AEGiS-11IAC: Induction of cellular kinase c-mos by infection of peripheral blood lymphocytes with primary HIV-1: association with viral propagation and cell death.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Induction of cellular kinase c-mos by infection of peripheral blood lymphocytes with primary HIV-1: association with viral propagation and cell death.

Int Conf AIDS 1996 Jul 7-12; 11:18 (abstract no. Th.A.926)
Cohen D, Wahl L, Sharpe S, Blatner G; CBMB, NICHD, NIH, Bethesda, MD. Fax: (301) 402-0078. E-mail: dc16x@nih.gov.

OBJECTIVE: To define specific cellular kinases participating in HIV-1 cytopathicity and propagation.

METHODS: Primary isolates and laboratory adapted strains of HIV-1 with varying cytopathic effect, defined by their ability to acutely deplete CD4+ T cells in vitro, were used to infect PHA-activated mononuclear blood cells (PBLs), or, CD4+ T cell tumor lines. Infections were analyzed for induction of c-mos kinase with an affinity-purified rabbit polyclonal antibody made against recombinant c-mos, and for viral spread by p24 ELISA.

RESULTS: The oncogene c-mos is a cellular serine/threonine kinase regulating G2 cell cycle progression during germ-cell meiosis, but not normally expressed during somatic cell cycle progression in T lymphocytes. Other laboratories have shown that aberrant expression of c-mos in somatic cells results in programmed cell death, multinuclear cells, and cell cycle abnormalities at S and G2 phase. Work from ours and other laboratories established that HIV infection of T cells initiated cytopathicity, G2 cell cycle arrest, and cell death. To examine the possibility that aberrant c-mos activation participates in these HIV-induced abnormalities, we have studied PBLs infected with primary isolates of HIV-1. We report here that HIV-1 strongly induces c-mos protein expression in infected PBLs, in a manner kinetically associated with viral propagation and quantitatively correlated with cell death. Mos kinase activity is also stimulated in dying cells. To investigate whether HIV propagation, cell death, and c-mos induction might be directly linked, PBLs treated with antisense c-mos oligonucleotides or composition-matched controls, were infected with different HIV-1 isolates in three separate laboratories. Antisense mos treatment dramatically enhanced CD4+ cell viability and inhibited viral replication (average 84.6% decrease) during HIV infection, without affecting PHA stimulation of uninfected cells. Because oligonucleotides may produce non-specific effects, we generated Jurkat CD4+ T cell lines stably expressing antisense c-mos mRNA. These T cell lines proliferated identically to CD4-matched control transfectants prior to infection, but displayed markedly prolonged survival and decreased viral replication (average 80.2% decrease) upon HIV-1 infection.

CONCLUSIONS: Aberrant induction of c-mos kinase is closely associated with HIV-1 propagation and cell death during PBL infection, and appears to participate directly in these processes. Its absence, in contrast, from normal T cell processes suggest c-mos may be an important therapeutic and diagnostic target in the control of HIV-1 infection.

Keywords: AEGIS, HIV-1, Lymphocytes, Proto-Oncogene Proteins c-mos, Antigens, CD4, HIV Infections, Virus Replication, T-Lymphocytes, Apoptosis, Phytohemagglutinins, Jurkat Cells, Case-Control Studies, Human, In Vitro, Animal, Rabbits, virology, complications, ICA11

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ThA926