DARE: Delaney AIDS Research Enterprise to Find a Cure
Location(s): Sweden; Australia
The major barrier to curing HIV infection is a reservoir of long-lived cells that contain replication-competent virus. We believe that a comprehensive assessment of the reservoir together with the in vivo testing of possible interventions aimed at reversing this process will almost certainly advance the field, and could in five years provide the rationale for advanced testing in humans of single or combination regimens aimed at fully eradicating HIV from an infected person. Project 1: Myeloid- T Cell Interactions That Sustain SIV Reservoirs During Effective Antiretroviral Therapy Project Leader (PL): Dr. Joseph McCune (Description as provided by applicant) 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. 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.