Productive HIV infection of resting CD4+ T cells: role of lymphoid tissue microenvironment and effect of immunomodulating agents.
The ability of resting CD4+ T cells to support HIV replication is relevant to understanding how the reservoir of HIV-1-infected resting CD4+ T cells is generated, maintained and, hopefully, how it might be reduced or eliminated. We have utilized a tonsillar histoculture system to demonstrate that HIV, particularly X4 strains, can productively infect phenotypically resting CD4+ T cells in vitro and that this event is largely dependent on the lymphoid tissue microenvironment. Highly purified CD4+ tonsillar T cells that lack expression of both cell surface and nuclear antigens characteristic of classic T cell activation produce X4 HIV-1 mRNA, p24, and infectious virus while maintaining a resting phenotype when cultured in a tonsillar tissue microenvironment; in contrast, comparable purified resting CD4+ tonsillar T cells that have been exposed to X4 HIV do not support HIV replication when cultured in the absence of a lymphoid tissue microenvironment. HIV production from phenotypically resting CD4+ T cells is dramatically inhibited by anti-proinflammatory cytokine agents or immunosuppressive cytokines, but is only modestly suppressed by an inhibitor of the cell cycle. The ability of resting CD4+ T cells to support HIV replication in the microenvironment of the lymphoid tissue has implications in the pathogenesis of HIV disease and may provide an additional avenue for therapeutic intervention.
Kinter
Audrey
A
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases/NIH, MSC-1576, Building 10, Room 6A33, 10 Center Drive, Bethesda, MD 20892-1576, USA. Akinter@nih.gov
Moorthy
Anitha
A
Jackson
Robert
R
Fauci
Anthony S
AS
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology / Q000821:virology*; D002478:Cells, Cultured; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D014066:Palatine Tonsil / Q000276:immunology*; D014779:Virus Replication