Document 1069
 DOCN  M9471069
 TI    Analysis of three distinct stages of replication in human retroviruses.
 DT    9409
 AU    Hammes SR; Duke Univ.
 SO    Diss Abstr Int [B]; 53(12):6113 1993. Unique Identifier : AIDSLINE
       ICDB/94696141
 AB    The type 1 human immunodeficiency and human T-cell leukemia viruses
       (HIV-1 and HTLV-I, respectively) use many mechanisms at various stages
       throughout their life cycles to regulate replication. Three of these
       processes were examined in detail in order to better understand some of
       the complexities of this regulation. The first mechanism studied
       involved the regulation of retroviral gene transcription. HIV-1 Nef
       protein has been reported to control viral replication by suppressing
       gene transcription directed by the HIV-1 LTR. In contrast, these studies
       demonstrate that Nef had no effect on transcriptional activity through
       the HIV-1 LTR. Furthermore, HIV-1 proviral clones containing either a
       wild type or mutated nef gene replicated equally well when transfected
       into cells. These findings suggest that, in contrast to previous
       reports, Nef is neither a transcriptional inhibitor nor a suppressor of
       viral replication. The second regulatory mechanism examined was the
       control of retroviral structural protein expression. HTLV-I Rex protein
       acts post-transcriptionally to enhance expression of incompletely
       spliced viral mRNAs encoding these structural proteins. Rex function
       involves its direct interaction with an RNA stem-loop structure located
       within the 3' LTR termed the Rex response element (RexRE). This
       interaction requires a positively charged arginine-rich domain in Rex
       that also serves as a nuclear localization signal. Mutagenesis of this
       basic region revealed that, while positive charge alone appears
       sufficient for nuclear localization, multiple arginine residues at
       specific sites are essential for complete RNA binding and functional
       activity of Rex. The final stage of retroviral replication studied was
       viral binding to target cells. Little is known about the identity of the
       HTLV-I receptor. These studies demonstrated that a direct interaction
       between the HTLV-I envelope glycoprotein gp46 and viral receptors on
       target cells was necessary for infection. Binding assays using purified
       gp46 revealed that HTLV-I receptors were expressed on all mammalian
       tumor lines tested, but were absent on non-mammalian cells. Furthermore,
       activation of resting primary human T-lymphocytes, which are devoid of
       gp46 binding sites, resulted in the induction of HTLV-I receptor
       expression. Together, these results suggest that HTLV-I infection may
       require T-cell activation, and that HTLV-I receptor expression may
       correlate with cellular proliferation. (Full text available from
       University Microfilms International, Ann Arbor, MI, as Order No.
       AAD93-11846)
 DE    Gene Products, nef/*GENETICS  Genes, pX/*GENETICS  HIV Long Terminal
       Repeat/GENETICS  HTLV-I/*GENETICS/PHYSIOLOGY  HTLV-I Infections/GENETICS
       Lymphocyte Transformation  RNA Splicing  Receptors, HIV/METABOLISM
       T-Lymphocytes/PHYSIOLOGY  Transcription, Genetic  *Virus Replication
       THESIS

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