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)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096109-04
Application #
8703594
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
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
Stevenson, Mario (2015) Role of myeloid cells in HIV-1-host interplay. J Neurovirol 21:242-8
Dunham, Richard M; Vujkovic-Cvijin, Ivan; Yukl, Steven A et al. (2014) Discordance between peripheral and colonic markers of inflammation during suppressive ART. J Acquir Immune Defic Syndr 65:133-41
Ribeiro, Susan P; Milush, Jeffrey M; Cunha-Neto, Edecio et al. (2014) The CD8? memory stem T cell (T(SCM)) subset is associated with improved prognosis in chronic HIV-1 infection. J Virol 88:13836-44
Stock, P G; Barin, B; Hatano, H et al. (2014) Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients. Am J Transplant 14:1136-41
Bullen, C Korin; Laird, Gregory M; Durand, Christine M et al. (2014) New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med 20:425-9
Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar et al. (2014) Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation. AIDS 28:2251-8
Gray, Lachlan R; Roche, Michael; Flynn, Jacqueline K et al. (2014) Is the central nervous system a reservoir of HIV-1? Curr Opin HIV AIDS 9:552-8
Kim, Michelle; Hosmane, Nina N; Bullen, C Korin et al. (2014) A primary CD4(+) T cell model of HIV-1 latency established after activation through the T cell receptor and subsequent return to quiescence. Nat Protoc 9:2755-70
Cockerham, Leslie R; Jain, Vivek; Sinclair, Elizabeth et al. (2014) Programmed death-1 expression on CD4? and CD8? T cells in treated and untreated HIV disease. AIDS 28:1749-58
Anderson, Jenny L; Cheong, Karey; Lee, Amas K H et al. (2014) Entry of HIV in primary human resting CD4(+) T cells pretreated with the chemokine CCL19. AIDS Res Hum Retroviruses 30:207-8

Showing the most recent 10 out of 53 publications