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

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 characterise 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, while 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 PMPA, 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.

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

“…Such prototypic non-primary R5 and X4 strains have been widely used to test the susceptibility to HIV infection of a range of tissues including the cervix, prostate gland, foreskin, and penis. 26,[31][32][33][34][35] With use of these two strains, we demonstrated that the human seminal vesicles are selectively infected by macrophage-tropic HIV-1 R5 ex vivo and release infectious virions. The R5 SF162 strain consistently replicated in the seminal vesicle tissues, as assessed by increased reverse transcriptase activity in seminal vesicle supernatants during culture, increased level of viral DNA in the explants, PBMC infection by the viral particles recovered from the infected seminal vesicle supernatants, and in situ detection of infected cells in the explants using immunohistochemistry for HIV p24.…”

The TRIM5 Gene Modulates Penile Mucosal Acquisition of Simian Immunodeficiency Virus in Rhesus Monkeys

“…The skin covering the glans and penis in rhesus monkeys is referred to as the prepuce and is similar to the human foreskin. The histologic architecture and populations of potential HIV/SIV target cells in the foreskins of the two species have been shown to be similar (5,7,25,26,29). For this study, we developed a technique of atraumatically exposing the rhesus monkey prepuce and penile mucosa to SIV.…”

The antiviral protein cyanovirin-N: the current state of its production and applications

“…In another preclinical test, CVN and two other microbicide candidates currently in clinical trials, i.e., PRO 2000 and PMPA gel (tenofovir), were evaluated in a novel penile tissue explant model (Fischetti et al 2009). It was found that CVN conferred 95% protection against HIV-1 at 11 μg/ml, which is similar to that seen in cervical explants and is a dose 1/500 of that shown to be protective in macaques.…”

“…In vivo studies with CVN formulated as a gel have shown promising efficacy as a microbicide candidate. In addition, a recent ex vivo test showed that the antiviral effect of CVN is stronger than that of PRO 2000 (Fischetti et al 2009;Huskens et al 2009), a non-specific polyanion microbicide.…”