How X4 Emerges in HIV: Implications for CCR5 Blockers

Weinberger, Ariel, University of California, Berkeley
Advisor: Wayne Getz
Basic Biomedical Sciences
Dissertation Award

One of the great mysteries of HIV is how, in about 50% of Western patients (i.e., those with Subtype B), a more deadly HIV strain emerges late in infection. The new strain, known as X4, differs from its predecessor R5, because X4 only infects CD4+ T cells (“helper” immune cells necessary for orchestrating one’s overall immune response) displaying the receptor CXCR4, whereas R5 only infects CD4s displaying CCR5. Because CXCR4 and CCR5 are found on different CD4s, X4 depletes an additional set of critical immune cells, accelerating immunodeficiency and death. Recently, the FDA began approving drugs that selectively block R5, and some researchers have touted anti-R5 therapy alone as a potentially safer alternative to current anti-HIV drugs. An open question is whether anti-R5 treatments push HIV toward the more deadly X4 variant earlier. Using a minimal mathematical model for multi-strain HIV infection that we derive from the ground up, we show that anti-R5 treatment alone likely accelerates X4 emergence and thus immunodeficiency (Weinberger et al., 2009 PLoS Comput Biol, 5(8):e1000467). But, despite X4’s late-stage ubiquity among Western/Subtype B patients, X4 has not been commonly observed in other viral subtypes such as subtype C, which represents the majority of the world’s HIV infections. We are building a model to test our theory of how X4 Virus persists in Western populations. We plan to apply specific knowledge garnered from this modeling study directly to an experimental perturbation study aimed at eradicating the scourge of X4 Virus from Western populations.