Henning T.R.,1600 Clifton Rd NE |
Butler K.,1600 Clifton Rd NE |
Hanson D.,1600 Clifton Rd NE |
Sturdevant G.,National Institute of Allergy and Infectious Diseases |
And 9 more authors.
Journal of Infectious Diseases | Year: 2014
Background: Sexually transmitted infections (STIs) are associated with an increased risk of human immunodeficiency virus (HIV) infection, but their biological effect on HIV susceptibility is not fully understood. Methods: Female pig-tailed macaques inoculated with Chlamydia trachomatis and Trichomonas vaginalis (n = 9) or medium (controls; n = 7) were repeatedly challenged intravaginally with SHIVSF162p3. Virus levels were evaluated by real-time polymerase chain reaction, plasma and genital cytokine levels by Luminex assays, and STI clinical signs by colposcopy. Results: Simian/HIV (SHIV) susceptibility was enhanced in STI-positive macaques (P =.04, by the log-rank test; relative risk, 2.5 [95% confidence interval, 1.1-5.6]). All STI-positive macaques were SHIV infected, whereas 3 controls (43%) remained uninfected. Moreover, relative to STI-negative animals, SHIV infections occurred earlier in the menstrual cycle in STI-positive macaques (P =.01, by the Wilcoxon test). Levels of inflammatory cytokines (interferon γ, interleukin 6, and granulocyte colony-stimulating factor [G-CSF]) were higher in STI-positive macaques during STI inoculation and SHIV exposure periods (P ≤.05, by the Wilcoxon test). Conclusions: C. trachomatis and T. vaginalis infection increase the susceptibility to SHIV, likely because of prolonged genital tract inflammation. These novel data demonstrate a biological link between these nonulcerative STIs and the risk of SHIV infection, supporting epidemiological assocations of HIV and STIs. This study establishes a macaque model for studies of high-risk HIV transmission and prevention.
Morris M.,Total Solutions |
Aubert R.D.,Centers for Disease Control and Prevention |
Butler K.,Centers for Disease Control and Prevention |
Henning T.,Centers for Disease Control and Prevention |
And 5 more authors.
Journal of Medical Primatology | Year: 2014
FTY720 has been shown to reduce inflammatory cytokines and immune cells in the genital mucosa of macaques. This pilot study examined the ability of FTY720 to inhibit HIV acquisition. Systemic treatment with FTY720 failed to prevent or delay vaginal SHIV transmission. © 2014 John Wiley & Sons A/S435 October 2014 10.1111/jmp.12120 Short Paper Short Papers Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
Tsuiki A.,Scientific-Atlanta |
Luo W.,NCHHSTP |
Henning T.,NCHHSTP |
Vishwanathan S.,NCHHSTP |
And 10 more authors.
Journal of Medical Primatology | Year: 2013
Background: FTY720 is an immunomodulatory agent that reduces lymphocytes in peripheral tissues and circulation. Such agents may be effective as vaginal microbicides for HIV prevention. Systemic or vaginal application of FTY720 may reduce lymphocyte concentrations in genital tissues, reducing HIV target cell numbers. Methods: Five female pigtail macaques received topical vaginal gel FTY720 (n = 2), intravenous (IV) FTY720 (n = 2), or placebo gel (n = 1) in this pilot study. Circulating and mucosal lymphocytes and genital mucosa, cytokines, and tissue histology were analyzed to document topical and IV FTY720 effects. Results: Topical and IV FTY720 appeared to decrease the levels of cervicovaginal IL-8, IL-1ra, and genital inflammatory cells. Small sample size precluded statistical analysis. Topical administration had no overt adverse effects. Conclusions: This study introduces FTY720 as an immunomodulatory agent for the vaginal mucosa, compares topical effects to those of IV administration, and provides the basis for future studies involving FTY720 for HIV prevention. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.
Dobard C.W.,Centers for Disease Control and Prevention |
Taylor A.,Total Solutions |
Sharma S.,Centers for Disease Control and Prevention |
Anderson P.L.,Aurora Pharmaceutical |
And 9 more authors.
Journal of Infectious Diseases | Year: 2015
Background. Rectal human immunodeficiency virus (HIV) transmission is an important driver of the HIV epidemic. Optimally formulated gels of antiretroviral drugs are under development for preventing rectally acquired HIV. We investigated in a macaque model the pharmacokinetics and efficacy of 3 rectal gel formulations Methods. Single-dose pharmacokinetics of low-osmolar 1% maraviroc (MVC), 1% tenofovir (TFV), or 1% MVC/1% TFV combination gel were evaluated in blood, rectal fluids, colorectal biopsy specimens, and rectal lymphocytes. Efficacy was evaluated over 10 twice-weekly rectal SHIV162p3 challenges in rhesus macaques that received either placebo (n = 7), MVC (n = 6), TFV (n = 6), or MVC/TFV (n = 6) gel 30 minutes before each challenge. Results. MVC and TFV were detected in plasma 30 minutes after gel application and remained above 95% inhibitory concentrations in rectal fluids at 24 hours. MVC, TFV, and TFV diphosphate (TFV-DP) concentrations in colorectal tissues collected up to 30 cm from the anal margin were all high at 2 hours, demonstrating rapid and extended tissue dosing. TFV-DP concentrations in tissue homogenates and rectal lymphocytes were highly correlated (r2 = 0.82). All 3 gel formulations were highly protective (82% efficacy; P. ≤02 by the log-rank test). Conclusions. Desirable pharmacokinetic profiles and high efficacy in this macaque model support the clinical development of these gel formulations for preventing rectal HIV infection. © 2015 The Author.
Morris M.R.,Total Solutions |
Byrareddy S.N.,Emory University |
Villinger F.,Emory University |
Henning T.C.,Centers for Disease Control and Prevention |
And 4 more authors.
Journal of Medical Primatology | Year: 2015
Varying susceptibility during menstrual cycling could be a factor for S(H)IV infection risk in female rhesus macaques. We retrospectively determined vaginal SIV infection time points relative to the menstrual cycle in a group of rhesus macaques (n=11) enrolled in an HIV transmission trial. Eight of nine rhesus macaques became infected around menstruation time. © 2015 John Wiley & Sons A/S.