Virus-specific CD4 and CD8 T cell responses are important in controlling HIV replication, but in most infected individuals these responses are inadequate to fully contain the virus. Emerging data indicate that there is a functional loss in cellular immune responses as HIV disease progresses, suggesting that efforts to augment immunity may provide a therapeutic benefit. Dendritic cells (DCs) are the most potent antigen presenting cells, and when manipulated ex vivo to express viral antigens these cells can efficiently boost T cell responses in humans after re-injection. One of the most promising methods of delivering antigen to DCs is by transfection with mRNA encoding specific immunogens, which has been shown in human cancer studies to induce CD4 and CD8 responses to those antigens. This new method allows delivery of autologous HIV sequences to DCs, which may provide a unique advantage in augmenting virus-specific immune responses in an infected individual. Thus, we believe that vaccination with DCs transfected with autologous HIV mRNA is a promising approach to immune-based therapy.
Our specific aims i n this proposal are to: 1) Define the optimal method of delivering autologous HIV antigens to DCs to elicit strong and diverse virus-specific CD4 and CD8 immune responses. This work will focus on mechanisms of antigen presentation, including issues of immune interference, the effect of subcellular compartmentalization of antigen on immunogenicity and the effect of a costimulatory molecule, OX40 ligand, on DC function; 2) Clone autologous HIV mRNA transcripts from infected individuals with suppressed virus loads for transfection into DCs; and 3) Test the safety, immunogenicity and antiviral effect of this method of inducing immune responses against autologous HIV antigens by conducting a clinical trial of mRNA-transfected DCs in HIV+ subjects who have suppressed virus loads on antiretroviral therapy. Relevance of this research to public health: This work will lead to a better understanding of how to boost immune responses against HIV using a new method of vaccination. By understanding the mechanisms by which immune responses against HIV can be augmented, this may lead to improved ways of treating this disease and may help in developing a vaccine to prevent this infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI066992-01A1
Application #
7064321
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Conley, Tony J
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$441,896
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Gandhi, Rajesh T; Kwon, Douglas S; Macklin, Eric A et al. (2016) Immunization of HIV-1-Infected Persons With Autologous Dendritic Cells Transfected With mRNA Encoding HIV-1 Gag and Nef: Results of a Randomized, Placebo-Controlled Clinical Trial. J Acquir Immune Defic Syndr 71:246-53
Tashima, Karen T; Mollan, Katie R; Na, Lumine et al. (2015) Regimen selection in the OPTIONS trial of HIV salvage therapy: drug resistance, prior therapy, and race-ethnicity determine the degree of regimen complexity. HIV Clin Trials 16:147-56
Gandhi, Rajesh T; Bosch, Ronald J; Aga, Evgenia et al. (2013) Residual plasma viraemia and infectious HIV-1 recovery from resting memory CD4 cells in patients on antiretroviral therapy: results from ACTG A5173. Antivir Ther 18:607-13
Henrich, Timothy J; Gandhi, Rajesh T (2013) Early treatment and HIV-1 reservoirs: a stitch in time? J Infect Dis 208:1189-93
Bogoch, I I; Andrews, J R; Nagami, E H et al. (2013) Clinical predictors for the aetiology of peripheral lymphadenopathy in HIV-infected adults. HIV Med 14:182-6
Hyle, Emily P; Wood, Brian R; Backman, Elke S et al. (2013) High frequency of hypothalamic-pituitary-adrenal axis dysfunction after local corticosteroid injection in HIV-infected patients on protease inhibitor therapy. J Acquir Immune Defic Syndr 63:602-8
Backman, E S; Triant, V A; Ehrenfeld, J M et al. (2013) Safety of midazolam for sedation of HIV-positive patients undergoing colonoscopy. HIV Med 14:379-84
Zheng, Lu; Bosch, Ronald J; Chan, Ellen S et al. (2013) Predictors of residual viraemia in patients on long-term suppressive antiretroviral therapy. Antivir Ther 18:39-43
Wilkin, Timothy J; Lalama, Christina M; McKinnon, John et al. (2012) A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4? T-cell recovery despite sustained virologic suppression: ACTG A5256. J Infect Dis 206:534-42
Gandhi, Rajesh T; Coombs, Robert W; Chan, Ellen S et al. (2012) No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr 59:229-35

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