GENERATION OF ENDOGENOUS TUMOR-NECROSIS-FACTOR-ALPHA IN MOLT-4 CELLS DURING THE ACUTE REPLICATION PHASE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 DETERMINES THE SUBSEQUENT LATENT INFECTION

We have characterized the mechanism for human immunodeficiency virus t ype 1 (HIV-1) latent infection in a human T cell line MOLT-4 subclone no.8 (MOLT-#8). The inocula used were HIV-1 recovered from MT-4 during the acute (NL-A) and persistent (NL-P) phases after HIV-1 infection. On infection of MOLT-#8 with NL-A, viral antigens first appeared in al most 100% of the cells whereafter the numbers of viable antigen-positi ve cells declined. In contrast, following infection with NL-P the expr ession of viral antigens was maintained in almost 100% of the cells. I n fact, limiting dilution of NL-P-infected cells allowed us to isolate 43 subclones, all of which were positive for viral antigen expression in almost 100% of the cells (type I). In sharp contrast, only two of 41 subclones from NL-A-infected cells were of type 1. Seven subclones were latently infected with HIV-1; latent HIV-1 in six subclones (type Il), but not in one type Ill subclone, was activated by tumour necros is factor (TNF)-alpha or phorbol 12-myristate 18-acetate. The remainin g subclones were negative for the viral genome. Of particular note is the effect of endogenous TNF-ce generated during the acute phase of vi rus replication which shifted the virus phenotype. Thus, the presence of TNF-ce during the acute phase of virus replication seems to play a key role in the selective destruction of cells expressing higher level s of viral antigens and in subsequent establishment of latent infectio n in host T cells.