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Antimicrobial Agents and Chemotherapy, February 2004, p. 444-452, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.444-452.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Gag Non-Cleavage Site Mutations Contribute to Full Recovery of Viral Fitness in Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1

Lay Myint,1 Masakazu Matsuda,1 Zene Matsuda,1 Yoshiyuki Yokomaku,1 Tomoko Chiba,1 Aiko Okano,1 Kaneo Yamada,2 and Wataru Sugiura1*

AIDS Research Center, National Institute of Infectious Diseases,1 Japanese Foundation for AIDS Prevention, Tokyo, Japan2

Received 28 July 2003/ Returned for modification 25 September 2003/ Accepted 4 November 2003

It is well documented that human immunodeficiency virus type 1 (HIV-1) Gag cleavage site mutations (CSMs) emerge in conjunction with various HIV-1 mutations for protease inhibitor (PI) resistance and improve viral replication capacity, which is reduced by acquisition of the resistance. However, CSMs are not the only mutations that emerge in Gag during treatment; many mutations other than CSMs (non-CSMs) have been found to accumulate in the Gag region. In the present study we demonstrate the important role of Gag non-CSMs with regard to viral fitness recovery. We selected three Gag-protease sequences with different PI resistance-associated mutations and CSMs from patients with antiretroviral treatment failure. To clarify the significance of CSMs and non-CSMs, four types of recombinant viruses with different patterns in each sequence were constructed. These were the GP type (patient-derived Gag and protease), the P type (HXB2 Gag and patient-derived protease), the GP-c type (CSMs removed from the GP type), and the P+c type (CSMs in the HXB2 Gag frame and patient-derived protease). By comparison of these four types of recombinant viruses in each patient-derived Gag-protease sequence, we found that non-CSMs, which had no systematic pattern, make a significant contribution to viral fitness recovery. Our findings demonstrate a delicate interaction between the in vivo evolution of Gag and protease to evade drug selective pressure and the importance of Gag in evaluating drug-resistant viruses.

* Corresponding author. Mailing address: AIDS Research Center, National Institute of Infectious Diseases, 4-7-1 Gakuenn, Musashimurayama, Tokyo 208 0011, Japan. Phone: 81-42-561-0771. Fax: 81-42-561-7746. E-mail: wsugiura{at}nih.go.jp.

Antimicrobial Agents and Chemotherapy, February 2004, p. 444-452, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.444-452.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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