Diskin R, Scheid JF, Marcovecchio PM, Western AP, Jr, Klein F, Gao H, Gnanapragasam PN, Abadir A, Seaman MS, Nussenzweig MC, Bjorkman PJ
Diskin R, Scheid JF, Marcovecchio PM, Western AP, Jr, Klein F, Gao H, Gnanapragasam PN, Abadir A, Seaman MS, Nussenzweig MC, Bjorkman PJ. 2011. neutralization assay shown that VRC01p offers gp120-binding affinity and HIV-1-neutralization capacity virtually identical to the human-cell-produced counterpart. To advance VRC01p’s use in topical microbicides, we analyzed combinations of the bnMAb with additional microbicide candidates holding unique antiviral mechanisms in an HIV-1 neutralization assay. VRC01p exhibited obvious synergy with the antiviral lectin griffithsin, the CCR5 antagonist maraviroc, and the reverse transcriptase inhibitor tenofovir in multiple CCR5-tropic HIV-1 strains from clades A, B, and C. In summary, VRC01p is definitely amenable to powerful, quick, and large-scale production and may become developed as an active component in combination microbicides with additional anti-HIV agents such as antiviral lectins, CCR5 antagonists, and reverse transcriptase inhibitors. Intro Despite the slowly declining incidence of global HIV infections Banoxantrone D12 in recent years, the HIV/AIDS epidemic causes over 2 million fresh infections every year, representing one of the leading causes of infection-related deaths worldwide (1). Because an effective HIV vaccine remains elusive and the majority of new infections happen in the developing countries, there is urgent need for safe, effective, and inexpensive preexposure prophylaxis (PrEP) modalities for avoiding viral mucosal transmission, such as topical microbicides (2, 3). Currently, most attempts in microbicide development are focused on small-molecule antiretrovirals (ARVs) that have been developed to treat HIV-infected individuals (4). This paradigm offers emerged since the seminal statement published in 2010 2010 within the CAPRISA 004 Phase IIb medical trial, showing that pericoital use of a gel comprising the reverse transcriptase (RT) inhibitor tenofovir (TFV) offered modest yet significant safety (5). Clinical development of ARVs for PrEP can be greatly facilitated by available safety and effectiveness information using their restorative use. However, it is desired to increase microbicide candidates to non-ARV-based HIV inhibitors, because of issues for the PrEP/microbicide use of ARVs. For example, potential conflicts of priorities between treatment and prevention may arise, and emergence of escape mutants could compromise available therapy options (6, 7). Human being anti-HIV-1 broadly neutralizing monoclonal antibodies (bnMAbs) may provide attractive options with this context, given their verified protective effectiveness against illness upon pre- and/or postexposure uses in animal challenge models Banoxantrone D12 (8C14) and inherent general safety because of their human being origin. A phase I randomized controlled medical trial offers been recently completed for any vaginal microbicide candidate comprising three bnMAbs, 2F5, 4E10, and 2G12, showing that daily vaginal administration of the bnMAbs (50 mg each) to healthy ladies for 12 days was safe and well tolerated (15). VRC01 is definitely a CD4-binding site (CD4bs)-specific bnMAb recently isolated from a slowly progressing HIV-1-infected donor (16). It has remarkable neutralization protection compared to most other HIV-1-neutralizing MAbs reported to day; about 90% of genetically varied heterologous HIV-1 strains have been neutralized with 50% inhibitory concentrations (IC50s) at 1 g/ml in HIV-1 neutralization assays (16). Transmitted/founder viruses of A, B, and C clades were shown to be susceptible to VRC01 neutralization (17C19). Veselinovic et al. recently reported that a topical gel formulation of VRC01 safeguarded against vaginal challenge with the chemokine receptor CCR5-using HIV-1 BaL inside a humanized mouse model (20). Collectively, these findings strongly suggest that VRC01 and additional related bnMAbs constitute some of the most encouraging non-ARV anti-HIV-1 molecules as topical microbicide candidates, justifying further preclinical investigation to determine their feasibility. Notwithstanding the impressive breadth and potency of VRC01’s anti-HIV-1 activity, the living of VRC01-resistant viruses was shown in the VRC01 donor and additional broadly neutralizing plasma donors (21). A recent passive immunotherapy study using a humanized mouse model has shown that a monotherapeutic use of the VRC01-like CD4bs-specific bnMAb NIH45-46G54W failed to control viremia and the emergence of resistant viruses, although combination with four Banoxantrone D12 additional bnMAbs rendered total safety (13). These findings suggest that a single-component microbicide based on VRC01 or any additional bnMAb may fail to provide sufficient protection and could even lead to the build up of resistant strains in circulating disease populations. In practice, a combinatorial strategy will have to be implemented for any microbicide candidates, as has been the case in the treatment of HIV-1-infected individuals (22). Thus, analysis of VRC01’s potential for synergy with additional microbicide candidates would provide valuable info toward the bnMAb’s potential as a component of combination LAMA4 antibody microbicides. While security and efficiency are vital factors in pharmaceutical advancement, additionally it is essential that microbicide applicants be economically practical (3). Indeed, this is actually the most crucial problem for MAbs Banoxantrone D12 probably, as with the existing mammalian cell culture-based creation system it.