Advances in HIV Microbicide Development

Abstract

There is an urgent need for a way to control the spread of the global HIV pandemic. A microbicide, or topical drug applied to the mucosal environment to block transmission, is a promising HIV prevention strategy. The development of a safe and efficacious microbicide requires a thorough understanding of the mucosal environment and it's role in HIV transmission. Knowledge of the key events in viral infection identifies points at which the virus might be most effectively targeted by a microbicide. The cervicovaginal and rectal mucosa play an important role in the innate defense against HIV, and microbicides must not interfere with these functions. In this review we discuss the current research on HIV microbicide development.

Evaluation of PD 404,182 as an Anti-HIV and Anti-Herpes Simplex Virus Microbicide

“…Four major types of vaginal HIV microbicides have been developed with various degrees of clinical success: surfactants, entry inhibitors, vaginal milieu protectors, and reverse transcriptase inhibitors (6). Surfactants nonspecifically disrupt membranes and were the first molecules to enter clinical trials as candidate HIV microbicides.…”

“…As a gauge of compound stability, we determined the antiviral activity of PD after storage under different conditions for different periods of time. PD was diluted in buffered DPBS (pH 4,6,8,10) or cervical fluids (a pool of fluids from 3 donors 5-fold diluted in DPBS; Lee Biosolutions, St. Louis, MO) to achieve a final concentration of 30 M. DPBS was buffered to the desired pH using hydrochloric acid or sodium hydroxide. Diluted drug was incubated at the desired temperature for 0, 8, 24, or 48 h. After the temperature incubation, the drug mixture was further diluted to 1, 0.1, and 0.05 M in complete growth medium and used for incubation with VSV-G lentiviral pseudoparticles (VSV-Gpp; harboring either pTRIP-Gluc or NL4-3.Luc viral supernatant diluted 500-fold in complete growth medium) at 37°C for 30 min.…”

“…This issue becomes more significant when the drug is used on a large scale, generating an extra incentive to identify new and specific anti-HIV microbicidal compounds with unique modes of action. In addition, a recently completed comprehensive HIV prevention trial among African women known as VOICE (Vaginal and Oral Interventions to Control the Epidemic) involving tenofovir failed to provide protection against HIV, underscoring the need for additional HIV prevention options that incentivize patient usage and adherence (6).…”

“…An ideal anti-HIV microbicide should fulfill most or all of the following criteria: (i) inhibit transmission of wild-type and drug-resistant virus (6); (ii) be stable and potent in seminal fluids and vaginal secretions; (iii) lack toxicity to the vaginal epithelium and commensal bacterial flora; (iv) be able to interfere with multiple transmission modes (e.g., as cell-free virus versus cell-associated virus), given the unknowns in the exact mode of HIV transmission in vivo; (v) possess a high genetic barrier to resistance development; (vi) preferably act through a mode of action distinct from the modes of action of existing therapeutics (7); and (vii) lack proinflammatory activity and immunotoxicity. The last consideration derives from the presence of rare preexisting drug-resistant viral variants, as well as drug-resistant HIV variants, from patients who underwent previous antiretroviral treatment that can bypass the microbicidal barrier and transmit to target cells.…”

“…The last consideration derives from the presence of rare preexisting drug-resistant viral variants, as well as drug-resistant HIV variants, from patients who underwent previous antiretroviral treatment that can bypass the microbicidal barrier and transmit to target cells. Most current anti-HIV microbicide candidates in clinical trials are formulated on the basis of existing antiretroviral drugs and target well-studied viral proteins such as HIV protease (PR), reverse transcriptase, and HIV envelope protein (Env) (6)(7)(8)(9)(10). In the CAPRISA 004 clinical trial involving 1% tenofovir gel, HIV type 1 (HIV-1) acquisition was reduced by ϳ38% in all woman and by 54% in woman who used the gel 80% or more of the time (11).…”