Last data update: May 20, 2024. (Total: 46824 publications since 2009)
Records 1-12 (of 12 Records) |
Query Trace: Deyounks F [original query] |
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Cabotegravir long-acting protects macaques against repeated penile SHIV exposures
Dobard C , Makarova N , Nishiura K , Dinh C , Holder A , Sterling M , Lipscomb J , Mitchell J , Deyounks F , Garber D , Khalil G , Spreen W , Heneine W , Garcia-Lerma JG . J Infect Dis 2020 222 (3) 391-395 We used a novel penile simian HIV (SHIV) transmission model to investigate if cabotegravir long-acting (CAB LA) prevents penile SHIV acquisition in macaques. Twenty-two macaques were exposed to SHIV via the foreskin and urethra once-weekly for 12 weeks. Of these, six received human-equivalent doses of CAB LA, six received oral FTC/TDF, and 10 were untreated. The efficacy of CAB LA was high (94.4% [95%CI=58.2%-99.3%]) and similar to that seen with oral FTC/TDF (94.0% [95%CI=55.1%-99.2%]). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA PrEP to heterosexual men. |
Efficacy of oral tenofovir alafenamide/emtricitabine combination or single agent tenofovir alafenamide against vaginal SHIV infection in macaques
Massud I , Cong ME , Ruone S , Holder A , Dinh C , Nishiura K , Khalil G , Pan Y , Lipscomb J , Johnson R , Deyounks F , Rooney JF , Babusis D , Park Y , McCallister S , Callebaut C , Heneine W , Garcia-Lerma JG . J Infect Dis 2019 220 (11) 1826-1833 BACKGROUND: Tenofovir alafenamide (TAF)-based regimens are being evaluated for pre-exposure prophylaxis (PrEP). We used a macaque model of repeated exposures to SHIV to investigate if TAF alone or the combination of TAF and emtricitabine (FTC) can prevent vaginal infection. METHODS: Pigtail macaques were exposed vaginally to SHIV162p3 once a week for up to 15 weeks. Animals received clinical doses of FTC/TAF (n=6) or TAF (n=9) orally 24h before and 2h after each weekly virus exposure. Infection was compared with 21 untreated controls. RESULTS: Five of the 6 animals in the FTC/TAF and 4 of the 9 animals in the TAF alone group were protected against infection (p=0.001 and p=0.049, respectively). The calculated efficacy of FTC/TAF and TAF was 91% (95% CI=[34.9%, 98.8%]) and 57.8% [-8.7%, 83.6%]), respectively. Infection in FTC/TAF but not TAF-treated macaques was delayed relative to controls (p=0.005 and p=0.114). Median tenofovir diphosphate (TFV-DP) levels in PBMCs were similar among infected and uninfected macaques receiving TAF PrEP (351 and 143 fmols/106 cells, respectively; p=0.921). CONCLUSIONS: FTC/TAF provided a level of protection against vaginal challenge similar to FTC/tenofovir disoproxil fumarate combination in the macaque model. Our results support the clinical evaluation of FTC/TAF for PrEP in women. |
A nonhuman primate model for rectally transmitted syphilis
Tansey C , Zhao C , Hopkins A , Ritter JM , Fakile YF , Pillay A , Katz SS , Pereira L , Mitchell J , Deyounks F , Kersh EN , McNicholl JM , Vishwanathan SA . J Infect Dis 2018 217 (7) 1139-1144 Among men who have sex with men (MSM), those with a diagnosis of syphilis or other rectal sexually transmitted infections (STIs) are at a higher risk for human immunodeficiency virus acquisition, which is concerning given the large increase in recently reported syphilis cases in the United States. We have developed the first nonhuman primate model for rectally transmitted syphilis by exposing simian/human immunodeficiency virus-infected and naive rhesus macaques to Treponema pallidum in the rectum. All animals showed mucosal lesions, systemic dissemination, and seroconversion (treponemal antibodies). This model would be valuable for studying the manifestations of and interventions for T. pallidum infection, with and without human immunodeficiency virus coinfection. |
Effects of gel volume on pharmacokinetics for vaginal and rectal applications of combination DuoGel-IQB4012, a dual chamber-dual drug HIV microbicide gel, in pigtailed macaques
Pereira LE , Singletary T , Martin A , Dinh CT , Deyounks F , Holder A , McNicholl J , Buckheit KW , Buckheit RWJr , Ham A , Katz DF , Smith JM . Drug Deliv Transl Res 2018 8 (5) 1180-1190 This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP-0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5 ml; following wash-out, 1 or 4 ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24 h. Vaginal and rectal tissue biopsies were collected at 4 and 24 h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 10(4)-10(5) ng/g, 10(5)-10(6) ng/ml, and 10(3)-10(5) ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24 h). Median vaginal TFV concentrations were 1-2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 10(3)-10(5) ng/ml and ~ 10(2)-10(3) ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 10(1)-10(3) ng/g). For 1 ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive. |
Development of a repeat-exposure penile SHIV infection model in macaques to evaluate biomedical preventions against HIV
Garber DA , Mitchell J , Adams D , Guenthner P , Deyounks F , Ellis S , Kelley K , Johnson R , Dobard C , Heneine W , McNicholl J . PLoS One 2018 13 (3) e0194837 Penile acquisition of HIV infection contributes substantially to the global epidemic. Our goal was to establish a preclinical macaque model of penile HIV infection for evaluating the efficacy of new HIV prevention modalities. Rhesus macaques were challenged once or twice weekly with consistent doses of SHIVsf162P3 (a chimeric simian-human immunodeficiency virus containing HIV env) ranging from 4-600 TCID50 (50% tissue culture infective dose), via two penile routes, until systemic SHIV infection was confirmed. One route exposed the inner foreskin, glans and urethral os to virus following deposition into the prepuce (foreskin) pouch. The second route introduced the virus non-traumatically into the distal urethra only. Single-route challenges resulted in dose-dependent rates of SHIV acquisition informing selection of optimal SHIV dosing. Concurrent SHIV challenges via the prepuce pouch (200 TCID50) and urethra (16 TCID50) resulted in infection of 100% (10/10) animals following a median of 2.5 virus exposures (range, 1-12). We describe the first rhesus macaque repeat-exposure SHIV challenge model of penile HIV acquisition. Utilization of the model should further our understanding of penile HIV infection and facilitate the development of new HIV prevention strategies for men. |
A macaque model for rectal lymphogranuloma venereum and non-lymphogranuloma venereum Chlamydia trachomatis: Impact on rectal simian/human immunodeficiency virus acquisition
Vishwanathan SA , Aubert RD , Morris MR , Zhao C , Philips C , Khalil GM , Deyounks F , Kelley K , Ritter JM , Chen CY , Kersh EN , McNicholl JM . Sex Transm Dis 2017 44 (9) 551-556 BACKGROUND: Sustained genital tract inflammation caused by sexually transmitted infections (STIs) is known to increase risk of vaginal human immunodeficiency virus (HIV) infections but, to our knowledge, there are no nonhuman primate studies that have evaluated its link to rectal HIV acquisition. METHODS: Rhesus macaques inoculated with Chlamydia trachomatis (CT) (serovars LGV-L2 and CT-E; n = 7) or saline (n = 7) received up to 20 rectal challenges twice a week of simian/HIV immunodeficiency virus (SHIVSF162p3). SHIV viremia was determined by real-time PCR and Chlamydia infection by APTIMA Combo 2 testing. The rectal cytokine-chemokine levels were evaluated by multiplex bead assays. RESULTS: Rectal Chlamydia infection was maintained throughout the study. We did not observe significant differences (P = 1.0) in frequency of SHIV acquisition between the STI and control arms. It took fewer SHIV challenges to infect the STI animals although the difference was not significant (P = 0.59). There were no significant differences in peak plasma viremia between STI and control arms (P = 0.63). The association of plasma viremia with rectal shedding was significantly different by arm (P = 0.038). CONCLUSIONS: In the first such study in a macaque model, we did not observe an increased risk of SHIV acquisition due to rectal Chlamydia coinfection. This macaque model can be further developed and expanded to better investigate the impact of different rectal STIs on HIV acquisition. |
Chemoprophylaxis with oral emtricitabine and tenofovir alafenamide combination protects macaques from rectal SHIV infection
Massud I , Mitchell J , Babusis D , Deyounks F , Ray AS , Rooney JF , Heneine W , Miller MD , Garcia-Lerma JG . J Infect Dis 2016 214 (7) 1058-62 Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that efficiently delivers tenofovir-diphosphate to lymphoid cells following oral administration. We investigated if the combination of TAF and emtricitabine (FTC) could prevent simian HIV (SHIV) infection in macaques to determine the potential use of TAF for HIV pre-exposure prophylaxis (PrEP). Macaques were exposed rectally to SHIV once a week for up to 19 weeks and received saline or FTC/TAF 24h before and 2h after each virus inoculation. All 6 controls were infected, while the 6 PrEP-treated animals were protected from infection. Our results support the clinical investigation of FTC/TAF for PrEP. |
Pharmacokinetic and pharmacodynamic evaluation following vaginal application of IQB3002, a dual chamber microbicide gel containing the NNRTI IQP-0528 in rhesus macaques
Pereira LE , Mesquita PM , Ham A , Singletary T , Deyounks F , Martin A , McNicholl J , Buckheit KW , Buckheit RW Jr , Smith JM . Antimicrob Agents Chemother 2015 60 (3) 1393-400 We evaluated in vivo pharmacokinetics and used a complementary ex vivo co-culture assay to determine pharmacodynamics of IQB3002 gel containing 1% IQP-0528, a non-nucleoside reverse transcriptase inhibitor, in rhesus macaques (RM). Gel (1.5 ml) was applied vaginally to 6 SHIV+ female RM. Blood, vaginal and rectal fluids were collected at 0, 1, 2, and 4 hours. RM were euthanized at 4 hours, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-HIV activity was evaluated ex vivo by co-culturing fresh or frozen vaginal tissue with activated human peripheral blood mononuclear cells (PBMCs), and measuring p24 levels for 10 days after HIV-1Ba-L challenge. Median levels of IQP-0528, determined using LC-MS methods, were between 104-105 ng/g in vaginal and cervical tissue, 103-104 ng/g in rectal tissues, and 105-107 ng/ml in vaginal fluids over the 4 hour period. Vaginal tissues protected co-cultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81-100% in fresh and frozen tissues that were proximal, medial, and distal relative to the cervix. No viral inhibition was detected in untreated baseline tissues. Collectively, the observed median drug levels were 5-7 logs higher than the in vitro EC50 range (0.21 ng/ml -1.29 ng/ml), suggesting that 1.5 ml of gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, anti-viral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo co-culture model for future NNRTI efficacy studies. |
Depot-medroxyprogesterone acetate does not reduce the prophylactic efficacy of emtricitabine and tenofovir disoproxil fumarate in macaques
Radzio J , Hanley K , Mitchell J , Ellis S , Deyounks F , Jenkins L , Heneine W , Garcia-Lerma JG . J Acquir Immune Defic Syndr 2014 67 (4) 365-9 Concerns that the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) may increase the risk of HIV acquisition in women led to questions on whether DMPA could reduce efficacy of pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model to investigate the impact of prolonged DMPA on PrEP with FTC/TDF. Twelve pigtail macaques treated with DMPA were exposed vaginally to SHIV once a week for up to 5 months and received either placebo (n=6) or FTC/TDF (n=6). All control macaques were infected while the PrEP-treated animals remained protected (p=0.0007). This model suggests that women using DMPA will fully benefit from PrEP. |
Physiologic doses of depot-medroxyprogesterone acetate do not increase acute plasma simian HIV viremia or mucosal virus shedding in pigtail macaques
Radzio J , Hanley K , Mitchell J , Ellis S , Deyounks F , Jenkins LT , Hanson D , Heneine W , Garcia-Lerma JG . AIDS 2014 28 (10) 1431-9 OBJECTIVE: Epidemiologic studies remain inconclusive on whether the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) increases mucosal HIV shedding and transmissibility. Nonhuman primate models may help to determine the effects of DMPA on acute HIV replication. DESIGN: We defined a physiologic dose of DMPA in macaques and assessed the impact of DMPA on acute simian HIV (SHIV) replication. METHODS: Pigtail macaques received 1-30 mg of DMPA intramuscularly followed by measurements of progesterone and medroxyprogesterone acetate (MPA). Vaginal epithelial thickness, number of cell layers and density of intraepithelial CD3 cells were measured. The effect of DMPA on SHIV viremia and genital virus shedding was investigated in six pigtail macaques infected during monthly treatment cycles with 3 mg DMPA. Six DMPA-untreated macaques were controls. RESULTS: Plasma MPA concentrations directly correlated with changes in epithelial thickness (correlation = 0.84; P < 0.001) and density of intraepithelial CD3 cells (correlation = 0.41; P = 0.02). A 3 mg DMPA dose recapitulated plasma MPA concentrations and changes in vaginal epithelial thickness seen in women. DMPA-treated and untreated macaques showed similar peak plasma viremia and RNA area under the curve0-12wk values (P = 0.94), although treated macaques had higher odds of having virus being detected in plasma (odds ratio 6.6, P = 0.02). Rectal and vaginal virus shedding was similar between treated and untreated macaques (P = 0.72 and P = 0.53, respectively). CONCLUSION: In this pigtail macaque model of DMPA and vaginal SHIV infection, we found little or no effect of DMPA on plasma viremia and mucosal virus shedding during acute infection. These results do not support a role of DMPA in increasing mucosal virus shedding. |
Increased susceptibility to vaginal SHIV transmission in pigtail macaques coinfected with Chlamydia trachomatis and Trichomonas vaginalis
Henning T , Butler K , Hanson D , Sturdevant G , Ellis S , Sweeney EM , Mitchell J , Deyounks F , Phillips C , Farshy C , Fakile Y , Papp J , Secor WE , Caldwell H , Patton D , McNicholl J , Kersh E . J Infect Dis 2014 210 (8) 1239-47 BACKGROUND: Sexually transmitted infections (STIs) are associated with increased HIV infection risk, but their biological effect on HIV susceptibility is not fully understood. METHODS: Female pigtail macaques, inoculated with C. trachomatis and T. vaginalis (n=9) or media (controls, n=7), were repeatedly intravaginally challenged with SHIVSF162p3. Virus levels were evaluated by real-time PCR, plasma and genital cytokine levels by Luminex assays, and STI clinical signs by colposcopy. RESULTS: SHIV susceptibility was enhanced in STI-positive macaques (p=0.04, log rank; 2.5-times as high relative risk of infection, 95% CI 1.1, 5.6). All STI-positive macaques were SHIV-infected, while n=3 (43%) of controls remained uninfected. Moreover, relative to non-STI, infections occurred earlier in the menstrual cycle in STI-positive macaques (p=0.01, Wilcoxon). Inflammatory cytokines were higher in STI-positive macaques during STI inoculation (IFN-gamma, IL-6, and G-CSF) and SHIV exposure periods (G-CSF) (p≤0.05, Wilcoxon). CONCLUSIONS: C. trachomatis and T. vaginalis increase susceptibility to SHIV, likely due to prolonged genital tract inflammation. These novel data demonstrate a biological link between these non-ulcerative STIs and (S)HIV risk, supporting epidemiological observations. This study establishes a macaque model for high-risk HIV transmission and prevention studies. |
Development of a rectal sexually transmitted infection - HIV coinfection model utilizing Chlamydia trachomatis and SHIV
Henning T , Butler K , Mitchell J , Ellis S , Deyounks F , Farshy C , Phillips C , Papp J , Patton D , Caldwell H , Sturdevant G , McNicholl J , Kersh E . J Med Primatol 2014 43 (3) 135-43 BACKGROUND: Rectal sexually transmitted infections (STIs) may increase HIV susceptibility in men who have sex with men (MSM), and Chlamydia trachomatis is prevalent among HIV-positive MSM. To study STIs and HIV infection in MSM, we first evaluated whether cynomolgus macaques can sustain both C. trachomatis and SHIVSF162p3 infections. METHODS: Four SHIVSF162p3 -positive male cynomolgus macaques were used (n = 3 rectally inoculated with 106 IFU; n = 1 control). Systemic and rectal SHIV RNA levels and cytokines were measured by real-time PCR and Luminex assays, respectively. RESULTS: Macaques were successfully Chlamydia infected. Rectal SHIV shedding (P = 0.02 chi2 ) and levels of G-CSF, IL-1ra, IL-6, IL-8, IFN-gamma, and TNF-alpha (P ≤ 0.01, Mann-Whitney) in rectal secretions increased following infection. CONCLUSIONS: These pilot data successfully demonstrate rectal C. trachomatis-SHIV coinfection in cynomolgus macaques and suggest the feasibility of a rectal C. trachomatis model for SHIV susceptibility and biomedical prevention studies in the context of rectal STIs. |
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