New 'Trick' Allows HIV To Overcome A Barrier To Infection

"Similar to a human skeleton, every cell has a cytoskeletal structure that supports the cell, gives it its shape, and provides a force that allows the cell to migrate. For the virus, this layer also presents a barrier," says  Yuntao Wu, assistant professor in George Mason University's Department of Molecular and Microbiology. "We never understood how the virus overcomes this barrier to gain access to the center of the cell. Now we know that HIV triggers the mimicking of a cell process that activates cofilin, which cuts and modifies the cortical actin cytoskeleton and permits the virus to cross it."

Wu notes that the goal of his research was to attain a fundamental understanding of how the virus interacts with cells and the immune system in order to identify new ways to treat the disease. There is still much basic research left to be conducted before the findings from this study produce a clinical benefit. However, he believes that this discovery may later be used to develop a new treatment that could block viral interaction with, or viral alteration of, the cortical actin cytoskeleton.

Specifically, they show, binding of HIV to the receptor known as CXCR4 activates cofilin, a protein that disassembles actin microfilaments in the resting T cells. Those actin microfilaments are important building blocks of the cytoskeleton. That process is a required step for the virus to infect those resting cells, suggesting it may provide a useful new target for therapy, the researchers said.

" The ability of co-receptor engagement to alter intracellular biochemistry suggests that exposure of cells to HIV may in fact prime cells for HIV infection," said Wu and Jon Marsh of the National Institute of Mental Health. This first identification of the necessity of receptor signaling for infection also suggests "that HIV's evolved selection of co-receptors is borne out of necessity."

In fact, the disassembly of actin microfilaments might actively assist HIV's entry into the nucleus, Wu added. "When actin is cut, it grows back. That process may carry the virus from the cortical actin to inside the nucleus."

" It's probably not just the breakdown of actin," Marsh agreed. Rather, he said, the rearrangement of actin may actively permit HIV's transport to the nucleus. In support of that notion they found that complete actin breakdown hinders the virus's ability to infect.

Earlier studies had shown that HIV relies on two CD4 coreceptors on the surface of T cells, CCR5 and CXCR4. CCR5 is expressed on activated, memory T cells where it plays a critical role in the susceptibility to HIV infection.

On the other hand, infection of resting T cells via CXCR4 seemed a more restricted process. Yet, in nearly one-half of the HIV-infected population, there is a conversion late in the disease to CXCR4 utilization, corresponding to an accelerated drop in T cell numbers, the researchers said.

Evidence had surfaced suggesting that the ability of HIV to establish itself in resting T cells, albeit slowly, is not purely passive, the researchers noted. Rather, studies had hinted that HIV may alter the cellular environment to facilitate infection and subsequent viral production. The new findings confirm that notion.

HIV's newfound ability to rearrange the cytoskeleton of resting T cells with the help of cofilin may not be necessary in active memory T cells, Wu explained. That's because cells that are actively cycling and migrating disassemble elements of the cytoskeleton themselves, leaving them naturally more susceptible to HIV's entry.

" This is the first time we've been aware of cofilin's activity in HIV infection of resting CD4 T cells," Wu said. Further study is required to identify exactly how the virus interacts to effect this change in cells and to further explore its potential as a target for treatment.

" This shows how much more we can learn," Marsh added. "HIV has evolved to utilize a great number of normal cellular processes. This is just another one."

The researchers include Alyson Yoder, George Mason University, Manassas, VA; Dongyang Yu, George Mason University, Manassas, VA; Li Dong, George Mason University, Manassas, VA Subashini R. Iyer, George Mason University, Manassas, VA Xuehua Xu, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; Jeremy Kelly, George Mason University, Manassas, VA Juan Liu, George Mason University, Manassas, VA Weifeng Wang, George Mason University, Manassas, VA Paul J. Vorster, George Mason University, Manassas, VA Liane Agulto, George Mason University, Manassas, VA David A. Stephany, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; James N. Cooper, George Mason University, Manassas, VA Jon W. Marsh, National Institute of Mental Health, Bethesda, MD; and Yuntao Wu, George Mason University, Manassas, VA, National Institute of Mental Health, Bethesda, MD.