HIV-1 infection of human penile explant tissue and protection by candidate microbicides

AIDS (post author corrections), 24 December 2008

Fischetti, Luci (a), Barry, Sheila M (b), Hope, Thomas J (b), Shattock, Robin J (a)

(a)Department of Cellular and Molecular Medicine, Centre for infection, St George's University of London, Cranmer Terrace, Tooting, London, UK

(b)Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

ABSTRACT

Objective: Factors governing events between exposure of male genital mucosa surfaces and the establishment of infection are poorly understood. Furthermore, little is known about the safety and efficacy of microbicides on male genital mucosa.

Design: Here we present a novel penile tissue explant model to characterize the mechanisms of HIV-1 infection of male genital tissue and evaluate candidate microbicides.

Methods: Mucosal explant culture conditions were determined for glans, urethra and foreskin obtained from gender reassignment and circumcision. Density and distribution of CD4+ and CD1a+ cells were visualized by microscopy. In vitro HIV-1 infection was determined by measuring p24 release, whereas microbicide biocompatibility and efficacy were assessed by measurement of tissue viability, cytokine expression and p24 production.

Results: Cultured glans and foreskin showed comparable epithelial thickness but some differences in CD4+ and CD1a+ cell density. All tissue sites examined (foreskin, glans, meatus, urethra) were equally susceptible to R5 HIV-1 infection, which was productively disseminated by migratory cells emigrating from tissue. In contrast, X4 HIV-1 failed to infect mucosal tissue and dissemination by migratory cells was less efficient. The three candidate microbicides poly(methyl 2-propionamidoacrylate), PRO 2000 and Cyanovirin-N, showed good tissue compatibility and efficient prevention of HIV-1 infection, causing only minor changes in tissue cytokine profile.

Conclusion: The described model provides a useful model to study the determinants of HIV-1 infection of male genital tissue and is likely to be an important tool for the future development of microbicide candidates and concepts.

(C) 2008 Lippincott Williams & Wilkins, Inc.