Enhancement of Human Immunodeficiency Virus Type 1 Replication Is Not Intrinsic to All Polyanion-Based Microbicides

Sonza, Secondo; Johnson, A. Peter; Tyssen, David; Spelman, Tim; Lewis, Gareth R.; Paull, Jeremy Ra; Tachedjian, Gilda

doi:10.1128/aac.00102-09

Cited by 8 publications

(8 citation statements)

References 21 publications

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“…In washout assays, alt -PSMA removal had no effect (enhancement or inhibition) on HIV-1 infection, whereas PSS significantly increased levels of infection relative to infection controls. The results of our previous studies with DS are consistent with previously published studies [29,60,61], which demonstrated that DS could enhance HIV-1 infection in monocyte-derived macrophages but not in CD4+ T lymphocytes [35]. The current experiments demonstrated DS-mediated enhancement in PBMCs but not in P4-CCR5 MAGI cells, presumably due to the inclusion of monocyte-derived macrophages in the former cell population.…”

Section: Discussionsupporting

confidence: 92%

Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1

Pirrone

Passic

Wigdahl

et al. 2012

Virol J

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BackgroundContinued efforts are being directed toward the development of microbicides that will be used to reduce or eliminate the risk of HIV-1 sexual transmission. Unfortunately, clinical trials involving polyanion-containing microbicide formulations, including Carraguard (λ-carrageenan [LC]) and Ushercell (cellulose sulfate [CS]) demonstrated that these products were ineffective and may have, in some circumstances, increased the risk of HIV-1 infection. These findings prompted reassessments of the in vitro activities of these agents to determine whether variables that can affect agent safety and efficacy had been overlooked during preclinical testing. One such variable is product retention and loss following topical application.ResultsIn the present studies involving an HIV-1-susceptible cell line and primary human immune cells, product loss was mimicked by introducing and then removing polyanionic compounds prior to HIV-1 infection. In these in vitro "washout" experiments, LC and CS significantly enhanced HIV-1 infection, despite potent antiviral activity when introduced simultaneously with the virus. The presence and magnitude of this effect were dependent on compound identity and concentration; target cell; interval between compound removal and virus challenge; and coreceptor usage. Levels of enhancement (relative to controls) were considerable, exceeding a 200% increase (CS) in P4-R5 MAGI cells and a 300% increase (LC) in human peripheral blood mononuclear cells.ConclusionsThese studies, which demonstrate significant increases in HIV-1 infection subsequent to application and removal of LC and CS, support plausible explanations for the failures of microbicides formulated from these compounds. Detailed studies are now underway to determine the mechanism responsible for this enhancement effect and to assess the potential contribution of this effect to the clinical failures of these agents.

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Section: Discussionsupporting

confidence: 92%

Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1

Pirrone

Passic

Wigdahl

et al. 2012

Virol J

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“…This ineffectiveness was due to the formation of a semen-derived enhancer of virus infection, which promoted HIV infection in the presence of semen. 47 , 48 Although Sonza et al reported that this enhancement effect is not applicable to all polyanions, 49 it highlighted the importance of performing the effectiveness tests in the presence of semen.…”

Section: Historical Development Of Vaginal Microbicidesmentioning

confidence: 99%

Historical development of vaginal microbicides to prevent sexual transmission of HIV in women: from past failures to future hopes

Notario-Pérez¹,

Ruíz-Caro²,

Veiga-Ochoa³

2017

DDDT

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Infection with human immunodeficiency virus (HIV) remains a global public health concern and is particularly serious in low- and middle-income countries. Widespread sexual violence and poverty, among other factors, increase the risk of infection in women, while currently available prevention methods are outside the control of most. This has driven the study of vaginal microbicides to prevent sexual transmission of HIV from men to women in recent decades. The first microbicides evaluated were formulated as gels for daily use and contained different substances such as surfactants, acidifiers and monoclonal antibodies, which failed to demonstrate efficacy in clinical trials. A gel containing the reverse transcriptase inhibitor tenofovir showed protective efficacy in women. However, the lack of adherence by patients led to the search for dosage forms capable of releasing the active principle for longer periods, and hence to the emergence of the vaginal ring loaded with dapivirine, which requires a monthly application and is able to reduce the sexual transmission of HIV. The future of vaginal microbicides will feature the use of alternative dosage forms, nanosystems for drug release and probiotics, which have emerged as potential microbicides but are still in the early stages of development. Protecting women with vaginal microbicide formulations would, therefore, be a valuable tool for avoiding sexual transmission of HIV.

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“…Some of these polyanions, in contrast to their very good in vitro activity, have failed to demonstrate efficacy in preventing HIV transmission in Phase III clinical trials, as was the case of cellulose sulfate (CS), terminated pre-terminated prematurely in early 2007 [89], and Carraguard [90]. Although some of these polyanion compounds enhance HIV infection, apparently this effect is not related to the nature of the polyanion, but to the assay conditions and therefore cannot be extrapolated [91].…”

Section: Virus Targets N Gp120 Bindersmentioning

confidence: 99%

Hiv Microbicides: State-Of-The-Art and New Perspectives on the Development of Entry Inhibitors

et al. 2010

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Since the discovery of HIV at the beginning of the 1980s, numerous efforts have been devoted to the search of an efficient vaccine. There are at least 25 drugs available for HIV treatment, but no cure is available. The observation that therapy for HIV disease is life long and that these drugs are associated with a number of side effects underlines the need for approaches aimed at preventing rather than treating infection. Additionally, the economic burden of treatment for the HIV infection occupies an increasing share of healthcare expenditure, making current practices likely to become difficult to sustain in the long run. Unfortunately, no effective vaccine for this disease is foreseeable in the near future. Microbicides could be an alternate way to build preventative approaches to HIV infection. Strategies based on preventing the virus from reaching its target cells seem to have some room for development and application. In this review we explore the state-of-the-art of available microbicides, focusing on HIV entry inhibitors. In addition, we discuss new compounds that show anti-HIV activity, which could be effective candidates.

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Enhancement of Human Immunodeficiency Virus Type 1 Replication Is Not Intrinsic to All Polyanion-Based Microbicides

Cited by 8 publications

References 21 publications

Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1

Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1

Historical development of vaginal microbicides to prevent sexual transmission of HIV in women: from past failures to future hopes

Hiv Microbicides: State-Of-The-Art and New Perspectives on the Development of Entry Inhibitors

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