Viruses 2010, 2, 1069-1105; doi:10.3390/v2051069 OPEN ACCESS
viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review
HIV-1 Entry, Inhibitors, and Resistance Michael A. Lobritz, Annette N. Ratcliff and Eric J. Arts * Department of Molecular Biology and Microbiology and Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA; E-Mails:
[email protected] (M.A.L.);
[email protected] (A.N.R.) * Author to whom correspondence should be addressed; E-Mail:
[email protected]; Tel.: +1-216-368-8904; Fax: +1-216-368-2034. Received: 23 February 2010; in revised form: 16 April 2010 / Accepted: 18 April 2010 / Published: 29 April 2010
Abstract: Entry inhibitors represent a new class of antiretroviral agents for the treatment of infection with HIV-1. While resistance to other HIV drug classes has been well described, resistance to this new class is still ill defined despite considerable clinical use. Several potential mechanisms have been proposed: tropism switching (utilization of CXCR4 instead of CCR5 for entry), increased affinity for the coreceptor, increased rate of virus entry into host cells, and utilization of inhibitor-bound receptor for entry. In this review we will address the development of attachment, fusion, and coreceptor entry inhibitors and explore recent studies describing potential mechanisms of resistance. Keywords: HIV-1; envelope; gp120; V3 loop; gp41; CCR5; maraviroc; vicriviroc
1. Overview of HIV-1 Antiretroviral Therapy The major approach to the medical management of HIV infection is the treatment of patients with antiviral drugs. The enzymatic processes of the HIV-1 replication cycle present unique approaches for targeted disruption by pharmacological agents. Due to the high rates of virus production and the mutation rate of the virus [1], treatment of HIV-1 infection generally includes administration of three agents in combination, referred to as highly active antiretroviral therapy (HAART). Sustained treatment of patients with three active drugs results in suppression of viral replication in peripheral blood to below detection limits of sensitive clinical assays (
