The Future of HIV Prevention: Prospects for an Effective Anti-HIV Microbicide

Nuttall, Jeremy; Romano, Joseph; Douville, Karen; Galbreath, Caroline; Nel, Annaléne; Heyward, William L.; Mitchnick, Mark; Walker, Saul; Rosenberg, Zeda F.

doi:10.1016/j.idc.2007.01.009

Cited by 45 publications

(37 citation statements)

References 61 publications

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“…Heterosexual transmission is the leading route of HIV dissemination (19,33,43); however, presently no method under the control of women is available to prevent transmission (40,48). Therefore, the development of microbicides, topically applied HIV-preventive compounds, represents an attractive protection option for women (1,30,31,48).…”

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confidence: 99%

“…The experience with early broad-spectrum candidate microbicides that have reached phase III clinical trial end points (e.g., nonoxynol-9 and cellulose sulfate) showed that products with moderate or low-level potency against HIV in vitro fail to block viral transmission in clinical trials (2,30,40). Moreover, this early class of microbicides is coitus dependent (e.g., they need to be applied shortly before high-risk contact), and they may damage epithelia upon frequent use (2,40).…”

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confidence: 99%

“…Moreover, this early class of microbicides is coitus dependent (e.g., they need to be applied shortly before high-risk contact), and they may damage epithelia upon frequent use (2,40). Therefore, more specific and potent anti-HIV agents, which may be coitus independent and should be devoid of toxicity, are being sought.…”

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confidence: 99%

“…Therefore, more specific and potent anti-HIV agents, which may be coitus independent and should be devoid of toxicity, are being sought. Basically, all early steps of HIV replication are potential targets (3,40). Since the integration of HIV reverse-transcribed DNA (cDNA) into the cell chromosome is crucial for irreversible and productive infection, integrase (IN) inhibitors (INIs) may be suitable to prevent HIV transmission.…”

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confidence: 99%

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Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Terrazas-Aranda

Herrewege

Hazuda

et al. 2008

Antimicrob Agents Chemother

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Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4؉ T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for microbicide development.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Terrazas-Aranda

Herrewege

Hazuda

et al. 2008

Antimicrob Agents Chemother

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“…As receptive partners, women are twice as likely as their male counterparts to acquire HIV during sex (3). Despite the knowledge of effective prevention strategies, such as the ABC approach (abstinence, be faithful, and use of condoms), the rate of HIV transmission remains high in developing countries (4). Moreover, many women cannot reliably negotiate safe sex practices, leaving them vulnerable to sexually transmitted infections.…”

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confidence: 99%

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

Chamoun‐Emanuelli

Bobardt

Moncla

et al. 2014

Antimicrob Agents Chemother

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؉ T cells, macrophages, and dendritic cells (CC 50 , >300 M). PD also exhibited high stability in pH-adjusted Dulbecco's phosphate-buffered saline with little to no activity loss after 8 weeks at pH 4 and 42°C, indicating suitability for formulation for transportation and storage in developing countries. Finally, for the first time, we show that PD inactivates herpes simplex virus 1 (HSV-1) and HSV-2 at submicromolar concentrations. Due to the prevalence of HSV infection, the ability of PD to inactivate HSV may provide an additional incentive for use as a microbicide. The ability of PD to inactivate both HIV-1 and HSV, combined with its low toxicity and high stability, warrants additional studies for the evaluation of PD's microbicidal candidacy in animals and humans.

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