Productive infection of double-negative T cells with HIV in vivo.
HIV induces CD4 down-regulation from the surface of infected cells by several independent mechanisms, suggesting an important biological role for this phenomenon. In vitro CD4 down-regulation generates T cells with a double-negative (DN) CD4(-)CD8(-) T cell receptor-alphabeta(+) phenotype. However, evidence that this down-regulation occurs in vivo in HIV-infected subjects is lacking, and viral load or viral production assays invariably focus on CD4(+) T cells. We show here that HIV infection can often be detected in sorted DN cells from peripheral blood and lymph nodes, even when plasma viral load is undetectable. DN T cells infected with HIV represented up to 20% of the cellular viral load in T cells, as determined by DNA PCR. In patients on successful highly active antiretroviral therapy, the viral load decreased in the plasma in CD4(+) and in DN T cells, suggesting that infected DN cells, like CD4(+) cells, contribute to viral production and are sensitive to highly active antiretroviral therapy. Indeed, HIV unspliced and multispliced RNAs were often detectable in DN T cells in spite of the small size of this subset. Infectious virus from DN T cells was transmitted efficiently in coculture experiments with uninfected T cell lymphoblasts, even when viral DNA in the DN cells was barely detectable. We conclude that a discrete population of infected DN T cells exists in HIV-positive subjects, even when the plasma viral load is undetectable. These cells may represent an important source of infectious virus.
Marodon
G
G
Department of Medicine, Division of Hematology/Oncology, Cornell University, Joan and Sanford I. Weill Medical College, New York, NY 10021, USA.
Warren
D
D
Filomio
M C
MC
Posnett
D N
DN
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D018791:CD4 Lymphocyte Count; D016827:CD8 Antigens / Q000276:immunology; D002455:Cell Division; D018076:DNA, Complementary / Q000032:analysis; D004279:DNA, Viral / Q000032:analysis*; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015750:Genes, gag / Q000235:genetics; D006678:HIV / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012367:RNA, Viral / Q000032:analysis; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D013997:Time Factors
D019380:Anti-HIV Agents; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D018076:DNA, Complementary; D004279:DNA, Viral; D012367:RNA, Viral