HIV-1 Establishes “Sanctuary Site” In the Testis by Disrupting Blood-Testis Barrier Function

HIV-1, the most common type of human immunodeficiency virus, invades the testis and is able to avoid combination antiretroviral (cART) drugs by permeating the blood-testis barrier (BTB) and perturbing BTB function, potentially through the Tat protein, according to a study recently published in Endocrinology.

Researchers led by C. Yan Cheng, PhD, senior scientist at The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, and Population Council at Rockefeller University in New York, point out that little is known about how HIV-1 crosses the BTB. However, HIV-1 encodes a trans-activating regulatory protein (Tat), used for efficient transcription of the viral genome. Tat can be released by infected cells in culture and is found in the blood of patients with HIV-1.

“Importantly, HIV-1-Tat contains a protein transduction domain (PTD), known as a cell-penetration peptide, capable of permeating and altering the blood-brain barrier (BBB), and thereby facilitating the entry of HIV-1 into the brain,” the authors write. “It was shown that Tat may permeate the BBB through a down-regulation of the expression of tight junction (TJ) proteins, such as claudin 5.”

For this study, the researchers used a two-prong approach: First, they looked to see whether recombinant Tat protein could perturb the BTB by using the primary rat Sertoli cell in vitro model that mimics the BTB in vivo. Then, they used HIV-1 infected cells to determine how HIV-1 affected co-cultured Sertoli cells.

The researchers found that HIV-1 penetrates the Sertoli cell BTB by using the Tat protein. The researchers also write that it is likely that HIV-1 also compromises the spatiotemporal expression of actin-, MT-, and possibly vimentin- and septin-based regulatory proteins, which in turn perturb the corresponding cytoskeletal organization. These changes thus destabilize the Sertoli cell barrier function, facilitating the entry of the HIV-1 into the adluminal compartment.

The authors end the paper with a call to action, particularly into the effects of administering antiretroviral drugs along with the recently discovered endogenous bioactive peptides produced locally from the structural proteins across the seminiferous epithelium in the testis. Since these peptides are known to perturb the BTB function transiently, the authors write, they could enhance drug permeation across the BTB. “Their combined use at the onset of cART can be an option to eradicate HIV-1 from its sanctuary site in the testis,” they conclude.

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