Hormonal synchronization of the menstrual cycles of pigtail macaques to facilitate biomedical research including modeling HIV susceptibility

Livingston, Lindsay Adamson; Sweeney, Elizabeth; Mitchell, James; Luo, Wei; Paul, Katherine; Powell, Nathaniel; Hendry, R. Michael; McNicholl, Janet M.; Kersh, Ellen N.

doi:10.1111/j.1600-0684.2010.00465.x

Cited by 12 publications

(16 citation statements)

References 10 publications

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“…Menstrual cycling was monitored by visual observation and plasma progesterone 18 . Visual observations were recorded on every weekday throughout, and included menstrual blood and perineal tumescence (“sex skin swelling”, documented in 23 ). Plasma progesterone and MPA were measured at the Wisconsin National Primate Research Center, as previously described 18 .…”

Section: Methodsmentioning

confidence: 99%

A Depot Medroxyprogesterone Acetate Dose That Models Human Use and Its Effect on Vaginal SHIV Acquisition Risk

Butler

Ritter

Ellis

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Introduction Hormonal contraception with DMPA may increase HIV acquisition risk, but observational human studies are inconclusive, and animal models can help investigate this risk. Here we test the impact of a low DMPA dose, designed to resemble human contraceptive use, on SHIV acquisition risk in pigtail macaques (Macaca nemestrina). Methods Macaques metabolize DMPA faster than humans. We previously identified a per-weight DMPA dose and administration frequency that achieves long-lasting suppression of ovulation in macaques. Eight macaques were given 1.5 mg/kg DMPA monthly, while eleven were untreated controls. For comparison, women receive 150 mg (approximately 2 mg/kg) every 3 months. We exposed monkeys to 20 sub-optimal SHIV challenges, designed to slowly infect half of controls and allow increased infection in the DMPA group. Results It took a median 5.5 viral challenges to infect DMPA-treated macaques, and 9 challenges for controls (p=0.27; exact conditional logistic regression). The exact odds ratio was 2.2 (CI 0.6 – 8.3). Ovulation was suppressed, and the vaginal epithelium was thinned after DMPA-treatment in all animals (mean 30 and 219 micrometers in DMPA-treated and control macaques, respectively, p=0.03, t-test using the Satterthwaite degrees-of-freedom approximation). Conclusions SHIV infections in DMPA treated macaques were 2.2 times those of controls, but this was not statistically significant. The result is remarkably similar to studies of human DMPA use, which have shown HIV risk increases of a similar magnitude and of variable significance. Taken together with previous studies of higher DMPA doses in macaques, the results suggest a dose-dependent effect of DMPA on SIV or SHIV acquisition.

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Section: Methodsmentioning

confidence: 99%

A Depot Medroxyprogesterone Acetate Dose That Models Human Use and Its Effect on Vaginal SHIV Acquisition Risk

Butler

Ritter

Ellis

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…We used a repeated-low-dose vaginal challenge macaque model. This model has several advantages, including the use of female pigtail macaques, which have a menstrual cycle and vaginal anatomy similar to those of women, an inoculum dose with viral RNA levels in the range similar to those detected in seminal fluid, twice-weekly challenges to mimic highrisk human exposure, and a SHIV-162p3 inoculum which constitutes an R5-tropic envelope similar to that of most transmitted HIV (14,22). We performed detailed PK analysis of intracellular TFV-DP drug levels in vaginal lymphocytes over time to better understand the relationship between tissue drug levels and protective efficacy.…”

mentioning

confidence: 99%

Durable Protection from Vaginal Simian-Human Immunodeficiency Virus Infection in Macaques by Tenofovir Gel and Its Relationship to Drug Levels in Tissue

Dobard

Sharma

Martin

et al. 2012

J Virol

100

117

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A vaginal gel containing 1% tenofovir (TFV) was found to be safe and effective in reducing HIV infection in women when used pericoitally. Because of the long intracellular half-life of TFV and high drug exposure in vaginal tissues, we hypothesized that a vaginal gel containing TFV may provide long-lasting protection. Here, we performed delayed-challenge experiments and showed that vaginal 1% TFV gel protected 4/6 macaques against vaginal simian-human immunodeficiency virus (SHIV) exposures occurring 3 days after gel application, demonstrating long-lasting protection. Despite continued gel dosing postinfection, neither breakthrough infection had evidence of drug resistance by ultrasensitive testing of SHIV in plasma and vaginal lavage. Analysis of the active intracellular tenofovir diphosphate (TFV-DP) in vaginal lymphocytes collected 4 h to 3 days after gel dosing persistently showed high TFV-DP levels (median, 1,810 fmol/10 6 cells) between 4 and 24 h that exceed the 95% inhibitory concentration (IC 95 ), reflecting rapid accumulation and long persistence. In contrast to those in peripheral blood mononuclear cells (PBMCs) following oral dosing, TFV-DP levels in vaginal lymphocytes decreased approximately 7-fold by 3 days, exhibiting a much higher rate of decay. We observed a strong correlation between intracellular TFV-DP in vaginal lymphocytes, in vitro antiviral activity, and in vivo protection, suggesting that TFV-DP above the in vitro IC 95 in vaginal lymphocytes is a good predictor of high efficacy. Data from this model reveal an extended window of protection by TFV gel that supports coitus-independent use. The identification of protective TFV-DP concentrations in vaginal lymphocytes may facilitate the evaluation of improved delivery methods of topical TFV and inform clinical studies. Human immunodeficiency virus (HIV) continues to spread primarily through heterosexual routes, with women being disproportionately infected in many parts of the world (30, 35). While condoms have been shown to be one of the most reliable methods for preventing HIV transmission, such interventions are often limited by adherence and the ability of women to negotiate their use (24, 37). In the absence of an effective HIV vaccine, increasing efforts have been made toward developing vaginal gels formulated with antiretroviral (ARV) drugs, as a femalecontrolled option for women to protect themselves against HIV acquisition (10,21,33,37).Topical gels containing tenofovir (TFV), a nucleotide analogue reverse transcriptase inhibitor, have recently shown great promise against vaginal HIV transmission. Results of the CAPRISA 004 trial demonstrated for the first time that women who used a vaginal gel containing 1% TFV were 39% less likely overall to contract HIV than those who used a placebo gel (1). The trial evaluated a coitus-dependent before-and-after (BAT) modality, with one gel application administered up to 12 h before sex followed by a second gel application up to 12 h after sex. Importantly, effectiveness was found to be dependen...

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“…In PTM, we have shown that a desogestrel and ethinyl estradiol combined oral contraceptive (administered orally) suppress progesterone and estradiol. 40 MPA, given by injection, also suppresses progesterone and estradiol in PTM 47,48 (and E. Kersh, unpublished observations). Finding the human-equivalent dose of exogenous hormones requires extensive pharmacokinetic and pharmacodynamic studies over several months, using a combination of measures including levels of proges- terone and estradiol and vaginal thinning.…”

Section: Types Of Non-human Primate Models For Studying How Hormonal mentioning

confidence: 81%

“…Table I indicates other features of RM and PTM macaque models that may be relevant in studies of HC and HIV susceptibility. Menstrual cycle synchronization of a group of macaques, often used to facilitate breeding in agricultural animals, can be induced using shortterm hormonal contraception, as we have shown in PTM 40 and can be carried out in RM (M. Lewis, personal communication). Animals then continue on synchronized cycles for months in the absence of any exogenous reproductive hormone.…”

Section: Types Of Non-human Primate Models For Studying How Hormonal mentioning

confidence: 99%

Non‐Human Primate Models of Hormonal Contraception and HIV

McNicholl

Henning

Vishwanathan

et al. 2014

American J Rep Immunol

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Hormonal synchronization of the menstrual cycles of pigtail macaques to facilitate biomedical research including modeling HIV susceptibility

Abstract: Progesterone and estradiol combination therapy can be used in pigtail macaques to induce synchronized cycling that persists in the absence of on-going hormone treatments.

Cited by 12 publications

References 10 publications

A Depot Medroxyprogesterone Acetate Dose That Models Human Use and Its Effect on Vaginal SHIV Acquisition Risk

A Depot Medroxyprogesterone Acetate Dose That Models Human Use and Its Effect on Vaginal SHIV Acquisition Risk

Durable Protection from Vaginal Simian-Human Immunodeficiency Virus Infection in Macaques by Tenofovir Gel and Its Relationship to Drug Levels in Tissue

Non‐Human Primate Models of Hormonal Contraception and HIV

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