Investigator's Application): The capacity of HIV-1 to establish a state of latent infection at the level of individual cells provides mechanism for viral persistence in the face of aggressive antiretroviral therapy. The goal of the proposed research is to understand that nature of latent cellular reservoirs for HIV-1, focusing on the viral reservoirs that persist in individuals on highly active antiretroviral therapy (HAART). The investigators central hypothesis is that resting memory CD4+ T cells with integrated HIV-1 DNA provide a long term reservoir for the virus that must be eliminated if eradication is to be achieved. In preliminary studies, they have directly demonstrated the presence of resting CD4+T cells with replication-competent provirus and have measured the frequency of these cells in the blood nd lymph nodes of infected individuals. Most importantly, the investigators have recently found that with appropriate stimulation methods, infectious virus can be routinely recovered from the resting CD4+T cells of individuals on HAART, including those who have had no detectable plasma virus for up to 30 months and for whom standard virus culture assays are negative. Preliminary estimates of the decay rate of this reservoir suggest that it may constitute the most significant long term viral reservoir in patients treated with HAART. Thus studies of the size, turnover rate, and immunologic and virologic characteristics of this reservoir are thus important for determining whether therapy should be given with the concrete goal of virus eradication. The major gaol of this proposal is to define the frequency nd rate of decay of latently infected CD4+T cells in infected individuals on HAART. The half-line of this compartment will be used to estimate the minimum time to virus eradication. In addition, the investigators will attempt to define important immunologic and virologic characteristics of the latent proviral reservoir in resting CD4+T cells. Viruses isolated from latently infected CD4+T cells will be characterized with respect to properties that are important for understanding their potential to cause disease following cessation of therapy. These include tropism, cytopthicity, and resistance to the relevant antiretroviral agents. Finally, the investigators will develop an experimental system for identifying stimuli that could be used to mobilize the latent reservoir for elimination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043222-04
Application #
6373848
Study Section
Special Emphasis Panel (ZRG5-ARRC (02))
Program Officer
Young, Janet M
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
4
Fiscal Year
2001
Total Cost
$299,469
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sengupta, Srona; Siliciano, Robert F (2018) Targeting the Latent Reservoir for HIV-1. Immunity 48:872-895
Bruner, Katherine M; Murray, Alexandra J; Pollack, Ross A et al. (2016) Defective proviruses rapidly accumulate during acute HIV-1 infection. Nat Med 22:1043-9
Hill, Alison L; Rosenbloom, Daniel I S; Goldstein, Edward et al. (2016) Real-Time Predictions of Reservoir Size and Rebound Time during Antiretroviral Therapy Interruption Trials for HIV. PLoS Pathog 12:e1005535
Norton, T D; Miller, E A; Bhardwaj, N et al. (2015) Vpx-containing dendritic cell vaccine induces CTLs and reactivates latent HIV-1 in vitro. Gene Ther 22:227-36
Deng, Kai; Pertea, Mihaela; Rongvaux, Anthony et al. (2015) Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517:381-5
Bruner, Katherine M; Hosmane, Nina N; Siliciano, Robert F (2015) Towards an HIV-1 cure: measuring the latent reservoir. Trends Microbiol 23:192-203
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
Blankson, Joel N; Siliciano, Janet D; Siliciano, Robert F (2014) Finding a cure for human immunodeficiency virus-1 infection. Infect Dis Clin North Am 28:633-50
Shan, Liang; Xing, Sifei; Yang, Hung-Chih et al. (2014) Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ T cells. J Antimicrob Chemother 69:28-33
Siliciano, Janet D; Siliciano, Robert F (2014) Recent developments in the search for a cure for HIV-1 infection: targeting the latent reservoir for HIV-1. J Allergy Clin Immunol 134:12-9

Showing the most recent 10 out of 81 publications