Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent

Khanna, Kristen V.; Whaley, Kevin J.; Zeitlin, Larry; Moench, Thomas R.; Mehrazar, Karim; Cone, Richard A.; Liao, Zhaohao; Hildreth, James E. K.; Hoen, Timothy E.; Shultz, Leonard D.; Markham, Richard B.

doi:10.1172/jci0213236

Cited by 107 publications

(88 citation statements)

References 38 publications

(37 reference statements)

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“…We found that both monocytes and PBLs were able to migrate through the epithelial monolayer and were found in the basal chamber of the Transwell. These in vitro data are consistent with our findings in vivo (5), which show that cells introduced vaginally into HuPBL-SCID mice migrate across the intact reproductive epithelium and can be found in regional lymph nodes within 4 h. The data are also consistent with in vitro findings from Phillips et al demonstrating that monocytes can cross cervical epithelial tissue by migrating between cells (32).…”

Section: Discussionsupporting

confidence: 93%

“…To determine the extent to which ICAM-1 is involved in the process of vaginal HIV-1 transmission in vivo, we administered anti-ICAM-1 Abs to HuPBL-SCID mice exposed vaginally to HIV-1-infected PBMCs as described (5). Briefly, anti-ICAM-1 or appropriate isotype control Abs (0.4 g in 10 l of PBS with 1% BSA) were administered vaginally followed 5 min later by 1 ϫ 10 6 human PBMCs, of which between 1 and 5% were infected with HIV-1 Ba-L as determined by LD-PCR.…”

Section: Anti-icam-1 Abs Inhibit Transepithelial Transmission Of Cellmentioning

confidence: 99%

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Lactobacilli-Expressed Single-Chain Variable Fragment (scFv) Specific for Intercellular Adhesion Molecule 1 (ICAM-1) Blocks Cell-Associated HIV-1 Transmission across a Cervical Epithelial Monolayer

Chancey

Khanna

Seegers

et al. 2006

The Journal of Immunology

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The vaginal and cervical epithelia provide an initial barrier to sexually acquired HIV-1 infection in women. To study the interactions between HIV-1-infected cells or cell-free HIV-1 and the reproductive epithelium, the transmission of HIV-1 by infected cells or cell-free virus across human cervical epithelial cells was examined using a Transwell culture system. Cell-associated HIV-1 was transmitted more efficiently than cell-free virus, and monocyte-associated virus was transmitted most efficiently. Abs to ICAM-1 added to the apical side of the epithelium blocked cell-mediated transepithelial HIV-1 transmission in vitro. When used in a previously described model of vaginal HIV-1 transmission in human PBL-SCID mice, anti-murine ICAM-1 Abs (0.4 μg/10 μl) also blocked vaginal transmission of cell-associated HIV-1 in vivo. To evaluate a candidate delivery system for the use of this Ab as an anti-HIV-1 microbicide, anti-ICAM single-chain variable fragment Abs secreted by transformed lactobacilli were evaluated for their protective efficacy in the Transwell model. Like the intact Ab and Fab derived from it, the single-chain variable fragment at a concentration of 6.7 μg/100 μl was able to reduce HIV-1 transmission by 70 ± 5%. These data support the potential efficacy of an anti-ICAM Ab delivered by lactobacilli for use as an anti-HIV-1 microbicide.

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Section: Discussionsupporting

confidence: 93%

Section: Anti-icam-1 Abs Inhibit Transepithelial Transmission Of Cellmentioning

confidence: 99%

Lactobacilli-Expressed Single-Chain Variable Fragment (scFv) Specific for Intercellular Adhesion Molecule 1 (ICAM-1) Blocks Cell-Associated HIV-1 Transmission across a Cervical Epithelial Monolayer

Chancey

Khanna

Seegers

et al. 2006

The Journal of Immunology

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“…In addition, ␤-cyclodextrin, a compound analogous to M␤CD and which selectively extracts cholesterol from plasma membranes, has been shown to cause hypolipidemic effects in genetically hypercholesterolimic rats when fed orally [35]. Very recently, topical application of ␤-cyclodextrin has been shown to block the transmission of cell-associated HIV-1 [36]. This is based on earlier observations on the involvement of cholesterol in the infection of HIV type 1 [30,31].…”

Section: Discussionmentioning

confidence: 99%

Cholesterol is required for Leishmania donovani infection: implications in leishmaniasis

Pucadyil

Tewary

Madhubala

et al. 2004

Molecular and Biochemical Parasitology

108

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“…BCD has been given intravaginally to mice at a 3% concentration in PBS (10), to rabbits at a 5% concentration in a gel formulation (5), and to women at 70% concentration in a gel formulation daily for 1 month (J. E. K. Hildreth, unpublished results) without pathological effects. To better understand the effects of short-term BCD exposure on individual cell types, we tested the toxicity of a 2-hour incubation with BCD on three cell lines: Caco-2, a human intestinal epithelial cell line; GHOST-Hi5, derived from human osteosarcoma cells; and HeLa, a human cervical epithelial cell line (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…BCD (3%) in phosphate-buffered saline (PBS) was shown to efficiently inhibit intravaginal transmission of cell-associated HIV-1 in a SCID-Hu mouse model of infection (10). Other attractive microbicidal characteristics of BCD were its high solubility in water, its lack of color or odor, and its low cost.…”

mentioning

confidence: 99%

Incomplete Protection against Simian Immunodeficiency Virus Vaginal Transmission in Rhesus Macaques by a Topical Antiviral Agent Revealed by Repeat Challenges

Ambrose

Compton

Piatak

et al. 2008

J Virol

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The rising prevalence of human immunodeficiency virus type 1 (HIV-1) infection in women, especially in resource-limited settings, accentuates the need for accessible, inexpensive, and female-controlled preexposure prophylaxis strategies to prevent mucosal transmission of the virus. While many compounds can inactivate HIV-1 in vitro, evaluation in animal models for mucosal transmission of virus may help identify which approaches will be effective in vivo. Macaques challenged intravaginally with pathogenic simian immunodeficiency virus (SIV mac251 ) provide a model to preclinically evaluate candidate microbicides. 2-Hydroxypropyl-␤-cyclodextrin (BCD) prevents HIV-1 and SIV infection of target cells at subtoxic doses in vitro. Consistent with these findings, intravaginal challenge of macaques with SIV mac251 preincubated with BCD prevented mucosal transmission, as measured by plasma viremia and antiviral antibodies, through 10 weeks postchallenge. In an initial challenge, BCD applied topically prior to SIV mac251 prevented intravaginal transmission of virus compared to controls (P < 0.0001). However, upon a second virus challenge following BCD pretreatment, the majority of the previously protected animals became infected. The mechanism through which animals become infected at a frequency similar to that of controls after prior exposure to BCD and SIV mac251 in subsequent intravaginal virus challenges (P ‫؍‬ 0.63), despite the potent antiviral properties of BCD, remains to be determined. These results highlight the unpredictability of antiviral compounds as topical microbicides and suggest that repeated exposures to candidate treatments should be considered for in vivo evaluation.

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Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent

Cited by 107 publications

References 38 publications

Lactobacilli-Expressed Single-Chain Variable Fragment (scFv) Specific for Intercellular Adhesion Molecule 1 (ICAM-1) Blocks Cell-Associated HIV-1 Transmission across a Cervical Epithelial Monolayer

Lactobacilli-Expressed Single-Chain Variable Fragment (scFv) Specific for Intercellular Adhesion Molecule 1 (ICAM-1) Blocks Cell-Associated HIV-1 Transmission across a Cervical Epithelial Monolayer

Cholesterol is required for Leishmania donovani infection: implications in leishmaniasis

Incomplete Protection against Simian Immunodeficiency Virus Vaginal Transmission in Rhesus Macaques by a Topical Antiviral Agent Revealed by Repeat Challenges

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