Langerhans cells (LC) are members of the dendritic cell (DC) family and function as the major antigen presenting cells of epidermis and genital mucosal surfaces. It is generally believed that LC are the initial target cells for HIV following mucosal exposure to virus. My lab is focused on studying how HIV interacts with LC and other DC, with the hope that this work will add insight into the early events involved in HIV primary infection. In the past year, we have published four papers on this topic and have one paper in press. Firstly, we investigated and reported on the role of cytokines in the regulation of HIV co-receptor expression and subsequent HIV infection in LC. We found that type 1 cytokines (e.g., IFNg) decreased expression of CXCR4 on LC and reduced subsequent infection of CXCR4-using HIV, whereas type 2 cytokines (e.g., IL-4) induced the opposite outcome. This was followed by a study where we determined the effects of HIV and human herpesvirus 6 (a purported co-factor involved in the pathogenesis of AIDS) in co- infected DC cultures; human herpesvirus 6 led to a marked decrease in HIV replication in co-infected cells. Very recently, we collaborated with Gene Shearers group on a project where we examined the immunologic function and chemokine production of monocyte-derived DC isolated from HIV-infected individuals. DC production of chemokines and cytokines, as well as T cell stimulatory capacity, were equivalent in HIV-infected versus uninfected persons, indicating that these cells could be used to enhance immune responses in future DC-based immunotherapeutic protocols. Currently, we are preparing to submit several manuscripts that describe novel models for various aspects of sexual HIV transmission. In one, we have used normal human skin explants to pre- clinically test potential topical microbicides designed to block transmission of HIV; the second model uses a combination of skin- derived LC and human tonsils to study events involved in transmission of HIV from LC to lymphoid tissue; in the third model, we have studied HIV infection of normal human vaginal mucosal LC in collaboration with the NIH gynecologist Larry Nelson. Finally, we have recently been able to identify and characterize single LC and DC infected with HIV using intracellular p24 monoclonal antibody staining and flow cytometry. This advance has allowed us to study more precisely the phenotype and immunologic function of HIV-infected DC.100% AIDS-RELATED - HIV, Langerhans cells, dendritic cells, chemokines, cytokines, - Human Subjects & Human Tissues, Fluids, Cells, etc.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010094-03
Application #
6290848
Study Section
Special Emphasis Panel (D)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Blauvelt, A; Glushakova, S; Margolis, L B (2000) HIV-infected human Langerhans cells transmit infection to human lymphoid tissue ex vivo. AIDS 14:647-51
Kawamura, T; Cohen, S S; Borris, D L et al. (2000) Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J Exp Med 192:1491-500
Grivel, J C; Penn, M L; Eckstein, D A et al. (2000) Human immunodeficiency virus type 1 coreceptor preferences determine target T-cell depletion and cellular tropism in human lymphoid tissue. J Virol 74:5347-51
Grivel, J C; Malkevitch, N; Margolis, L (2000) Human immunodeficiency virus type 1 induces apoptosis in CD4(+) but not in CD8(+) T cells in ex vivo-infected human lymphoid tissue. J Virol 74:8077-84
Asada, H; Klaus-Kovtun, V; Golding, H et al. (1999) Human herpesvirus 6 infects dendritic cells and suppresses human immunodeficiency virus type 1 replication in coinfected cultures. J Virol 73:4019-28
Chougnet, C; Cohen, S S; Kawamura, T et al. (1999) Normal immune function of monocyte-derived dendritic cells from HIV-infected individuals: implications for immunotherapy. J Immunol 163:1666-73
Papadopoulos, E J; Sassetti, C; Saeki, H et al. (1999) Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation. Eur J Immunol 29:2551-9
Anderson, H A; Bergstralh, D T; Kawamura, T et al. (1999) Phosphorylation of the invariant chain by protein kinase C regulates MHC class II trafficking to antigen-processing compartments. J Immunol 163:5435-43