Molecular Engineering of a Banana Lectin that Inhibits HIV-1 Replication.

Abstract

Despite years of research, a vaccine that can end the HIV/AIDS pandemic is not in the foreseeable future. Although the search for a vaccine is ongoing, novel methods to prevent HIV-1 infection should be pursued. We found that a lectin isolated from bananas, BanLec, is a potent inhibitor of HIV-1 infection. BanLec is able to bind to the high mannose structures found on the heavily glycosylated envelope protein of HIV-1, which allows it to recognize a broad range of different viral isolates. We determined that BanLec inhibits entry of the virus into the cell before cellular attachment of the virus. The anti-HIV-1 activity of BanLec compares well to the clinically approved anti-HIV drugs T-20 and maraviroc. These drugs and other anti-HIV lectins are being considered as components of a vaginally-applied anti-HIV microbicide for inhibition of sexual transmission. Therefore, we began to assess the potential of BanLec as a microbicide component. Since pro-inflammatory conditions have been the bane of clinical trials of potential microbicides, we decided to assess whether BanLec has mitogenic activity that could lead to cellular activation and proliferation. These conditions could lead to inflammatory cytokine production that favor increased HIV-1 replication. We found that the addition of BanLec to peripheral blood lymphocytes induced mitogenic activity. However, a lectin related to BanLec, griffithsin, has anti-HIV-1 activity and is not mitogenic. Therefore, we hypothesized that the mitogenic activity of BanLec could be reduced without abolishing its anti-viral activity. Using a recombinant version of BanLec, we found that substituting the histidine at position 84 leads to altered mitogenic activity. In particular, a histidine to threonine substitution (H84T) resulted in a loss of mitogenic activity, yet that mutant retained potent anti-HIV activity. In addition, the H84T mutant has reduced agglutination activity, suggesting that impaired cross-linking ability may be responsible for reduced mitogenicity. We have demonstrated that BanLec is a potent inhibitor of HIV-1 replication and that its mitogenic activity is separable from its anti-HIV-1 activity. Our results suggest that the BanLec mutant H84T is a promising candidate for future anti-HIV therapies.