No abstract

The T-cell surface glycoprotein, CD4 (T4), acts as the cellular receptor for human immunodeficiency virus, type 1 (HIV-1), the first member of the family of viruses that cause acquired immunodeficiency syndrome. HIV recognition of CD4 is probably mediated through the virus envelope glycoprotein (gp120) as shown by co-immunoprecipitation of CD4 and gp120 (ref.5) and by experiments using recombinant gp120 as a binding probe. Here we demonstrate that recombinant soluble CD4(rsT4) purified from the conditioned medium of a stably transfected Chinese hamster ovary cell line is a potent inhibitor of both virus replication and virus-induced cell fusion (syncytium formation). These results suggest that rsT4 is sufficient to bind HIV, and that it represents a potential anti-viral therapy for HIV infection.

Two sCD4-resistant, primary viruses (P-08 and P-17) were compared with two sCD4-sensitive, T cell line-adapted variants (C-08 and C-17) for their biochemical responses to sCD4. At 37 degrees C, neither primary virus shed gp120 within 8 hr at sCD4 concentrations of up to 500 nM, whereas C-08 and C-17 lost gp120 within minutes of addition of 5-10 nM sCD4. At 4 degrees C, however, P-17 and C-17 shed gp120 at similar rates in response to the same sCD4 concentration. Irrespective of the temperature, gp120 dissociation from both P-17 and C-17 was inhibited by CD4 MAbs 6H10 and 5A8, the latter of which blocks events subsequent to sCD4 binding. Binding of sCD4 to P-17 was greater at 4 degrees C than at 37 degrees C, whereas the converse was found for C-17. Consistent with this, P-17 was neutralized much more potently by sCD4 at 4 degrees C than at 37 degrees C, whereas C-17 was slightly more sensitive to sCD4 at 37 degrees C than at 4 degrees C. Resistance to neutralization by sCD4 is probably determined by kinetic parameters. We suggest that the acquisition of sCD4 neutralization sensitivity and the above biochemical responses to sCD4 are coincidental to the process by which some primary viruses adapt to growth in transformed T cells. Sequence data indicate that there are a limited number of amino acid differences between the Env glycoproteins of the primary viruses and their T cell line-adapted counterparts; the significance of the individual changes is under investigation, but both pairs of viruses have amino acid substitutions in a region of gp41 thought to contact gp120.

August 16, 1991) ABSTRACT Recombinant soluble CD4 (rsCD4) has potent antiviral activity against cell line-adapted isolates of the human immunodeficiency virus type 1 (iHV-1) but low activity toward H1V-1 primary isolates from patients. A simple hypothesis proposed to explain this discrepancy, which questions the therapeutic utility of soluble CD4-based approaches, is that the major envelope glycoprotein, gpl20, of patient virus has lower

The coding sequence for Anabaena 7120 glutamine synthetase [L-glutamate:ammonia ligase (ADP-forming), EC 6.3