Global COE Program Global Education and Research Center Aiming at the control of AIDS

Program Overview > Program Members > Hiroaki, Mitsuya

Faculty of Life Sciences / Center for AIDS Research, Professor
AIDS & Infectious Diseases, M.D., Ph.D. Program director, Program Board member, Research & Development of AIDS therapeutics

Development of Novel Antiretroviral Drugs That Are Potent against HIV-1 and Resistance-Deferring and Study of In Vivo Dynamics of HIV-1 Virions and HIV-1-Infected Cells upon Initial HIV-1 Infection and Its Alteration by Antiretroviral Treatment

Continuing challenges in the HAART era

Currently available combination therapy or highly active antiretroviral therapy (HAART) using reverse transcriptase inhibitors (RTIs), protease inhibitors (PIs), and/or other newly developed drugs has been shown to suppress the replication of HIV-1 and extend the life expectancy of HIV-1-infected individuals and the mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of HAART. However, an ability to provide effective long-term antiretroviral therapy for HIV-1 infection has become a complex issue since those who initially achieved favorable viral suppression to undetectable levels have experienced treatment failure. In addition, it is evident that with these anti-HIV drugs, only partial immunologic reconstitution is attained in patients with advanced HIV-1 infection.Without continuously developing further more potent, less toxic (or non-toxic), and resistance-deferring (or resistance-disallowing) antiretroviral agents, it will not be possible to improve or even maintain thus-far attained improved quality of life of patients with HIV-1 infection and AIDS.

More potent and less toxic agents are in need

Thus, our continuing attempt to develop more potent and less toxic antiretroviral agents will be one of the major enterprises in the global COE projects in the upcoming years. To this end, we will employ our long-standing structure-guided molecular targeting approach combining conventional cell-based assay, biochemical assays, crystallography, and molecular dynamics simulations (1, 2).

HIV-1 drug resistance is a persistent and major challenge

It is also of note that the issue of the emergence of drug-resistant HIV-1 variants is one of the most formidable challenges in HAART era. Indeed, the very features that contribute to the specificity and efficacy of RTIs and PIs provide the virus with a strategy to develop resistance and it seems inevitable that this resistance issue will remain problematic for many years to come, although a few recently developed drugs such as darunavir (DRV), which we have successfully brought to the clinical area, have been relatively successful in treating individuals carrying multi-drug-resistant HIV-1 variants (3, 4). We will target on how we can respond to this challenging drug-resistance issue in our global COE projects, in particular by attempting to study the mechanism(s) of the emergence of drug-resistance and to develop "resistance-deferring" or "resistance-disallowing" antiretroviral agents.

Dynamics of HIV-1 and HIV-1-infected cells in vivo and its alteration by treatment

Although the pathogenesis of HIV infection has been extensively studied over the past 25 years, the complex and multifactorial factors involved in HIV-1 infection prevent our understanding of the dynamics of HIV-1 infection leading to the full-blown AIDS. In particular, it is thought that lymphoid tissues represent the principal targets and reservoir of HIV-1 infection and certain assays including RT-PCR helped directly detect HIV RNA quantitatively, leading to the elucidation of viral dynamics, characterized by the immense level of turnover of HIV-1 and CD4 cell dynamics. However, the actual behavior of HIV-1 virions and HIV-1-infected cells during/between the initial HIV-1 entry and the establishment of systemic HIV-1 infection is not yet completely understood. Thus, in another area of our global COE projects, we will attempt to study the behavior of HIV-1 virions and HIV-1-infected cells using human peripheral blood mononuclear cells-implanted SICD mouse models and employing infectious HIV-1 isolates carrying various fluorescence probes and the state-of-the-art molecular imaging technologies. We will also determine how the behavior of HIV-1 virions and HIV-1-infected cells will be altered when antiretroviral regimens (reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and/or entry inhibitors) are administered to such SCID mice.

1.	Maeda K, Das D, Yin P, Tsuchiya K, Ogata-Aoki H, Nakata H, Norman R, Hackney L, Takaoka Y, and Mitsuya H. Involvement of the second extracellular loop and transmembrane residues of CCR5 in inhibitor binding and HIV-1 fusion: Insights to mechanism of allosteric inhibition. J. Mol. Biol. 381:956-974, 2008.
2.	Koh Y, Matsumi S, Amano M, Das D, Davis D, Li J, Leschenko S, Baldridge A, Shioda T, Yarchoan R, Ghosh AK, and Mitsuya H. Potent inhibition of HIV-1 replication by non-peptidyl small molecule inhibitors of HIV-1 protease dimerization. J. Biol. Chem. 282: 28709-28720, 2007.
3.	Mitsuya H, Maeda K, Das D, and Ghosh AK. Development of protease inhibitors and the fight with drug-resistant HIV-1 variants. Adv. Pharmacol. 56:169-197, 2008.
4.	Ghosh AK, Chapsal BD, Weber IT, and Mitsuya H. Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance. Acc. Chem. Res. 41: 78-86, 2008.