THERAPEUTIC AGENTS DIRECTED AT GP120

HIV gp120 plays a critical role in HIV viral assembly, HIV infectivity, and the signaling of host cellular death. As a result, a number of therapeutic agents have been designed to inhibit gp120 binding, signaling, and effector host-cell infection.

One important area of focus is inhibiting viral entry and cellular apoptosis by blocking the interaction of gp120 with the CD4 receptor. Recombinant soluble CD4 was designed as a viral attachment decoy and has been effective at blocking HIV-1 infection in vitro.⁶⁹⁷⁰ However, in clinical studies, sCD4 proved ineffective except at very high doses.⁷¹,⁷² Although early studies proved ineffective, gp120 and CD4 interactions are still being targeted as possible therapeutic sites. Hybrid tetramers that contain a CD4 receptor domain within an IgG2 backbone are being used as a decoy for gp120 binding.⁷³ Monoclonal anti-CD4 antibodies that block the CD4/gp120 interaction and can block HIV-1 replication in vitro are also being developed.⁷⁴ Although anti-CD4 antibodies may cause an immunosuppressive effect, clinical studies are underway to determine whether they may suppress HIV gp120-CD4 interactions. In addition, small-molecule inhibitors have been designed to compete with gp120 binding to the CD4 receptor, thereby inhibiting viral entry or signaling to the CD4⁺ T cell. Thus far, these compounds vary in their effect against different HIV-1 strains. Mutation in the region where the gp120 binds to the CD4 receptor confers resistance to the effects of viral inhibition and blocking.⁷⁵ Despite the limited success of the early CD4 decoys and inhibitors, it is appealing to pursue this mode of therapeutics, as inhibiting CD4 would be effective in R5 and X4 viruses and their numerous strains.

Several agents have also been developed that bind to the CCR5 or CXCR4 co-receptors and block HIV-1 binding, apoptosis, and infectivity of the cell. Blocking the CCR5 receptor seems logical, because natural human mutations in the CCR5 receptor that prevent expression on the cell surface are much more resistant to infection with HIV and apoptotic signaling to the T cell, and those who do become infected have a much better outcome, with minimal immune depletion over time.⁷⁶,⁷⁷ The natural ligands for CCR5 are the β-chemokines MIP 1-à, MIP 1-β, and RANTES. Incubating any of these chemokines with a CD4⁺ T cell will downregulate the CCR5 receptor expression on the surface of the cell and inhibit HIV replication in vitro.⁷⁸ As a result, several small­molecule inhibitors of CCR5 and monoclonal antibodies to CCR5 have been developed and are being used in early clinical trials alone and in conjunction with highly active antiretroviral therapy (HAART) for HIV. The preliminary results look promising, although there is significant intrapersonal variation in effect, and some small-molecule inhibitors induced viral resistance in vitro.⁷⁹

Because X4 strains of HIV are present at the end stages of HIV disease and are associated with a more rapid decline in the immune cells, great effort has been made to block the gp120∕CXCR4 interaction and, therefore, block infection and the rapid CXCR4-mediated apoptosis. CXCR4, however, is present on a greater number of cells than CCR5, and universally blocking this receptor may cause adverse physiological sequelae. In support of this concern, CXCR4-knockout mice die as a result of congenital defects,⁸⁰ including cardiac malformation. Several CXCR4 antagonists have been developed and brought to the phase of clinical trials, but so far, all have been difficult to administer and have had little to no effect on X4 HIV-viral load or disease progression.^81-83 Further reflecting the difficult nature of developing effective chemotherapeutics, changes in gp120 around the V3 loop render the virus resistant to the CXCR4 small-molecule inhibitor.⁸⁴

Synthetic peptides have also been created that target the gp41 portion of the HIV envelope glycoprotein and serve to inhibit HIV viral entry.