, alone or in concert. In this Project, this approach is taken in the context of SIV infection of the rhesus macaque (Macaca mulatta), pursuing experiments in the following Specific Aims: (1) to determine whether and how foci of persistently replicating and/or latent virus are sustained in the optimally-treated host by pathologic myeloid-T cell interactions;(2) to determine whether the persistent/latent virus pool can be diminished by inhibition of indoleamine 2,3- dioxygenase (IDO), an immunoregulatory enzyme that mediates the pro-inflammatory effects of myeloid cells on CD4+ T cells;and (3) to determine whether the persistent/latent virus pool can be diminished by inhibition of monocyte colony stimulating factor (MCSF), a cytokine which is upregulated by SIV/HIV and that prevents apoptosis of macrophages.

Public Health Relevance

Interacting closely with the work in Projects 2-5 and 7, this Project will explore the extent to which various interactions between CD4[+] T cells and myeloid cells are associated with persistence/latency of SIV virus after the initiation of ART. We will also develop a quantitative framework by which to assess changes in the total body load of viral genomes, before and after each mechanism is interrupted pharmacologically in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096109-04
Application #
8703594
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Delagrèverie, Héloïse M; Delaugerre, Constance; Lewin, Sharon R et al. (2016) Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents. Open Forum Infect Dis 3:ofw189
Hansen, Erik C; Ransom, Monica; Hesselberth, Jay R et al. (2016) Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells. Elife 5:
Barton, Kirston; Hiener, Bonnie; Winckelmann, Anni et al. (2016) Broad activation of latent HIV-1 in vivo. Nat Commun 7:12731
Murray, Alexandra J; Kwon, Kyungyoon J; Farber, Donna L et al. (2016) The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence. J Immunol 197:407-17
Crowell, Trevor A; Fletcher, James Lk; Sereti, Irini et al. (2016) Initiation of antiretroviral therapy before detection of colonic infiltration by HIV reduces viral reservoirs, inflammation and immune activation. J Int AIDS Soc 19:21163
Yong, Yean K; Shankar, Esaki M; Solomon, Ajantha et al. (2016) Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy. AIDS 30:2159-68
Siliciano, Janet D; Siliciano, Robert F (2016) Recent developments in the effort to cure HIV infection: going beyond N = 1. J Clin Invest 126:409-14
Phillips, Andrew N; Cambiano, Valentina; Revill, Paul et al. (2016) Identifying Key Drivers of the Impact of an HIV Cure Intervention in Sub-Saharan Africa. J Infect Dis 214:73-9
Sattentau, Quentin J; Stevenson, Mario (2016) Macrophages and HIV-1: An Unhealthy Constellation. Cell Host Microbe 19:304-10
Massanella, Marta; Fromentin, Rémi; Chomont, Nicolas (2016) Residual inflammation and viral reservoirs: alliance against an HIV cure. Curr Opin HIV AIDS 11:234-41

Showing the most recent 10 out of 133 publications