NeuroAIDS Vol. 1, No. 2, June 1998
How does HIV-1 cross the blood-brain barrier?
M. Mukhtar and R. J. Pomerantz
Thomas Jefferson University, Division of Infectious Diseases, Philadelphia, Pennsylvania, United States
Address correspondence to:

Q: What is the blood-brain barrier?

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The blood-brain barrier exists at the interface between the bloodstream and central nervous system (CNS) tissues. This barrier mainly consists of microvascular endothelial cells (MVEC), forming tight junctions between neighboring endothelial cells and overlying astrocytic foot processes. Functionally, this structure separates and isolates the micro-environment of the CNS to permit unhampered synaptic activity, essential for neuronal transmission.

Q: Why is it important to study the blood brain barrier in HIV?

Several recent scientific studies demonstrate the presence of HIV-1 in microvascular endothelial cells, as well as other CNS-based elements in vivo. A clinical condition termed acquired immune deficiency syndrome dementia complex (ADC) which leads to neurological impairment has also been demonstrated in many HIV-1-seropositive patients. It has become an established fact that HIV-1 enters the brain after viral exposure leading to clinical dementia, i.e. ADC. The virus can cross the blood-brain barrier either during primary infection or at a later stage. While it is known that neurotropic viruses can get entry into the brain by interaction with the endothelium or by attaching to T-cells and macrophages that migrate to the brain, the exact mechanism by which HIV-1 traverses the blood-brain barrier remains enigmatic. In addition, we need to better understand how and whether therapeutic agents are crossing the blood-brain barrier and killing off virus in the brain.

Q: How does virus get into the CNS?

One of the hypotheses suggests direct infection of microvascular endothelial cells as a major route of entry of the virus into the CNS, followed by replication of the virus in CNS-based cells. As we know that MVEC are the major constituent of the blood-brain barrier, HIV-1 can either cross the barrier by transcellular migration or the infection may alter the tight junction property of MVEC, creating a breach which allows viral entry.

Another hypothesis supports the idea of cell-associated HIV-1 entry into CNS. According to this hypothesis, CD4+ T-cells and monocytes that traffic across the blood-brain barrier potentially transfer the infection to other CNS-based cells. It has also been suggested that certain cytokines, HIV-1 proteins, and a number of cellular factors may induce alterations in the blood-brain barrier creating a breach in the tight junctions of microvascular endothelial cells. This breach helps the virus gain entry into CNS-based cells

Q: What are some of the methods that can be used to study how HIV crosses the blood-brain barrier?

One of the major methods used to answer the above described questions is the procurement of CNS-based cellular elements and the establishment of an in vitro blood-brain barrier mimicking the in vivo system. This could be followed by cell-associated (as well as cell-free virion) infection of the barrier-forming elements, and one could then observe the changes associated with the infection.

This approach can be accomplished by culturing microvascular endothelial cells to 100% confluency on a porous membrane followed by determining whether these cells form tight junctions, analogous to the in vivo situation. The capability of MVECs to form tight junctions in vitro could be assessed by expression of ZO-1 (Zona Occludens-1), a protein specifically associated with tight junctions and intracellular sealing of the adjancent cells in vivo. Formation of tight junctions could be confirmed either by the passage of small molecules, such as radiolabeled sucrose or inulin, or by measurement of transendothelial resistance (TER), when these cells attain 100% confluency. Once the blood-brain barrier has been established, this could be further manipulated to study alterations of the barrier as a result of HIV-1 infection.

Other techniques that can be used to study this question consist of animal models: two such models are the SIV/Macaque model , and possibly, SCID hu mice.

Q: What are some other questions that need to be answered?

Certain strains of HIV-1 may cause productive infection of MVEC, the major portion of the blood-brain barrier, compared with other viral strain. It will be interesting to ask what is the neurotropism of various viral strains? ( Editor's note: this topic will be the focus of a later Q & A section). Also, how are infections with primary isolates different from infections with cloned strains?

What is the role of specific cytokines, chemokine receptors, adhesions molecules, and HIV-1 viral proteins in the transendothelial migration of HIV-1?

What changes are associated with the interaction of HIV-1-infected and uninfected monocytes and lymphocytes and what are the mechanism(s) of cell-associated entry of the virus, as well as the related changes in the blood-brain barrier?

Finally, what are the molecular mechanism(s) related to neurotropic viral strains compared with non-neurotropic viral strains?

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