Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6

Abstract

DURING intrathymic T-cell ontogenesis, functionally competent CD3⁺CD4⁺CD8⁻ and CD3⁺CD4⁻CD8⁺ T lymphocytes develop from immature CD4⁻CD8⁻ thymocytes after transiently acquiring a double-positive CD4⁺CD8⁺ phenotype^1–3. The partition between CD4⁺CD8⁺ and CD4⁻CD8⁺ T cells is generally considered to be irreversible, although a small percentage of circulating CD3⁺ T lymphocytes coexpressing CD4 and CD8 molecules has been identified⁴. It has been suggested that in CD8⁺ T cells the CD4 genes may be methylated and thus highly repressed⁵, whereas in CD4⁺ T cells the CDS genes are unmethylated⁶ and their transcription can be induced by physiological stimuli such as interleukin-4 (ref. 7). Here, we demonstrate that infection with human herpesvirus 6 (HHV-6) (ref. 8), a virus proposed as a potential cofactor in AIDS (ref. 9), dramatically upregulates the expression of CD4— the receptor for human immunodeficiency virus type-1 (HIV-1) (refs 10–12)—in a human neoplastic T-cell line. More importantly, HHV-6 induces de novo expression of CD4 messenger RNA and protein in normal mature CD8⁺ T lymphocytes, rendering them susceptible to infection with HIV-1. These findings demonstrate that human CD3⁺CD4⁻CD8⁺ T lymphocytes can reacquire CD4 in the post-thymic life and elucidate a novel mechanism—receptor regulation—through which HHV-6 may positively interact with HIV-1 in coinfected patients.