Inhibitory Effect of PRO 2000, a Candidate Microbicide, on Dendritic Cell-Mediated Human Immunodeficiency Virus Transfer

Abstract

Without an effective vaccine against human immunodeficiency virus (HIV) infection, topical microbicide development has become a priority. The sulfonated polyanion PRO 2000, a candidate topical microbicide now in phase II/III clinical trials, blocks HIV infection of cervical tissue in vitro. Dendritic cells (DC) are among the first cell types to contact HIV in the genital tract and facilitate the spread of the virus. Thus, interfering with virus-DC interactions is a desirable characteristic of topical microbicides as long as that does not interfere with the normal function of DC. PRO 2000 present during capture of the replication-defective HIVJRFL reporter virus or replication-competent HIVBaL by monocyte-derived DC (MDDC) inhibited subsequent HIV transfer to target cells. Continuous exposure to PRO 2000 during MDDC-target cell coculture effectively inhibited HIV infection of target cells. PRO 2000 inhibited HIV capture by MDDC. In addition, the compound blocked R5 and X4 HIV envelope-mediated cell-cell fusion. Interestingly, simultaneous exposure to PRO 2000 and lipopolysaccharide attenuated the cytokine production in response to stimulation, suggesting that the compound altered DC function. While efficient blocking of MDDC-mediated virus transfer and infection in the highly permissive MDDC-T-cell environment reinforces the potential value of PRO 2000 as a topical microbicide against HIV, the impact of PRO 2000 on immune cell functions warrants careful evaluation.

Targeting Trojan Horse leukocytes for HIV prevention

“…Other compounds that may act against HIV binding or entry include cyanovirin-N and sulfonamide derivatives [225]. However, the entry inhibitor that has undergone the greatest level of clinical evaluation is PRO2000, a highly sulfated polyanion [293–295] that was associated with a modest 30% reduction in HIV transmission in HPTN 035 [278] and is being studied in a larger efficacy trial conducted by the UK Medical Research Council in east Africa. If the study findings corroborate HPTN 035, it will be the first demonstration of topical microbicide efficacy for HIV prevention.…”

Vaccines and Microbicides Preventing HIV-1, HSV-2, and HPV Mucosal Transmission

“…These results are encouraging because they suggest some efficacy of a microbicide in clinical cohorts. In addition to its role in preventing HIV-1 attachment, PRO 2000 was recently reported to inhibit DC-CD4 þ T-cell transmission (Teleshova et al, 2008).…”

A look at HIV journey

“…Recent candidate microbicides, like PRO2000, were shown to potently block dendritic cell-mediated HIV transfer and infection in the highly permissive dendritic cell-T-cell environment [44]. Microbicidal agents can be designed to target viral or cellular components and, recently, entry inhibitors targeting the viral envelope (BMS-C and T-1249) or CCR5 (CMPD167) at the surface of dendritic cell were proven to efficiently block HIV infection in dendritic cell-T-cell co-cultures [45].…”