Role of the HIV gp120 Conserved Domain 5 in Processing and Viral Entry

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Abstract
The importance of the HIV gp120 conserved domain 5 (gp120-C5) to envelope function has been examined by alanine scanning mutagenesis and subsequent characterization of the mutagenic effects on viral entry and envelope expression, processing, and incorporation, as well as gp120 association with gp41. With respect to the wild-type gp120, mutational effects on viral entry fall into three classes: (1) functional (V489A, E492A, P493A, T499A, K500A, K502A, R503A, R504A, V505A, and V506A; (2) nonfunctional (I491A, L494A, V496A, and P498A); (3) enhanced (K490A, G495A, and Q507A). The nonfunctionality of the mutants is attributed to a combination of deleterious effects on processing, gp120-gp41 association, and membrane fusion. In the case of the nonfunctional mutant P498A, the introduction of the SOS mutation (A501C/T601C) results in substantially increased envelope processing and a gain of function. The effects of the mutants are interpreted with respect to the structures of gp41 and gp120. The extent of sensitivity of gp120-C5 to alanine substitutions underscores the importance of this domain to envelope function and suggests that gp120-C5 is an attractive and novel target for future drug discovery efforts.