Harnessing Viral Devices as Pharmaceuticals: Fighting HIV-1's Fire with Fire

Garry P. Nolan the delivered “drug” creates more copies of itself within the HIV-1 cells targeted for destruction and then moves Department of Molecular Pharmacology Department of Microbiology and Immunology on to seek out other HIV-1 infected cells, killing them in turn. The approach resulted in a significant suppression Stanford University School of Medicine Stanford, California 94305 of HIV-1 replication for over 30 days in the test tube in what appeared to be a classic case of predator–prey population dynamics at the molecular level. The reports from the Yale and Tübingen groups Often, understanding the manner in which a dynamic system operates can provide an opportunity to take (Schnell et al., 1997, and Mebatsion et al., 1997, respectively) are highly significant as they represent a leap advantage selectively of the outcome. Most modern biomedical endeavors seek to combat disease processes forward in how we might apply basic understandings of viral biology to the design of therapies that are capable with such a guiding principle in mind. One form of this approach begins by understanding the key aspect(s) of of seeking out and destroying designated cells, in this case HIV-1. Although the current work is not yet ready a pathologic disease process—be it a gene product, a misguided cellular response system, or an infectious for a clinical setting, the research boldly demonstrates that it isnow possible to reverse the aim of the biochemiviral disease. Biopharmaceuticals seek to restore the body’s natural functioning by targeting the defective cal grappling hooks HIV-1 uses to enter cells and to employ them against the virus itself. One advantage of gene or cell system with a drug or gene therapy, or by some other innovative manipulation of the body’s the approach is that it should be difficult for HIV-1, even with its prodigious mutation rate, to sidestep an assault physiology. The challenge is to target the drug or therapy selectively to the place where it does the most good that employs the exact chemical cues HIV-1 seeks on target cells—since such escape mutations would impair and creates the fewest side effects. In the arena of pharmaceutical design encompassing chemotherapy against HIV-1’s ability to enter the immune system cells it must defeat in order to remain pathogenic. The therapeutic viruses or cancers, this general schema is termed “selective toxicity.” possibilities go beyond the delivery of engineered viruses, noteworthy as that is, and suggest immediate Two groups apply such a philosophy in this issue of Cell with reports of anti-HIV-1 strategies that use, rather applications that directly deliver drug candidates only to cells expressing markers of HIV-1 infection. These, than drugs, sophisticatedly engineered viruses capable of specifically seeking out and killing human cells that and other matters, are discussed below. Coreceptors: Determinants of HIV-1 Entry display markers of HIV-1 infection (Mebatsion et al., 1997; Schnell et al., 1997). Perhaps more remarkable, to Immune Cells A viral infection is in essence a mobile genetic disease the engineered hunter–seeker viruses they create are derived from domesticated versions of an ancient enthat parasitizes host cellular machinery for the purpose of the virus’ own replication. HIV-1 begins infection of emy of humanity—the Rabies virus (family Rhabdoviridae in the order Mononegavirales) and a Rabies viral a cell by recognizing specific “coreceptor complexes” on the surfaces of T cells or macrophages. HIV-1 binds relative, the vesicular stomatitus virus (VSV). Certain of these engineered Rhabdoviruses deliver genes only to to this cellular coreceptor complex via a protein, termed gp120, found at the membrane surface of the virus, (see HIV-1-infected target cells, but not to healthy bystander cells. In one case the engineered Rhabdovirus was caFigure 1 for details), allowing physical association of the virus with the target cell. After binding the coreceptor, pable of preferential self-replication in, and destruction of, HIV-1-infected cells only. Thus, in a unique sense gp120 signals another protein in the viral membrane,