Neutralization of infectivity of diverse R5 clinical isolates of human immunodeficiency virus type 1 by gp120-binding 2'F-RNA aptamers.
Human immunodeficiency virus type 1 (HIV-1) has evolved a number of strategies to resist current antiretroviral drugs and the selection pressures of humoral and cellular adaptive immunity. For example, R5 strains, which use the CCR5 coreceptor for entry and are the dominant viral phenotype for HIV-1 transmission and AIDS pathogenesis, are relatively resistant to neutralization by antibodies, as are other clinical isolates. In order to overcome these adaptations, we raised nucleic acid aptamers to the SU glycoprotein (gp120) of the R5 strain, HIV-1(Ba-L). These not only bound gp120 with high affinity but also neutralized HIV-1 infectivity in human peripheral blood mononuclear cells (PBMCs) by more than 1,000-fold. Furthermore, these aptamers were able to neutralize the infectivity of R5 clinical isolates of HIV-1 derived from group M (subtypes A, C, D, E, and F) and group O. One aptamer defined a site on gp120 that overlaps partially with the conserved, chemokine receptor-binding, CD4-induced epitope recognized by monoclonal antibody 17b. In contrast to the antibody, the site is accessible to aptamer in the absence of CD4 binding. Neutralizing aptamers such as this could be exploited to provide leads in developing alternative, efficacious anti-HIV-1 drugs and lead to a deeper understanding of the molecular interactions between the virus and its host cell.
Khati
Makobetsa
M
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
Schüman
Michael
M
Ibrahim
Jamal
J
Sattentau
Quentin
Q
Gordon
Siamon
S
James
William
W
D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism*
D017931:DNA Primers; D015699:HIV Envelope Protein gp120; D012367:RNA, Viral