Ss. Rhee et Jw. Marsh, HIV-1 NEF ACTIVITY IN MURINE T-CELLS - CD4 MODULATION AND POSITIVE ENHANCEMENT, The Journal of immunology, 152(10), 1994, pp. 5128-5134
Immediately after infection of the targeted cell by HIV-1, proviral ge
ne expression is limited to the three regulatory proteins, Tat, Rev, a
nd Nef, with the nef transcript representing nearly 80% of total expre
ssion. Additionally, simian immunodeficiency virus Nef has been shown
to be essential for high in vivo titer and the development of immunode
ficiency. Recent findings demonstrate that the negative effects of Nef
expression, as first defined in transformed T cell lines, are not pre
sent when Nef is expressed in primary human T cells or in T cells from
transgenic mice, in which one sees moderate positive enhancements of
HIV replication and the T cell activation process, respectively. We fi
nd that Nef expression in an Ag-specific murine T cell hybridoma resul
ts in both the down-modulation of CD4, as seen in primary cells and hu
man T cell lines, and a positive enhancement of the TCR response to st
imuli. Examination of a CD4(-) cell demonstrated that the positive enh
ancement is independent of CD4 expression or modulation. CD4 down-modu
lation is shown to be caused by a post-Golgi, acid-dependent process,
which dramatically decreases the lifespan of the CD4 molecule. The TCR
, Thy Ag, and CD45 remained unchanged in their surface expression. The
se findings suggest that Nef alters the normal routing and residencies
of the CD4 molecule and that the positive effect of Nef on T cell act
ivation is independent of this modulation.