Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells.
Changes in T-cell function are a hallmark of human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms leading to these changes are unclear. We examined the gene expression profiles in ex vivo human CD4+ and CD8+ T cells from untreated HIV-1-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4+ and CD8+ T-cell subsets from HIV-1-infected nonprogressors with controlled viremia were indistinguishable from those of individuals not infected with HIV-1. Similarly, no gene clusters could distinguish T cells from individuals with early infection from those seen in chronic progressive HIV-1 infection, whereas differences were observed between uninfected individuals or nonprogressors versus early or chronic progressors. In early and chronic HIV-1 infection, three characteristic gene expression signatures were observed. (i) CD4+ and CD8+ T cells showed increased expression of interferon-stimulated genes (ISGs). However, some ISGs, including CXCL9, CXCL10, and CXCL11, and the interleukin-15 alpha receptor were not upregulated. (ii) CD4+ and CD8+ T cells showed a cluster similar to that observed in thymocytes. (iii) More genes were differentially regulated in CD8+ T cells than in CD4+ T cells, including a cluster of genes downregulated exclusively in CD8+ T cells. In conclusion, HIV-1 infection induces a persistent T-cell transcriptional profile, early in infection, characterized by a dramatic but potentially aberrant interferon response and a profile suggesting an active thymic output. These findings highlight the complexity of the host-virus relationship in HIV-1 infection.
Hyrcza
Martin D
MD
Clinical Sciences Division, University of Toronto, Medical Sciences Building, Rm. 6271, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Kovacs
Colin
C
Loutfy
Mona
M
Halpenny
Roberta
R
Heisler
Lawrence
L
Yang
Stuart
S
Wilkins
Olivia
O
Ostrowski
Mario
M
Der
Sandy D
SD
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D008297:Male; D005810:Multigene Family / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
D007372:Interferons