ABSTRACT
We used a novel penile simian-human immunodeficiency virus (SHIV) transmission model to investigate whether long-acting cabotegravir (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, 6 received human-equivalent doses of CAB LA, 6 received oral emtricitabine/tenofovir disoproxil fumarate, and 10 were untreated. The efficacy of CAB LA was high (94.4%; 95% confidence interval, 58.2%-99.3%) and similar to that seen with oral emtricitabine/tenofovir disoproxil fumarate (94.0%; 55.1%-99.2%). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA preexposure prophylaxis to heterosexual men.
Subject(s)
HIV Integrase Inhibitors/administration & dosage , Pyridones/administration & dosage , Simian Acquired Immunodeficiency Syndrome/prevention & control , Simian Acquired Immunodeficiency Syndrome/transmission , Simian Immunodeficiency Virus/drug effects , Animals , Chemoprevention/methods , Disease Models, Animal , Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/therapeutic use , HIV Integrase Inhibitors/pharmacokinetics , Macaca mulatta , Male , Penis/virology , Pre-Exposure Prophylaxis , Pyridones/pharmacokinetics , Simian Immunodeficiency Virus/metabolismABSTRACT
BACKGROUND: Tenofovir alafenamide (TAF)-based regimens are being evaluated for pre-exposure prophylaxis (PrEP). We used a macaque model of repeated exposures to simian human immunodeficiency virus (SHIV) to investigate whether 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 24 hours before and 2 hours 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 = .001 and P = .049, respectively). The calculated efficacy of FTC/TAF and TAF was 91% (95% confidence interval [CI], 34.9%-98.8%) and 57.8% (95% CI, -8.7% to 83.6%), respectively. Infection in FTC/TAF but not TAF-treated macaques was delayed relative to controls (P = .005 and P = .114). Median tenofovir diphosphate (TFV-DP) levels in peripheral blood mononuclear cells (PBMCs) were similar among infected and uninfected macaques receiving TAF PrEP (351 and 143 fmols/106 cells, respectively; P = .921). CONCLUSIONS: Emtricitabine/TAF provided a level of protection against vaginal challenge similar to FTC/TFV disoproxil fumarate combination in the macaque model. Our results support the clinical evaluation of FTC/TAF for PrEP in women.
Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/administration & dosage , Disease Transmission, Infectious/prevention & control , Emtricitabine/administration & dosage , HIV Infections/prevention & control , Pre-Exposure Prophylaxis/methods , Vagina/virology , Adenine/administration & dosage , Alanine , Animals , Chemoprevention/methods , Disease Models, Animal , Female , HIV/genetics , HIV/isolation & purification , Macaca , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/isolation & purification , Tenofovir/analogs & derivatives , Treatment OutcomeABSTRACT
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 ~ 104-105 ng/g, 105-106 ng/ml, and 103-105 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 ~ 103-105 ng/ml and ~ 102-103 ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 101-103 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.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Pyrimidinones/pharmacokinetics , Tenofovir/pharmacokinetics , Administration, Rectal , Animals , Anti-HIV Agents/administration & dosage , Female , Macaca , Pyrimidinones/administration & dosage , Tenofovir/administration & dosage , Vaginal Creams, Foams, and JelliesABSTRACT
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.
Subject(s)
HIV Infections/prevention & control , Simian Acquired Immunodeficiency Syndrome/diagnosis , Simian Immunodeficiency Virus/pathogenicity , Animals , Disease Models, Animal , Foreskin/virology , Humans , Macaca mulatta , Male , RNA, Viral/analysis , Simian Acquired Immunodeficiency Syndrome/pathology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/genetics , Urethra/virology , Viral LoadABSTRACT
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.
Subject(s)
Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/complications , Syphilis/transmission , Animals , CD4-Positive T-Lymphocytes , Coinfection , Disease Models, Animal , Female , Male , Peptides, Cyclic , Rectum , Sexually Transmitted Diseases , Simian Immunodeficiency Virus , Treponema pallidum , ViremiaABSTRACT
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.
Subject(s)
Chlamydia Infections/complications , Coinfection , HIV Infections/complications , Lymphogranuloma Venereum/complications , Sexually Transmitted Diseases/complications , Simian Acquired Immunodeficiency Syndrome/complications , Animals , Chlamydia Infections/microbiology , Chlamydia trachomatis/physiology , Disease Models, Animal , HIV Infections/virology , Humans , Lymphogranuloma Venereum/microbiology , Macaca mulatta , Rectum/microbiology , Risk , Sexually Transmitted Diseases/microbiology , Simian Acquired Immunodeficiency Syndrome/virology , Simian Immunodeficiency Virus/physiologyABSTRACT
Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir that efficiently delivers tenofovir diphosphate to lymphoid cells following oral administration. We investigated whether the combination of TAF and emtricitabine (FTC) could prevent simian/human immunodeficiency virus (SHIV) infection in macaques to determine the potential use of TAF for pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus infection. Macaques were exposed rectally to SHIV once per week for up to 19 weeks and received saline or FTC/TAF 24 hours before and 2 hours 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.
Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/administration & dosage , Chemoprevention/methods , Emtricitabine/administration & dosage , Simian Acquired Immunodeficiency Syndrome/prevention & control , Adenine/administration & dosage , Alanine , Animals , Macaca , Tenofovir/analogs & derivatives , Treatment OutcomeABSTRACT
We evaluated the in vivo pharmacokinetics and used a complementary ex vivo coculture assay to determine the pharmacodynamics of IQB3002 gel containing 1% IQP-0528, a nonnucleoside reverse transcriptase inhibitor (NNRTI), in rhesus macaques (RM). The gel (1.5 ml) was applied vaginally to 6 simian-human immunodeficiency (SHIV)-positive female RM. Blood, vaginal fluids, and rectal fluids were collected at 0, 1, 2, and 4 h. RM were euthanized at 4 h, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-human immunodeficiency virus (HIV) activity was evaluated ex vivo by coculturing fresh or frozen vaginal tissues with activated human peripheral blood mononuclear cells (PBMCs) and measuring the p24 levels for 10 days after an HIV-1Ba-L challenge. The median levels of IQP-0528, determined using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods, were between 10(4) and 10(5) ng/g in vaginal and cervical tissue, between 10(3) and 10(4) ng/g in rectal tissues, and between 10(5) and 10(7) ng/ml in vaginal fluids over the 4-h period. The vaginal tissues protected the cocultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81 to 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 median drug levels observed were 5 to 7 logs higher than the in vitro 50% effective concentration (EC50) range (0.21 ng/ml to 1.29 ng/ml), suggesting that 1.5 ml of the gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, antiviral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo coculture model for future NNRTI efficacy studies.
Subject(s)
Piperidines/administration & dosage , Piperidines/pharmacokinetics , Pyrimidinones/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Administration, Intravaginal , Animals , Coculture Techniques , Cryopreservation , Female , HIV Infections/prevention & control , HIV-1/drug effects , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Macaca mulatta , Pyrimidinones/administration & dosage , Reverse Transcriptase Inhibitors/administration & dosage , Simian Acquired Immunodeficiency Syndrome/drug therapyABSTRACT
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 exposure on PrEP with emtricitabine/tenofovir disoproxil fumarate. Twelve pigtail macaques treated with DMPA were exposed vaginally to simian HIV once a week for up to 5 months and received either placebo (n = 6) or emtricitabine/tenofovir disoproxil fumarate (n = 6). All control macaques were infected, whereas the PrEP-treated animals remained protected (P = 0.0007). This model suggests that women using DMPA will fully benefit from PrEP.
Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/therapeutic use , Contraceptive Agents, Female/adverse effects , Deoxycytidine/analogs & derivatives , HIV Infections/prevention & control , Medroxyprogesterone Acetate/adverse effects , Phosphorous Acids/therapeutic use , Pre-Exposure Prophylaxis/methods , Adenine/administration & dosage , Adenine/therapeutic use , Animals , Anti-HIV Agents/administration & dosage , Contraceptive Agents, Female/administration & dosage , Contraceptive Agents, Female/therapeutic use , Delayed-Action Preparations , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Disease Models, Animal , Drug Interactions , Drug Therapy, Combination , Emtricitabine , Female , Macaca nemestrina , Medroxyprogesterone Acetate/administration & dosage , Medroxyprogesterone Acetate/therapeutic use , Phosphorous Acids/administration & dosage , Treatment OutcomeABSTRACT
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 âmg 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 âmg 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 curve values over 12 weeks (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 â= 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 HIV shedding.
Subject(s)
Contraceptive Agents, Female/administration & dosage , Medroxyprogesterone Acetate/administration & dosage , Mucous Membrane/virology , Plasma/virology , Simian Immunodeficiency Virus/isolation & purification , Viremia , Virus Shedding/drug effects , Animals , Contraceptive Agents, Female/adverse effects , Female , Macaca nemestrina , Medroxyprogesterone Acetate/adverse effects , Plasma/chemistry , RNA, Viral/bloodABSTRACT
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 associations of HIV and STIs. This study establishes a macaque model for studies of high-risk HIV transmission and prevention.
Subject(s)
Chlamydia Infections/complications , Chlamydia trachomatis , Coinfection/immunology , Simian Immunodeficiency Virus/physiology , Trichomonas Vaginitis/complications , Trichomonas vaginalis , Animals , Cervix Uteri/microbiology , Cervix Uteri/parasitology , Cervix Uteri/pathology , Colposcopy , Female , Macaca nemestrina , Risk Factors , Sexually Transmitted Diseases/complications , Simian Acquired Immunodeficiency Syndrome/transmission , Simian Acquired Immunodeficiency Syndrome/virologyABSTRACT
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 10(6) 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 χ(2) ) and levels of G-CSF, IL-1ra, IL-6, IL-8, IFN-γ, and TNF-α (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.