COMMENTARY

Expert Perspective: Will CCR5 Inhibitors Overcome Obstacles and Become the Next Major Advance in Antiretroviral Therapy?

Mark A. Wainberg, PhD

Disclosures

January 09, 2006

In This Article

Introduction

The development of antiretroviral drugs is not for the fainthearted. Nothing more clearly illustrates the problems of HIV drug development and the potential vulnerability of drug companies than recent results pertaining to a new class of agents that act by blocking the cellular CCR5 receptor, which plays an essential role in governing HIV entry into susceptible cells. This category of drugs represents the first major attempt on the part of pharmaceutical companies to directly target a cellular rather than a viral moiety as a means of interfering with viral replication.

There are a number of reasons that support this approach. First, although a series of naturally occurring deletions have been detected within the CCR5 genes of many people, most do not seem to have suffered any deleterious consequences as a result.[1,2] Most individuals with these deletions seem to have well-functioning immune systems, even though they lack a complete CCR5 intracellular motif. Second, most individuals with this deletion who are infected with HIV do not progress rapidly in their HIV disease course, demonstrating the importance of CCR5 in mediating HIV entry into cells.[3] In addition, it is suspected that many carriers of the CCR5 partial deletion may be resistant to HIV infection.[4]

These findings provide an impetus to pharmaceutical companies to develop CCR5 antagonists for clinical use. Theoretically, these products would bind the CCR5 receptor at the cell surface, thereby interfering with the entry of HIV into the cell. As recently as October 2005, 3 companies were studying such products in phase 2 or 3 clinical trial patients with early disease who were naive to antiretroviral treatment (ART), as well as those with more advanced disease who were treatment-experienced.

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