Combinations of 3-hydroxyphthalic anhydride-modified ovalbumin with antiretroviral drug-based microbicide candidates display synergistic and complementary effects against HIV-1 infection

Abstract

Background: The development of a safe, effective, and affordable microbicide to prevent the sexual transmission of HIV combination is urgently needed. Our previous studies demonstrated that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) exhibited potent antiviral activity against a broad spectrum of HIV, simian immunodeficiency virus, and herpes simplex virus, making it a promising candidate as a component of combination microbicide. We intended to evaluate potential the synergistic anti-HIV-1 effect of HP-OVA in combination with antiretroviral drug (ARV)-based microbicide candidates.

Methods: The antiviral activity of HP-OVA and the ARVs, including HIV-1 entry inhibitors (T20, C52L, NB64, NBD556, AMD3100, and Maraviroc) and reverse transcriptase inhibitors (Tenofovir, UC781, and TMC120), tested alone or in combination, against HIV-1 X4 and R5 viruses, including some drug-resistant strains, was determined in MT-2 and peripheral blood mononuclear cells using p24 assay. The immune responses induced by HP-OVA that was applied in the vaginas of rats were detected by enzyme-linked immunosorbent assay.

Results: When each of these ARV-based microbicide candidates was combined with HP-OVA, synergistic activity was observed against infection by both X4 and R5 strains, and the degree of synergy differed in each case. HP-OVA was highly effective against several ARV-resistant HIV-1 strains, suggesting that combining HP-OVA with these ARV-based microbicide candidates might work cooperatively against both drug-sensitive and -resistant HIV-1 strains. Human body fluids and human proteins had little or no effects on HP-OVA-mediated inhibitory activity against HIV-1 infection. HP-OVA formulated in the universal gel maintained its antiviral activity for at least 1 month and only induced weak immune responses after its multiple applications in the vaginas of rats.

Conclusions: Synergistic and complementary effects against infection by a broad spectrum of HIV-1 strains were observed by combining HP-OVA with the ARV-based microbicide candidates. These findings provide a sound scientific platform for the development of a safe, effective, and affordable combination microbicide to prevent the sexual transmission of HIV and other sexually transmissible viruses.

Figure 1

Influence of human body fluids and proteins on anti-HIV-1 activities of HP-OVA. (A) The effect of human SF and VSF on HP-OVA-mediated anti-HIV-1_IIIB activity; (B) The effect of human SF and VSF on HP-OVA-mediated anti-HIV-1_BaL activity; (C) The effect of HSA and NHIgG on HP-OVA-mediated anti-HIV-1_IIIB activity and (D) The effect of HSA and NHIgG on HP-OVA-mediated anti-HIV-1_BaL activity. Each sample was tested in triplicate, and the data are presented as means ± SD.