Effect of polyanion-resistance on HIV-1 infection.
Polyanions are potent HIV-1 entry inhibitors. Nevertheless, resistant viruses may emerge under polyanion inhibitory pressure. Specifically, a polyanion-resistant virus replicates in T cells even in the presence of high concentrations of polyanions. We found that although the polyanion-resistant virus grows in suspension CD4+ T cells efficiently, it infects nonlymphocytic adherent CD4+ cells poorly. Given that a main distinction between suspension and adherent cells is the absence or presence of cell-surface heparan sulfate proteoglycan (HSPG), we investigated if the failure of the polyanion-resistant virus to infect adherent CD4+ cells arises from its inability to bind HSPG. We found that the emergence of mutations in gp120 associated with polyanion resistance resulted in a decreased capacity of HIV-1 to bind HSPG. We also found that the polycation polybrene rescued the capacity of the polyanion-resistant virus to bind HSPG and to infect adherent CD4+ cells. The identification of this virus, unable to bind HSPG, provides a convenient probe to measure the impact of HIV-1-HSPG interactions in vivo. Altogether, these findings suggest that polyanion-resistance narrows the range of potential target cells for HIV-1 in the host. This reinforces the hypothesis that cell-free or cell-associated polyanions such as HSPG possess the capacity to modulate HIV-1 pathogenesis.
Bobardt
Michael D
MD
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Armand-Ugón
Mercedes
M
Clotet
Imma
I
Zhang
Zhe
Z
David
Guido
G
Este
Jose A
JA
Gallay
Philippe A
PA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006583:Hexadimethrine Bromide / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology*; D014774:Virulence / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D019812:Heparan Sulfate Proteoglycans; D006583:Hexadimethrine Bromide; D010446:Peptide Fragments; D000071228:Polyelectrolytes; D011108:Polymers; C059762:HIV envelope protein gp120 (305-321)