September 30, 2002
All currently available antiretroviral agents act on one of two key enzymes in HIV replication -- reverse transcriptase and protease. Among investigational drug classes, the agents in the latest stages of development are those that inhibit virus-cell fusion. This report by Robert Doms, Ph.D. from the University of Pennsylvania, outlined the multiple steps in cell fusion that are potential targets for drug delivery.
Doms began by reviewing the steps involved in cell function: 1) the virus binds to the surface CD4 receptor; 2) a second binding step, to one of the co-receptors CCR5 or CXCR4; and then finally 3) cell fusion. Noting that individuals who harbor mutations in the genes encoding CCR5 are highly resistant to becoming HIV positive, making this an ideal drug target, Doms reviewed the agents furthest along in blocking CCR5, specifically SCH-C. A possible concern with this strategy is that viruses may evolve under the selective pressure of a CCR5 inhibitor to the more virulent CXCR4 variant, although fortunately this phenomenon has not yet been observed.
Once the virus has attached to the cell, the surface protein gp41 undergoes a conformational change, exposing gp120 and allowing co-receptor binding. Through interaction of two coil-like proteins, the virus is brought closer to the cell, ultimately allowing virus and cell membranes to fuse. This "coil-coil" interaction is the step blocked by the soon-to-be-approved drug T-20 (enfuvirtide, Fuzeon). Doms highlighted the short window period -- only during exposure of the coil proteins -- during which time T-20 acts, and then showed experimental evidence that increased expression of CCR5, or increased affinity of the virus for CCR5 proteins, would lead to less T-20 activity.
What are the practical implications of these findings? First, it may be helpful to conduct genetic testing to determine whether individuals harbor a CCR5 or CXCR4 tropic virus. In addition, there may be people who have either higher or lower density of CCR5 expression, which would predict a less or more robust response to fusion inhibitors such as T-20.
The multiple steps in viral fusion have other potential implications for therapeutics. Agents that block several of these steps would be predicted to work synergistically, and indeed in vitro evidence already exists demonstrating this favorable interaction. With the approval of T-20 expected soon, and several other agents in various stages of pre-clinical and clinical development, people with HIV and their providers can be optimistic about one day combining drugs from this exciting new therapeutic class.