Selective Engineering of the CD4 Receptor: A Host-Directed Strategy to Reduce Cellular Susceptibility to HIV Entry

Abstract

HIV infection remains incurable due to the integration of the viral genome into CD4+T cells and the establishment of latent reservoirs, which persist despite effective antiretroviral therapy. CCR5-editing strategies, while promising, face inherent limitations including viral tropism switching to CXCR4 and genetic heterogeneity across human populations [4, 6, 10, 13, 16].

Here, we propose a theoretical framework for the selective engineering of the CD4 receptor, aimed at reducing T-cell susceptibility to HIV entry through targeted structural modification. This framework is grounded in a key biophysical distinction: the high-affinity, focused binding of viral gp120 versus the lower-affinity, dynamic, and spatially extended interaction of CD4 with MHC-II [9, 14].

We hypothesize that the insertion of a protective domain in proximity to the gp120-binding site could selectively impair viral docking while preserving CD4–MHC-II engagement within a physiologically tolerable range [1, 7, 15]. Such modification may also constrain the evolutionary adaptability of HIV more effectively than coreceptor-targeted strategies [10, 11, 13].

This conceptual framework provides a foundation for the experimental evaluation of host receptor engineering as a complementary approach to achieving sustained cellular resistance to HIV infection.