In addition to fusion and co-receptor inhibitors, there are additional ways to block HIV entry into cells. One such approach is to target the gp120 protein on the HIV envelope. Researchers are studying small molecules that prevent gp120 from attaching to CD4. In test-tube studies, researchers have also tested agents called glycosylation inhibitors (including castanospermine) that prevent the normal formation of the sugars that make up the gp120 glycoprotein, so they no longer fit the CD4 receptor.

An alternative is to block gp120 using an artificial version of the CD4 protein. One soluble CD4 product, PRO 542, demonstrated promising results in Phase 1 and 2 trials, but Progenics decided to suspend development to focus on more promising candidates^[1].

TNX-355, a genetically engineered monoclonal antibody that acts on the CD4 receptor, has shown considerable promise. TNX-355 targets a part of the CD4 receptor that is responsible for the shape changes that occur after gp120 binds to the receptor. In a Phase 2 study, treatment-experienced patients who received intravenous infusions of TNX-355 plus optimised background therapy for 48 weeks achieved greater viral load suppression and larger CD4 cell increases than those who received a placebo, with no serious side-effects^[2]. For more information, see TNX-355 in A-Z of drugs.

It may also be possible to interfere with the expression of CD4 receptors on host cells. As is the case with the CCR5 and CXCR4 co-receptors, however, interfering with CD4 is a potentially risk approach.