Anti-HIV-1 activity of cellulose acetate phthalate: synergy with soluble CD4 and induction of "dead-end" gp41 six-helix bundles.
BACKGROUND
Cellulose acetate phthalate (CAP), a promising candidate microbicide for prevention of sexual transmission of the human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted disease (STD) pathogens, was shown to inactivate HIV-1 and to block the coreceptor binding site on the virus envelope glycoprotein gp120. It did not interfere with virus binding to CD4. Since CD4 is the primary cellular receptor for HIV-1, it was of interest to study CAP binding to HIV-1 complexes with soluble CD4 (sCD4) and its consequences, including changes in the conformation of the envelope glycoprotein gp41 within virus particles.


METHODS
Enzyme-linked immunosorbent assays (ELISA) were used to study CAP binding to HIV-1-sCD4 complexes and to detect gp41 six-helix bundles accessible on virus particles using antibodies specific for the alpha-helical core domain of gp41.


RESULTS
1) Pretreatment of HIV-1 with sCD4 augments subsequent binding of CAP; 2) there is synergism between CAP and sCD4 for inhibition of HIV-1 infection; 3) treatment of HIV-1 with CAP induced the formation of gp41 six-helix bundles.


CONCLUSIONS
CAP and sCD4 bind to distinct sites on HIV-1 IIIB and BaL virions and their simultaneous binding has profound effects on virus structure and infectivity. The formation of gp41 six-helical bundles, induced by CAP, is known to render the virus incompetent for fusion with target cells thus preventing infection.
Neurath
A Robert
AR
Biochemical Virology Laboratory, The Lindsley F. Kimball Research Institute of the New York Blood Center, New York, NY 10021, USA. arneurath@worldnet.att.net
Strick
Nathan
N
Jiang
Shibo
S
Li
Yun-Yao
YY
Debnath
Asim K
AK
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism* / Q000494:pharmacology; D002461:Cell Line, Transformed; D002482:Cellulose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility; D013601:T-Lymphocytes / Q000821:virology; D014771:Virion / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D011994:Recombinant Proteins; D002482:Cellulose; C011708:cellulose acetate phthalate