Document 0791
 DOCN  M9590791
 TI    Dissociation of the CD4 downregulation and viral infectivity enhancement
       functions of human immunodeficiency virus type 1 Nef.
 DT    9509
 AU    Goldsmith MA; Warmerdam MT; Atchison RE; Miller MD; Greene WC; Gladstone
       Institute of Virology and Immunology, School of; Medicine, University of
       California San Francisco 94141, USA.
 SO    J Virol. 1995 Jul;69(7):4112-21. Unique Identifier : AIDSLINE
       MED/95287461
 AB    Recent evidence indicates that the nef gene of human immunodeficiency
       virus type 1 augments rather than inhibits viral replication in both
       cell culture and in vivo models. In addition, nef alters various normal
       cellular processes, including the display of CD4 on the cell surface.
       However, it remains unknown whether the enhancement of infectivity and
       the downregulation of CD4 represent linked or independent biologic
       properties of this single protein. In the present studies, mutational
       analyses were performed to define structure-function relationships
       within the Nef protein that mediate these effects. To assess the
       functional consequences of these mutations, sensitive and reliable
       assays were developed to quantitate the viral infectivity enhancement
       and CD4 downregulation functions of Nef. The results indicate that
       membrane-targeting sequences at the N terminus of Nef are important for
       both functions of Nef, while certain other conserved regions are
       dispensable for both functions. A conserved proline-X-X repeat segment
       in the central core of the protein, which is reminiscent of an
       SH3-binding domain, is critical for the enhancement of infectivity
       function but is dispensable for CD4 downregulation. However, the
       downregulation of CD4 by Nef appears to involve a two-step process
       requiring the initial dissociation of p56lck from CD4 to permit
       engagement of the endocytic apparatus by CD4. Together, these findings
       demonstrate that the infectivity enhancement and CD4 downregulation
       activities of human immunodeficiency virus type 1 Nef can be
       dissociated. Thus, these processes may be independent of one another in
       the viral replication cycle.
 DE    Antigens, CD4/ANALYSIS/*PHYSIOLOGY  Base Sequence  Down-Regulation
       (Physiology)  Gene Products, nef/*PHYSIOLOGY  Human
       HIV-1/*PATHOGENICITY  Molecular Sequence Data  Mutagenesis,
       Site-Directed  Protein-Tyrosine Kinase/BIOSYNTHESIS  Support, Non-U.S.
       Gov't  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).