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Structural basis for coreceptor selectivity by the HIV type 1 V3 loop
Abstract & Commentary
By Dean L. Winslow, MD, FACP
Dr. Winslow serves as a consultant to Siemens Diagnostics and is on the Speakers Bureaus of Boehringer-Ingelheim and GSK. This article originally appeared in the July 2007 issue of Infectious Disease Alert. It was peer reviewed by Connie Price, MD and edited by Stan Deresinski, MD. Infectious Disease Alert's Physician Editor, Stan Deresinski, MD, FACP, serves on the speaker's bureau of Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. Peer reviewer Connie Price, MD, reports no consultant, stockholder, speaker's bureau, research, or other financial relationship with any company related to this field of study.
Source: Cardozo T, et al. Structural basis for coreceptor selectivity by the HIV type 1 V3 loop. AIDS Res Hum Retroviruses 2007; 23:415-426.
Synopsis: 217 clinical isolates of HIV-1 had tropism determined using various biological techniques and included virus actually isolated by the authors and viruses reported in the literature where sequence of the V3 loop was known. Sequencing of the V3 loop resulted in the development of a reliable prediction rule where X4 tropic virus was predicted by the presence of a positively charged amino acid at position 11, 24, or 25. Otherwise the virus was R5 tropic.
Over the last 15 years increased understand ing of the complicated process of HIV attachment and entry into host cells has developed. After initial binding of the virus' external envelope glycoprotein gp120 to CD4, the trimeric gp120 structure undergoes conformational change resulting in exposure of the third variable domain of gp120 (V3 loop) which then interacts with one of two coreceptors, CCR5 or CXCR4. This coreceptor binding is then followed by fusion of the viral transmembrane glycoprotein gp41 to the host cell. The natural ligands of CCR5 are the chemokines MIP-1 alpha, MIP-1 beta, and RANTES whereas the natural ligand for CXCR4 is SDF-1.
The need for determining coreceptor tropism of HIV isolated from patients has taken on some importance in the last year due to the availability and impending FDA clearance of maraviroc, a small molecule CCR5 antagonist. The widely used cell-based biological assay developed by Monogram (formerly ViroLogic) is expensive, difficult to perform, has a turnaround time of several weeks, and is probably not capable of detecting mixed tropic virus when the proportion of X4-tropic viruses present in a mixture are less than 10-20% of the population. Development of a sequenced based assay (if demonstrated to reliably predict coreceptor usage) would clearly result in more reliable, rapid, more sensitive determination of virus coreceptor usage. In addition, a sequence based assay would clearly be a fraction of the cost of the Monogram bioassay.
This paper nicely demonstrates and uses computer modeling to illustrate the structural basis for the tight correlation between the presence of any positively charged amino acid at positions 11, 24, and 25 (e.g. arginine, lysine) and X4 virus as well as the absence of a positively charged amino acid with the presence of generally one negatively charged amino acid (e.g. aspartate, glycine) and R5. As expected, computer modeling of the natural ligands of CXCR4 (SDF-1) and CCR5 (MIP-1 beta) and the corresponding viral V3 loops show remarkable structural similarity.
These results have potentially important implications for not only guiding therapy with coreceptor antagonists, but for design of future small molecule inhibitors and immunogens targeting the V3 loop.