A major goal of immunologic research in HIV/AIDS is to determine whether """"""""natural"""""""" protective immunity exists against infection and disease progression, and if so, to elucidate the mechanisms of such protection. This information might provide insight into the design of effective vaccines and immune-based therapeutic strategies against HIV/AIDS. This laboratory was the first to establish that individuals within several different cohorts HIV-exposed people exhibited potent cellular immunity against HIV. In keeping with my interest in this area, we found that in vitro stimulation of PBMC from healthy individuals with aloogeneic leukocytes induced the production of soluble factors that inhibit HIV replication prior to reverse transcription. ALLO stimulation inhibited HIV-1 but not CMV or HTLV-1, and was not associated with any of several cytokines that we tested. The generation of potent ALLO-stimulated HIV inhibitory activity was associated with expression of the HLA-A2 gene. This finding is consistent with epidemiologic reports indicating that vertical transmission of HIV was reduced by 10-fold if the HIV-infected mothers were maximally different from their newborns at HLA and by an additional 7-to-9-fold if the infants expressed HLA-A2. These parallel findings raise the possibility that the soluble factors that we are studying contribute to protection against transmission of HIV. We recently identified one of the soluble factors contained in the ALLO culture supernatnats as the ribonuclease, EDN, or a closely-related RNase. The severe loss of CD4+ T cells is a hallmark of AIDS progression, and the mechansim responsible for this depletion of helper cells remains unresolved. Because more than 99% of the HIV particles in blood are noninfectious, we have used a chemically-inactivated, noninfectious form of HIV (AT-2 virus)to investigate its effect on apoptotic T cell death. We have recently found that exposure of PBMC from healthy blood donors produce the TRAIL (TNF-related apoptotic-inducing ligand)and express the complementing TRAIL death receptor. This study may shed light on the loss of T cells in the progression of AIDS, and raise the possibility that noninfectious virus contributes to AIDS progression.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009267-20
Application #
6762158
Study Section
(EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Herbeuval, Jean-Philippe; Nilsson, Jakob; Boasso, Adriano et al. (2009) HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS 23:35-40
Boasso, Adriano; Vaccari, Monica; Fuchs, Dietmar et al. (2009) Combined effect of antiretroviral therapy and blockade of IDO in SIV-infected rhesus macaques. J Immunol 182:4313-20
Broliden, K; Haase, A T; Ahuja, S K et al. (2009) Introduction: Back to basics: mucosal immunity and novel HIV vaccine concepts. J Intern Med 265:5-17
Boasso, Adriano; Shearer, Gene M (2007) How does indoleamine 2,3-dioxygenase contribute to HIV-mediated immune dysregulation. Curr Drug Metab 8:217-23
Boasso, Adriano; Herbeuval, Jean-Philippe; Hardy, Andrew W et al. (2007) HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood 109:3351-9
Chougnet, Claire A; Shearer, Gene M (2007) Regulatory T cells (Treg) and HIV/AIDS: summary of the September 7-8, 2006 workshop. AIDS Res Hum Retroviruses 23:945-52
Hryniewicz, Anna; Price, David A; Moniuszko, Marcin et al. (2007) Interleukin-15 but not interleukin-7 abrogates vaccine-induced decrease in virus level in simian immunodeficiency virus mac251-infected macaques. J Immunol 178:3492-504
Herbeuval, Jean-Philippe; Shearer, Gene M (2007) HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol 123:121-8
Nilsson, Jakob; Boasso, Adriano; Velilla, Paula Andrea et al. (2006) HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood 108:3808-17
Bedoya, Victoria I; Boasso, Adriano; Hardy, Andrew W et al. (2006) Ribonucleases in HIV type 1 inhibition: effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression. AIDS Res Hum Retroviruses 22:897-907

Showing the most recent 10 out of 32 publications