HIV takes double hit before entry
© Sanders; licensee BioMed Central Ltd. 2012
Received: 29 November 2012
Accepted: 5 December 2012
Published: 7 December 2012
In the absence of a vaccine or a cure, identification of novel HIV-1 inhibitors remains important. A paper in Retrovirology describes a rationally designed bi-specific protein that irreversibly damages the viral envelope glycoprotein complex via a two-punch mechanism. In contrast to traditional drugs that inhibit essential steps in the viral life cycle at the cell surface or in the infected cells, this inhibitor cripples free virus in the absence of cells.
See research article: http://www.retrovirology.com/content/9/1/104
Antiviral drugs are potent at suppressing viral replication in HIV infected individuals. Unfortunately, current drug regimens cannot cure infected persons because of the establishment very early in infection of latent viral reservoirs that cannot be eliminated by conventional drugs. The continuous virus evolution and the danger of viral escape from the available drugs necessitate the search for novel inhibitors. HIV drugs can target a variety of processes of the viral life cycle that include viral entry into host cells, viral reverse transcription, integration into the host genome, and virus maturation.
Now a team led by Shibo Jiang has designed a novel bi-specific inhibitor, 2DLT, which essentially is a fusion protein of a soluble version of CD4 and the third generation fusion inhibitor T1144 . As such it can inhibit the interaction of gp120 with CD4 as well as the conformational changes in gp41 that result in membrane fusion, resulting in HIV-1 inhibition at low nanomolar concentrations. While bi-specific and multispecific proteins are widely studied for use in cancer therapy, only a few bi-specific molecules have been designed for HIV-1. One such molecule, termed sCD4-17b, shares a CD4 mimetic component with 2DLT, but further contains an antibody fragment directed to an epitope on gp120 that is induced by CD4 binding and that overlaps with the co-receptor binding site . A second approach uses bi-specific antibody molecules targeting two different epitopes, one on gp120 and one on gp41 . Both sCD4-17 and the bi-specific antibodies result in low nanomolar inhibition of HIV similar to 2DLT.
The beauty of the 2DLT inhibitor is not its dual activity per se, but its potential to inactivate the virus in the absence of cells. For viral entry into cells it is essential that the mousetrap shuts when a mouse is eating from the cheese, in other words when the virus is attaching to a target cell. This timing is coordinated by the activation of Env's spring-loaded fusion machinery only when the virus is attaching to an infectable cell via CD4. It has been previously recognized that CD4 mimetics induce a short-lived activated Env state that deteriorates into an inactive Env form ; however, CD4 mimetics are usually not very potent in doing so. The CD4 component of 2DLT also induces the short-lived activated Env form, but then the fusion inhibitor component, T1144, delivers a second blow by binding and blocking the activated fusion machinery in gp41. Thus, 2DLT induces a premature and irreversible collapse of the viral mousetrap, thereby preventing viral entry into target cells. As a consequence, in regular infection inhibition experiments in the presence of target cells, 2DLT is as potent as its most potent constituent, T1144. However, in sharp contrast, 2DLT is able to disable the virus in the absence of target cells, while T1144 is not. What Lu et al.  did not study is whether the two separate components of 2DLT, T1144 and soluble CD4, can disable the virus when simply mixed. This would reveal whether the combined action of the two components of 2DLT require a physical linkage.
Despite the promise of its novel mechanism of action, some formidable challenges lie ahead before 2DLT or 2DLT-derivates will be suitable for wide clinical use. Poor bioavailability and expensive manufacturing put 2DLT at a disadvantage compared to currently available small molecule inhibitors. However, its mechanism of viral deactivation away from cells puts it at a unique advantage, and as such it warrants further research. 2DLT may be considered for use as a microbicide - for example, in vaginal gels that are aimed at preventing HIV-1 transmission at the vaginal mucosal surface. Another interesting application of 2DLT could be in viral immune prophylaxis (VIP). VIP is a gene therapy vaccination approach in which the constitutive expression by host cells of a neutralizing antibody or an inhibitory protein provides vaccine-like protection against viral infection . In summary, the bi-specific and dual active 2DLT inhibitor described by Lu et al., with its one-two punch that inactivates free virus, represents a novel drug approach that warrants further evaluation.
The author is a recipient of a Vidi fellowship from the Netherlands Organization for Scientific Research (NWO), and a Starting Investigator grant from the European Research Council (ERC-StG-2011-280829-SHEV).
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