Human Immunodeficiency Virus Type I HIV1

The human immunodeficiency virus type I (HIV-1) has developed several strategies to condition the host environment to promote viral replication and spread. Viral proteins have evolved to perform multiple functions, aiding in the replication of the viral genome and modulating the cellular response to the infection (1). MicroRNAs (miRNAs) are a class of small, non-coding RNAs, 19-24 nucleotides in length that bind to host mRNAs and regulate protein expression by mostly by binding through complementary binding sites located primarily at the 3?UTR of mRNAs (2).

While several viruses have been shown to encode for viral miRNAs, controversy persists over the expression of a functional miRNA encoded in the human immunodeficiency virus type 1 (HIV-1) genome (3). Previous studies have shown that the HIV-1 Tat, a non-structural viral protein is secreted by infected cells adversely affects BMVECs. HIV-1 proteins Tat and gp120 both directly damage the BBB by:

a) altering the expression and distribution of tight junction proteins (claudins & occludins) (4).

b) Transfecting Tat onto HBMECs up-regulates matrix metallopeptidase-9 (MMP-9) causing an increase in the permeability of brain endothelial cells by degrading occludins.

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c) causes dysregulation of nitric oxide production in brain endothelial cells

d) modulating the expression of miRNAs in neuronal cells (5).

The CNS is protected by the blood-brain barrier (BBB). The BBB is composed of human brain microvascular endothelial cells (BMVECs) supported by astrocytic end feet and pericytes. The barrier properties of BMVECs are due to tight junction proteins (TJPs) and adherens junction proteins (AJPs). TJPs mainly include claudins, occludins, and zona occludens (ZO).

VE-cadherin, an endothelial cell-specific transmembrane AJP is also known to coordinate endothelial growth, TJ organization, and permeability (6).

An understanding of the importance of miRNAs in the blood brain barrier integrity is emerging. Recent studies revealed that miRNAs play a critical role in controlling the function of the endothelial barrier of the brain under various conditions (7). Exosomal secretion of mirnas has also been known as an extremely efficient pathway of glia-neuron communications and astrocytes uses this delivery mechanism for the provision of neurotrophic factors and danger-associated molecular patterns to neurons (8).

HIV-1 crosses the BBB during the early course of infection and infects resident brain macrophages/microglia. The predominant route of CNS exposure to HIV-1 is through peripheral blood monocytic cells/macrophages that have been infected by virus and transmigrate across the BBB [9]. Peripheral blood monocytes are categorized into:

• classical "resting" monocytes that express only CD14 (CD14++CD16-),
• intermediate monocytes that maintain high levels of CD14, while gaining CD16 positivity (CD14++ CD16+)
• non-classical "activated" monocytes that express high CD16 levels and lower levels of CD14 (CD14+CD16++).

CD16++ monocytes are more susceptible to HIV infection.

Infected CD16++ monocytes have been shown to transmigrate more efficiently across the BBB in response to a chemokine. While CD4+ T lymphocytes have been suggested to play a role in trafficking HIV into the CNS, most HIV-1 isolates derived from CNS tissue appear to macrophage-tropic.