Despite many advances in AIDS research, including the availability of potent anti-retroviral therapy (ART) that effectively controls virus replicatio in a large proportion of HIV-infected patients, a treatment that can cure the infection remains elusive. To this end, new approaches are required to eradicate the reservoirs of latently infected cells that persist during ART and are the source of virus reactivation when therapy is interrupted. In the R21 phase of this grant application we propose to use the existing, well-established non-human primate model of SIVmac infection of rhesus macaques (RMs) to validate studies of HIV eradication/functional cure by developing an experimental system in which virus replication is fully and persistently suppressed in vivo by a potent ART regimen (Aim 1). We will then use this validated model to investigate directly in vivo and in multiple organs th anatomic and phenotypical nature of the persistent reservoirs of latently infected cells, with specific focus on the relationship between expression of co-inhibitory molecules (i.e. PD-1, CTLA-4, TIM-3, and LAG-3) and size of the persistent reservoirs (Aim 2). The results of the studies proposed in the R21 part of this application will pave the way for further experiments, to be conducted in the R33 phase of this proposal, in which we will test, in ART-treated SIV-infected RMs with full suppression of virus replication, immune-based interventions aimed at reducing and possibly eliminating in vivo the persisting reservoirs of latently infected cells. The key proposed intervention consists of a blockade of the co-inhibitory pathway most closely associated with SIV latency, which will be performed as a stand-alone therapy or in combination with a non-specific virus reactivating agent (i.e. the histone deacytelase inhibitor, SAHA). We believe that the proposed studies will provide unprecedented insights into the biology of persistent virus reservoirs of latently infected cells, and elucidate the potential of targeting co inhibitory pathways to reduce the reservoir during SIV infection.

Public Health Relevance

Despite many advances in AIDS research, a treatment that can cure HIV infection remains elusive. A fundamental obstacle to develop a functional cure for HIV is the limited knowledge of the nature of the reservoirs of latently infected cells that persis during HAART. In this grant application, using the SIV-infected rhesus macaques model, we will investigate directly in vivo the anatomic and phenotypical nature of the persistent reservoirs of latently infected cells, and elucidate the potential of targeting co-inhibitory pathways to reduce the reservoir during SIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI104278-01
Application #
8462840
Study Section
Special Emphasis Panel (ZAI1-JRR-A (S1))
Program Officer
Sanders, Brigitte E
Project Start
2013-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$267,750
Indirect Cost
$117,750
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
McGary, Colleen S; Silvestri, Guido; Paiardini, Mirko (2014) Animal models for viral infection and cell exhaustion. Curr Opin HIV AIDS 9:492-9