Eric J. Arts, Ph.D.
Associate Professor of Medicine (Infectious Diseases)
Biomedical Research Building, 1029 School of Medicine
2109 Adelbert Rd.
Case Western Reserve University
Mailing Address:
10900 Euclid Ave.
Cleveland, Ohio 44106-4951
Phone: (216) 368-8904
Fax: (216) 368-2034
E-mail: eja3@case.edu
Research
The mutation frequency during human immunodeficiency virus replication is at least 1000 times greater than that of its host. As a result of this infidelity, anti-retroviral therapies appear only to delay viremia, molding or selecting the outgrowth of a drug resistant phenotype. Most drug-resistant HIV-1 isolates confer resistance through specific mutations, i.e. a single methionine to valine change at position 184 of the 1100 amino acid HIV-1 reverse transcriptase (RT) encodes 1000-fold resistance to the drug 3TC (2',3'-dideoxy-3'-thiacytidine). However, different, single substitution mutations are responsible for resistance to nucleoside analogs (e.g. 3TC AZT, ddI) in HIV-1 RT. In addition, many of these drug-resistant genotypes utilize radically different resistant mechanisms. AZT has been utilized in HIV-1 therapy for over ten years and yet, the mechanism of AZT resistance by HIV-1 has not been resolved. In AZT-resistant HIV-1, unlike other nucleoside analog-resistant viruses, it appears that an AZT anabolite can act as a co-factor of AZT-resistant RT, stimulating HIV-1 reverse transcription and overriding the inhibitory effects of AZT. This AZT-resistant virus is not cross-resistant to other nucleoside analogs alone (e.g. 3TC, ddI). However, cross-resistance by AZT-resistant viruses does occur when these drugs are administered in combination with AZT. In lieu of these observations, AZT may not be suitable in combination with other nucleoside analogs, particularly if a patient already harbors AZT-resistant virus. Further studies are focusing on the mechanisms of AZT resistance both in vivo and in vitro.
We are also investigating HIV-1 heterogeneity during infection of an individual in various population groups. As observed in the evolution of influenza virus, an HIV-1 subtype may undergo a major antigenic shift by recombining with another HIV-1 subtype. Although this evolution is apparent in nature, it has not been defined in vitro. Currently, we are studying recombination between different HIV-1 subtypes following infection of various CD4-positive primary cells (e.g. peripheral blood lymphocytes and macrophages, lung macrophages, and Langerhans' cells) to determine possible "hot sites" for this recombination.
SELECTED REFERENCES:
Quinones-Mateu, M.E., J.L. Albright, A. Mas, V. Soriano, and E.J. Arts. 1998. Pol gene quasi-species in patients infected with HIV-1 group O: An evolutionary and drug resistance study using genotypic and heteroduplex tracking analyses. J. Virol. 72:9002-9015.
Quinones-Mateu, M.E., J.L. Albright, V. Torre, M. Reinis, J. Vandasova, M. Bruckova, and E. J. Arts. 1999. Molecular epidemiology of HIV-1 isolates from the Czech Republic. Identification of an env E subtype case. AIDS Res. Hum. Retroviruses. 15:85-89.
Quinones-Mateu, M.E., and E.J. Arts. 1999. Recombination in human immunodeficiency virus type-1 (HIV-1): Update and implications. AIDS Rev. 1:89-100.
Torre, V.S., A.J. Marozsan, J.L. Albright, K.R. Collins, O. Hartley, R. E. Offord, M.E. Quinones, and E.J. Arts. 2000. Variable sensitivity of CCR5-tropic HIV-1 isolates to inhibition by RANTES analogs. J. Virol. 74: In press.
Blauvelt, and E.J. Arts*. 2003. Poor ex vivo fitness of CCR5-tropic subtype C human immunodeficiency virus type 1. J. Virol. 77:1021-1038.
Quinones-Mateu, M. E., Y. Gao, S.C. Ball, A.J. Marozsan, A. Abraha, and E.J. Arts*. 2002. In vitro intersubtype recombinants of human immunodeficiency virus type 1: Comparison to recent and circulating in vivo recombinant forms. J. Virol.76:9600-9613.
Arts, E.J.* and M.E. Quinones-Mateu. 2003. Sorting out the complexities of HIV-1 fitness. AIDS. 17:780-7811.
Quinones-Mateu, M. E., and E.J. Arts. 2002. Fitness of drug resistant HIV-1: methodology and clinical implications. Drug Res. Updates 5:224-233.
Collins, K.R., M.E. Quinones-Mateu, Z. Toossi, and E.J. Arts*. 2002. Impact of tuberculosis on HIV-1 replication, diversity, and disease. AIDS Rev. 4:165-176.
Ball, S.C., A. Abraha, K.R. Collins, A.J. Marozsan, M.E. Quinones-Mateu, A. Penn-Nicholson, M. Murray, N. Richard, M. Lobritz, P. A. Zimmerman, T. Kawamura, A. Blauvelt, and E.J. Arts*. 2003. Poor ex vivo fitness of CCR5-tropic subtype C human immunodeficiency virus type 1. J. Virol. 77:1021-1038.