Use of Human Mucosal Tissue to Study HIV-1 Pathogenesis and Evaluate HIV-1 Prevention Modalities

Abstract

The use of human mucosal tissue models is an important tool advancing our understanding of the specific mechanisms of sexual HIV transmission. Despite 30 years of study, major gaps remain, including how HIV-1 transverses the epithelium and the identity of the early immune targets (gate keepers). Because defining HIV-1 transmission in vivo is difficult, mucosal tissue is being used ex vivo to identify key steps in HIV-1 entry and early dissemination. Elucidating early events of HIV-1 infection will help us develop more potent and specific HIV-1 preventatives such as microbicides and vaccines. Mucosal tissue has been incorporated into testing regimens for antiretroviral drugs and monoclonal antibodies. The use of mucosal tissue recapitulates the epithelium and immune cells that would be exposed in vivo to virus and drug. This review will discuss the use of mucosal tissue to better understand HIV-1 pathogenesis and prevention modalities.

MIV-150-Containing Intravaginal Rings Protect Macaque Vaginal Explants against SHIV-RT Infection

“…A recent study defined female genital tract tissue collection procedures for use in the ex vivo challenge assays (49). These approaches are being evaluated in ongoing clinical trials (41). Our data demonstrate that vaginal and cervical tissue PD studies are feasible in macaques.…”

“…However, testing of several products in these models demonstrated some predictability for results in the clinic. In line with lack of efficacy or lack of efficacy and safety concerns in phase 2/3 clinical trials (36)(37)(38), nonoxynol-9 was toxic and Carraguard was safe but only partially effective in cervical explants (39)(40)(41). The 2% PRO 2000 gel arm, but not 0.5% PRO 2000, was halted due to futility in the MDP301 trial (42).…”

The Molecular Characterization of Intestinal Explant HIV Infection Using Polymerase Chain Reaction-Based Techniques

“…7 Furthermore, rectal explant tissues do not need artificial stimulation with IL-2 or PMA for productive infection with HIV-1. 8 Gut-associated lymphoid tissue (GALT) has many components of the lymphatic system including CD4 + /CCR5 + -activated T cells, which are targeted by HIV-1 infection. 9 The gastrointestinal tract is thought to be the site most vulnerable to sexual transmission of HIV-1, exceeding that of the genital mucosa by 10-to 20-fold.…”

Pharmacokinetics of antiretrovirals in mucosal tissue

“…One reason is the lack of consensus on appropriate preclinical models of infection for defining concentration response relationships. The limitations of in vitro and ex vivo models have been reviewed in detail elsewhere (90, 91), but include a lack of tissue architecture and relevant microenvironment, and the use of clinically appropriate virus and viral inoculum.…”