Targeting Host Cell Genes for HIV Treatment

Human Immunodeficiency Virus (HIV) is the etiological agent of Acquired Immune Deficiency Syndrome (AIDS), a condition in which the host immune system is progressively decimated. Specifically, HIV infects and consequentially lowers the number of CD4 T-cells. The development of AIDS ultimately leads to mortality from an opportunistic pathogen that a healthy immune system would normally control. The vast majority of current therapies available to control HIV infection target viral genes and are effective in restricting virus replication, but do so at a high cost to the patient both economically and physically. In addition, current therapies that target HIV genes are postulated to drive mutation of the virus into treatment resistant forms, further highlighting the need for a novel therapeutic approach.

Current experts in the HIV field have suggested the development of therapies targeting host genes needed for viral replication, rather than HIV genes themselves. Since these genes cannot mutate at a rapid rate, in contrast to HIV encoded genes, ablating their function should not readily allow for the emergence of treatment resistant virus. The host gene, chemochine-receptor-5 (CCR5), has long been known to regulate viral entry into host cells. Recently, the FDA approved Selzentry, a CCR5 receptor antagonist and product from Pfizer. The results of a large phase III trial were published in the New England Journal of Medicine demonstrating the drug's effectiveness and safety as an adjunct to well established anti-viral therapies.

Although Selzentry targets a host gene, the virus has the known capability of circumventing the drugs target, CCR5, by exploiting a different receptor for entry, the CXCR4 receptor. This caveat will potentially make Selzentry obsolete in the future and underscores the need for the discovery and development of therapeutics against "essential" host genes that the virus cannot circumvent. To further bolster the number of potential host derived therapeutic targets, large-scale functional genomic screens have been undertaken to discover genes required for HIV infection and propagation.

Several landmark studies published in various scientific journals have found a few hundred novel host genes that are required for HIV infection. The basic study design employed was to individually reduce the expression of every gene in the genome in cells grown in tissue culture. The cells were then incubated with a lab strain of HIV; if the reduction in the levels of a particular gene prevented infection, or the release of infection competent HIV, the gene was considered a necessary host cell factor required for the HIV life cycle.

The next step in the process of developing therapeutics targeting host cell factors is to determine which genes, when perturbed, give the most potent inhibition of HIV replication. Targeted genes must be selected carefully, as the reduction in the levels of certain genes could have toxic consequences for patients. Devising a method to reduce the function of the target gene will also need to be undertaken; whether it's inhibiting gene expression or the gene product itself. Of course, these developed drugs will ultimately have to be proven to be both safe and effective for HIV therapy in humans. Although in its infancy in the HIV field, functional genomic studies will allow for the identification and development of a novel therapeutic niche of HIV drugs that target host genes.

References:

Brass, AL. Science. 2008. 319: 921-926

Goff, SP. Cell. 2008. 135: 417-420

Gulick, RM. NEJM. 2008. 359:1429-1441