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A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice.

Neff CP, Kurisu T, Ndolo T, Fox K, Akkina R - PLoS ONE (2011)

Bottom Line: Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field.Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus.Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.

ABSTRACT
For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field.

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CD4 T cell decline in non-treated vaginally challenged mice in contrast to mice protected with maraviroc gel.Levels of CD4 T cells were monitored on a weekly by FACS basis to determine their decline in treated versus non-treated mice. Baseline values for each of the mice were established prior to infection as described in Methods.
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pone-0020209-g003: CD4 T cell decline in non-treated vaginally challenged mice in contrast to mice protected with maraviroc gel.Levels of CD4 T cells were monitored on a weekly by FACS basis to determine their decline in treated versus non-treated mice. Baseline values for each of the mice were established prior to infection as described in Methods.

Mentions: A typical finding in HIV-1 infected humanized mice is a gradual CD4 T cell loss as seen in the human. Although the PCR data demonstrated no viral infection in maraviroc treated mice, we further evaluated the virus challenged mice for any evidence of CD T cell loss to confirm lack of any HIV associated pathology [20], [29]. Peripheral blood was collected bi-weekly and subjected to FACS analysis. To establish a baseline, CD4 T cell levels were measured prior to viral challenge for each of the experimental mice and later compared to the levels determined post-viral challenge. While there was a clear pattern of CD4 T cell decline in placebo-gel treated and viral challenged mice, their levels were stable in mice receiving maraviroc gel (Fig. 3) further validating the prevention of HIV-1 transmission in these mice.


A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice.

Neff CP, Kurisu T, Ndolo T, Fox K, Akkina R - PLoS ONE (2011)

CD4 T cell decline in non-treated vaginally challenged mice in contrast to mice protected with maraviroc gel.Levels of CD4 T cells were monitored on a weekly by FACS basis to determine their decline in treated versus non-treated mice. Baseline values for each of the mice were established prior to infection as described in Methods.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105981&req=5

pone-0020209-g003: CD4 T cell decline in non-treated vaginally challenged mice in contrast to mice protected with maraviroc gel.Levels of CD4 T cells were monitored on a weekly by FACS basis to determine their decline in treated versus non-treated mice. Baseline values for each of the mice were established prior to infection as described in Methods.
Mentions: A typical finding in HIV-1 infected humanized mice is a gradual CD4 T cell loss as seen in the human. Although the PCR data demonstrated no viral infection in maraviroc treated mice, we further evaluated the virus challenged mice for any evidence of CD T cell loss to confirm lack of any HIV associated pathology [20], [29]. Peripheral blood was collected bi-weekly and subjected to FACS analysis. To establish a baseline, CD4 T cell levels were measured prior to viral challenge for each of the experimental mice and later compared to the levels determined post-viral challenge. While there was a clear pattern of CD4 T cell decline in placebo-gel treated and viral challenged mice, their levels were stable in mice receiving maraviroc gel (Fig. 3) further validating the prevention of HIV-1 transmission in these mice.

Bottom Line: Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field.Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus.Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.

ABSTRACT
For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field.

Show MeSH
Related in: MedlinePlus