Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 94 Records) |
Query Trace: McNicholl J[original query] |
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Broadly neutralizing antibody-mediated protection against SHIV infection among macaques with vaginal sexually transmitted infections
Garber DA , Guenthner P , Zhao C , Mitchell J , Ellis S , Jia H , Manganare M , Gazumyan A , Seaman MS , Vishwanathan SA , Heneine W , McNicholl JM . AIDS 2023 37 (5) 723-731 OBJECTIVE: Sexually transmitted infections (STIs) increase mucosal HIV infection risk and have the potential to reduce preexposure prophylaxis efficacy. Clinical trials of a broadly neutralizing antibody (bNAb) provided proof-of-concept that passive immunization against HIV can be efficacious in people. We sought to evaluate preclinically the protective efficacy of passive bNAb immunization against simian-human immunodeficiency virus (SHIV) infection in the context of concurrent vaginal STIs. DESIGN: Using a macaque model of combined ulcerative and nonulcerative vaginal STIs caused by Treponema pallidum, Chlamydia trachomatis, and Trichomonas vaginalis, we determined the protection that passively administered bNAb 10-1074 conferred against repeated vaginal SHIV challenges and compared correlates of protection to contemporaneous and historical controls without STIs. METHODS: Plasma viremia was monitored via RT-qPCR assay. Concentrations of 10-1074 were determined longitudinally in plasma samples via TZM-bl pseudovirus neutralization assay. RESULTS: Among macaques with vaginal STIs, a single subcutaneous injection of 10-1074 durably protected against vaginal SHIV acquisition, as compared with untreated controls. Interestingly, the median plasma concentration of 10-1074 at the time of SHIV breakthrough among macaques with STIs was significantly higher (10-fold) than that previously observed among 10-1074-treated macaques in the absence of STIs. CONCLUSION: Passive immunization with 10-1074 conferred significant protection against repeated vaginal SHIV challenges among macaques harboring vaginal STIs. However, our findings suggest that higher bNAb concentrations may be required for prophylaxis when STIs are present. Our findings potentially impact dose selection for the clinical development of bNAbs and highlight the importance of additional preclinical efficacy testing in STI models. |
Severe monkeypox in hospitalized patients - United States, August 10-October 10, 2022
Miller MJ , Cash-Goldwasser S , Marx GE , Schrodt CA , Kimball A , Padgett K , Noe RS , McCormick DW , Wong JM , Labuda SM , Borah BF , Zulu I , Asif A , Kaur G , McNicholl JM , Kourtis A , Tadros A , Reagan-Steiner S , Ritter JM , Yu Y , Yu P , Clinton R , Parker C , Click ES , Salzer JS , McCollum AM , Petersen B , Minhaj FS , Brown E , Fischer MP , Atmar RL , DiNardo AR , Xu Y , Brown C , Goodman JC , Holloman A , Gallardo J , Siatecka H , Huffman G , Powell J , Alapat P , Sarkar P , Hanania NA , Bruck O , Brass SD , Mehta A , Dretler AW , Feldpausch A , Pavlick J , Spencer H , Ghinai I , Black SR , Hernandez-Guarin LN , Won SY , Shankaran S , Simms AT , Alarcón J , O'Shea JG , Brooks JT , McQuiston J , Honein MA , O'Connor SM , Chatham-Stephens K , O'Laughlin K , Rao AK , Raizes E , Gold JAW , Morris SB . MMWR Morb Mortal Wkly Rep 2022 71 (44) 1412-1417 As of October 21, 2022, a total of 27,884 monkeypox cases (confirmed and probable) have been reported in the United States.(§) Gay, bisexual, and other men who have sex with men have constituted a majority of cases, and persons with HIV infection and those from racial and ethnic minority groups have been disproportionately affected (1,2). During previous monkeypox outbreaks, severe manifestations of disease and poor outcomes have been reported among persons with HIV infection, particularly those with AIDS (3-5). This report summarizes findings from CDC clinical consultations provided for 57 patients aged ≥18 years who were hospitalized with severe manifestations of monkeypox(¶) during August 10-October 10, 2022, and highlights three clinically representative cases. Overall, 47 (82%) patients had HIV infection, four (9%) of whom were receiving antiretroviral therapy (ART) before monkeypox diagnosis. Most patients were male (95%) and 68% were non-Hispanic Black (Black). Overall, 17 (30%) patients received intensive care unit (ICU)-level care, and 12 (21%) have died. As of this report, monkeypox was a cause of death or contributing factor in five of these deaths; six deaths remain under investigation to determine whether monkeypox was a causal or contributing factor; and in one death, monkeypox was not a cause or contributing factor.** Health care providers and public health professionals should be aware that severe morbidity and mortality associated with monkeypox have been observed during the current outbreak in the United States (6,7), particularly among highly immunocompromised persons. Providers should test all sexually active patients with suspected monkeypox for HIV at the time of monkeypox testing unless a patient is already known to have HIV infection. Providers should consider early commencement and extended duration of monkeypox-directed therapy(††) in highly immunocompromised patients with suspected or laboratory-diagnosed monkeypox.(§§) Engaging all persons with HIV in sustained care remains a critical public health priority. |
The predictive value of macaque models of preexposure prophylaxis for HIV prevention
García-Lerma JG , McNicholl JM , Heneine W . Curr Opin HIV AIDS 2022 17 (4) 179-185 PURPOSE OF REVIEW: We review macaque models for preexposure prophylaxis (PrEP) for HIV prevention and highlight their role in advancing currently approved and novel PrEP agents. RECENT FINDINGS: The development of the repeat low dose simian HIV (SHIV) challenge models represented a significant advancement in preclinical PrEP modeling that has allowed the investigation of PrEP under conditions that better mimic HIV exposures in humans. These models incorporate relevant drug pharmacology to inform drug correlates of PrEP protection. Models of rectal, vaginal, and penile infection are now available and have been found to predict clinical efficacy of all the currently approved PrEP strategies including daily oral PrEP with the combination of emtricitabine and tenofovir disoproxil fumarate or tenofovir alafenamide, and a long-acting formulation of the integrase inhibitor cabotegravir. These models are being used to test new PrEP modalities including the nucleoside reverse transcriptase-translocation inhibitor islatravir and long-acting capsid inhibitors. The SHIV models have also been supplemented by sexually transmitted infection co-infections with Chlamydia trachomatis, Treponema pallidum or Trichomonas vaginalis to assess the impact of inflammation on PrEP efficacy. SUMMARY: Clinical efficacy validated current PrEP macaque models supporting their continued use to advance novel PrEP agents to improve global PrEP coverage. |
Sexually transmitted infections and depot medroxyprogesterone acetate do not impact protection from SHIV acquisition by long-acting cabotegravir in macaques
Vishwanathan SA , Zhao C , Luthra R , Khalil GK , Morris MM , Dinh C , Gary MJ , Mitchell J , Spreen WR , Pereira LE , Heneine W , García-Lerma JG , McNicholl JM . AIDS 2021 36 (2) 169-176 OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STI) that are known to increase HIV susceptibility in women. DESIGN: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. METHODS: The first study (n = 11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV). Six animals were CAB-LA treated and 5 were controls. The second study (n = 9) included a triple STI model with repeated exposures to CT, TV and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared to untreated controls over time. RESULTS: All 6 CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges while the untreated animals became SHIV-infected after a median of 2 challenges (log-rank p < 0.001) or 1 challenge (log-rank p = 0.002), respectively. Both models recapitulated human STI disease, with vaginal discharge, ulcers and seroconversion. CONCLUSION: In these high and sustained susceptibility models spanning more than 3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the CAB-LA dose used in clinical trials, and suggesting its insensitivity to multiple STIs and DMPA. |
Broadly neutralizing antibody-mediated protection of macaques against repeated intravenous exposures to simian-human immunodeficiency virus
Garber DA , Guenthner P , Mitchell J , Ellis S , Gazumyan A , Nason M , Seaman MS , McNicholl JM , Nussenzweig MC , Heneine W . AIDS 2021 35 (10) 1567-1574 OBJECTIVE: The opioid epidemic has increased parentally acquired HIV infection. To inform the development of a long-acting prevention strategy, we evaluated the protective efficacy of broadly neutralizing antibodies (bNAbs) against intravenous SHIV infection in macaques. DESIGN: Five cynomolgus macaques were injected once subcutaneously with 10-1074 and 3BNC117 (10 mg each kg-1) and were repeatedly challenged intravenously once weekly with SHIVAD8-EO (130 TCID50), until infection was confirmed via plasma viral load assay. Two control macaques, which received no antibody, were challenged identically. METHODS: Plasma viremia was monitored via RT-qPCR assay. bNAb concentrations were determined longitudinally in plasma samples via TZM-bl neutralization assays using virions pseudotyped with 10-1074-sensitive (X2088_c9) or 3BNC117-sensitive (Q769.d22) HIV envelope proteins. RESULTS: Passively immunized macaques were protected against a median of five weekly intravenous SHIV challenges, as compared to untreated controls, which were infected following a single challenge. Of the two bNAbs, 10-1074 exhibited relatively longer persistence in vivo. The median plasma level of 10-1074 at SHIV breakthrough was 1.1 μg ml-1 (range: 0.6-1.6 μg ml-1), whereas 3BNC117 was undetectable. Probit modeling estimated that 6.6 μg ml-1 of 10-1074 in plasma corresponded to a 99% reduction in per-challenge infection probability, as compared to controls. CONCLUSIONS: Significant protection against repeated intravenous SHIV challenges was observed following administration of 10-1074 and 3BNC117 and was due primarily to 10-1074. Our findings extend preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the possibility that intermittent subcutaneous injections of 10-1074 could serve as long-acting pre-exposure prophylaxis for persons who inject drugs. |
Altered antibody responses in persons infected with HIV-1 while using PrEP
Parker I , Khalil G , Martin A , Martin MT , Vanichseni S , Leelawiwat W , McNicholl JM , Hickey A , Garcia-Lerma JG , Choopanya K , Curtis K . AIDS Res Hum Retroviruses 2020 37 (3) 189-195 BACKGROUND: Pre-exposure prophylaxis (PrEP) is an effective HIV prevention tool, although effectiveness is dependent upon adherence. It is important to characterize the impact of PrEP on HIV antibody responses in people who experience breakthrough infections in order to understand the potential impact on timely diagnosis and treatment. METHODS: Longitudinal HIV-1-specific antibody responses were evaluated in 42 people who inject drugs (PWID) from the Bangkok Tenofovir Study (placebo=28; PrEP=14) who acquired HIV while receiving PrEP. HIV-1 antibody levels and avidity to three envelope proteins (gp41, gp160, and gp120) were measured in the plasma using a customized Bio-Plex (Bio-Rad Laboratories) assay. A survival analysis was performed for each biomarker to compare the distribution of times at which study subjects exceeded the recent/long-term assay threshold, comparing PrEP and placebo treatment groups. We fit mixed-effects models to identify longitudinal differences in antibody levels and avidity between groups. RESULTS: Overall, longitudinal antibody levels and avidity were notably lower in the PrEP breakthrough group compared to the placebo group. Survival analyses demonstrated a difference in time to antibody reactivity between treatment groups for all Bio-Plex biomarkers. Longitudinal gp120 antibody levels within the PrEP breakthrough group were decreased compared to the placebo group. When accounting for PrEP adherence, both gp120 and gp160 antibody levels were lower in the PrEP breakthrough group compared to the placebo group. CONCLUSION: We demonstrate hindered envelope antibody maturation in PWID who became infected while receiving PrEP in the Bangkok Tenofovir Study, which has significant implications for HIV diagnosis. Delayed maturation of the antibody response to HIV may increase the time to detection for antibody-based tests. |
Durable protection against repeated penile exposures to simian-human immunodeficiency virus by broadly neutralizing antibodies
Garber DA , Adams DR , Guenthner P , Mitchell J , Kelley K , Schoofs T , Gazumyan A , Nason M , Seaman MS , McNicholl J , Nussenzweig MC , Heneine W . Nat Commun 2020 11 (1) 3195 Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 mug ml(-1) correlated with >/=99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women. |
Impact of Q-Griffithsin anti-HIV microbicide gel in non-human primates: In situ analyses of epithelial and immune cell markers in rectal mucosa
Gunaydin G , Edfeldt G , Garber DA , Asghar M , Noel-Romas L , Burgener A , Wahlby C , Wang L , Rohan LC , Guenthner P , Mitchell J , Matoba N , McNicholl JM , Palmer KE , Tjernlund A , Broliden K . Sci Rep 2019 9 (1) 18120 Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin(+) cells, CD4(+) cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin(+) cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4(+) cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4(+) cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4(+) lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4(+) rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa. |
HIV-1 genetic diversity to estimate time of infection and infer adherence to pre-exposure prophylaxis.
Council OD , Ruone S , Mock PA , Khalil G , Martin A , Curlin ME , McNicholl JM , Heneine W , Leelawiwat W , Choopanya K , Vanichseni S , Cherdtrakulkiat T , Anekvorapong R , Martin M , Garcia-Lerma JG . AIDS 2019 33 (15) 2299-2307 OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for pre-exposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10 to 25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median=47 [IQR=35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and non-adherence in three. CONCLUSIONS: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%. |
HIV-1 genetic diversity to estimate time of infection and infer adherence to preexposure prophylaxis.
Council OD , Ruone S , Mock PA , Khalil G , Martin A , Curlin ME , McNicholl JM , Heneine W , Leelawiwat W , Choopanya K , Vanichseni S , Cherdtrakulkiat T , Anekvorapong R , Martin M , Garcia-Lerma JG . AIDS 2019 33 (15) 2299-2307 OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for pre-exposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10 to 25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median=47 [IQR=35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and non-adherence in three. CONCLUSIONS: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%. |
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. |
HIV incidence and risk behaviours of people who inject drugs in Bangkok, 19952012
Martin M , Vanichseni S , Sangkum U , Mock PA , Leethochawalit M , Chiamwongpaet S , Pitisuttithum P , Kaewkungwal J , van Griensven F , McNicholl JM , Tappero JW , Mastro TD , Kittimunkong S , Choopanya K . EClinicalMedicine 2019 9 44-51 Background: Three consecutive prospective studies were conducted among people who inject drugs (PWID) from May 1995 through June 2012 in Bangkok, Thailand. We examined data from these studies to evaluate HIV incidence and explore trends in risk behaviours. Methods: We used data from a 1995–1998 cohort study, a 1999–2004 HIV vaccine trial, and a 2005–2012 HIV pre-exposure prophylaxis (PrEP) study to examine per-quarter trends in HIV incidence, using a restricted cubic spline function for time in a Poisson regression. We also examined temporal trends in HIV-associated risk behaviours. Findings: HIV incidence declined from 5.7 per 100 person-years during the cohort study, to 2.7 per 100 person-years in the vaccine trial, to 0.7 per 100 person-years among PrEP study placebo recipients. Incidence peaked at 12.1 per 100 person-years in 1996 and declined to < 1.0% during 2005–2012. Reports of injecting drugs and sharing needles also declined from the cohort study to the PrEP study (p < 0.0001). Heroin was the most common drug injected during the cohort study and the vaccine trial, but stimulants (e.g., methamphetamine) and sedatives (e.g., midazolam) were injected more often during the PrEP study. Interpretation: HIV incidence among PWID declined during 2005–2012. Several factors likely contributed to the decline, including decreases in the frequency of injecting and sharing, improved access to HIV testing and antiretroviral therapy, and the use of PrEP. Expanding access to effective HIV prevention tools can hasten control of the HIV epidemic among PWID. Funding: The Bangkok Metropolitan Administration and U.S. Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention. |
Hepatitis C virus infection among people who inject drugs in Bangkok, Thailand, 2005-2010.
Martin M , Vanichseni S , Leelawiwat W , Anekvorapong R , Raengsakulrach B , Cherdtrakulkiat T , Sangkum U , Mock PA , Leethochawalit M , Chiamwongpaet S , McNicholl JM , Kittimunkong S , Curlin ME , Choopanya K . WHO South East Asia J Public Health 2019 8 (1) 50-55 Background: Approximately 1% of adults in Thailand are infected with hepatitis C virus (HCV). New direct-acting antiviral agents achieve sustained virologic responses in >95% of HCV-infected patients and are becoming available in countries around the world. To prepare for new HCV treatment options in Thailand, this study characterized HCV infections among people who inject drugs (PWID) in Bangkok. Methods: The Bangkok Tenofovir Study (BTS) was a pre-exposure prophylaxis trial conducted among PWID, 2005-2013. Blood specimens were randomly selected from PWID screened for the BTS, to test for anti-HCV antibody and HCV RNA. The HVR1 region was amplified by polymerase chain reaction, using multiplex primer sets with unique identifier sequences; amplification products were pooled in sets of 25; and consensus sequencing was performed to characterize individual HCV genotypes. Results: The median age of 3679 participants tested for anti-HCV antibody was 31 years, 3016 (82.0%) were male and 447 (12.2%) were HIV infected. The prevalence of anti-HCV antibody was 44.3%. The adjusted odds of testing positive for anti-HCV antibody were higher in men (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI] 2.4-4.3), those aged 40 years or older (aOR 2.7, 95% CI 2.1-3.5), those who had more than a primary school education (aOR 1.7, 95% CI 1.4-2.1), and those who tested HIV positive (aOR 5.2, 95% CI 3.7-7.4). HCV RNA was detected in 644 (81.3%) of the 792 anti-HCV antibody-positive specimens, yielding an HCV RNA-positive prevalence of 36.0% (95% CI 33.8-38.2). Among a random sample of 249 of the 644 specimens, 218 could be characterized, and the most common HCV subtypes were 1a (30.3%), 1b (12.8%), 3a (35.8%), 3b (6.9%) and 6n (8.7%). Conclusion: The prevalence of anti-HCV antibody among PWID was 44.3% and more than one third (36.0%) were HCV RNA positive. Genotypes 1, 3 and 6 accounted for all typable infections. As the government of Thailand considers introduction of direct-acting antiviral medications for people with hepatitis C, it will be important to ensure that the medications target these subtypes. |
Reply to Burgner, et al
Bardenheier BH , McNeil MM , Wodi AP , McNicholl JM , DeStefano F . Clin Infect Dis 2018 66 (2) 319 We thank Dr Burgner [1] for his interest in our study [2]. Dr Burgner pointed out the potential for oversimplification of our survival model by summarizing prematurity and low birth weight, which may have resulted in effect modification being overlooked. This is an interesting idea, and we agree that perhaps a stratified approach could provide more meaningful estimates of such effect measure modification. However, stratifying on these dichotomous variables is not possible with our data due to the small sample size. We think this would be an important approach for future studies and look forward to publications evaluating possible effect modification by gestational age or birth weight. |
Progestin-based contraception regimens modulate expression of putative HIV risk factors in the vaginal epithelium of pig-tailed Macaques.
Bosinger SE , Tharp GK , Patel NB , Zhao C , Payne TL , Dietz Ostergaard S , Butler K , Ellis S , Johnson RL , Kersh EN , McNicholl JM , Vishwanathan SA . Am J Reprod Immunol 2018 80 (4) e13029 PROBLEM: In women, the use of progestin-based contraception may increase the risk of vaginal HIV acquisition. We previously showed in macaques that there is a significantly higher simian-human immunodeficiency virus (SHIV) acquisition rate in the luteal phase of the menstrual cycle, which presents a naturally high-progesterone state, and this may be attributable to altered expression of innate immune factors. We hypothesized that progestin-based contraception, especially depot medroxyprogesterone acetate (DMPA), would, in a similar way, affect mucosal immune factors that influence HIV acquisition risk. METHOD OF STUDY: We used a pig-tailed macaque model to evaluate the effects of two progestin-based contraceptives, DMPA, and levonorgestrel (LNG)/ethinyl estradiol (EE)-based combined oral contraceptives (COCs), on innate mucosal factors. We compared the vaginal epithelial thickness data from previous studies and used cytokine profiling and microarray analysis to evaluate contraception-induced molecular changes in the vagina. RESULTS: The administration of DMPA caused a reduction in the thickness of the vaginal epithelium relative to that of the follicular or luteal phase. DMPA also induced a significant increase in vaginal levels of the anti-inflammatory cytokine IL-10. Both DMPA- and LNG-based contraception induced a signature of gene expression similar to that of the luteal phase, only more exacerbated, including widespread downregulation of antiviral genes. CONCLUSION: The use of progestin-based contraception might engender a milieu that poses an increased risk of HIV acquisition as compared to both the luteal and follicular phases of the menstrual cycle. |
Impact of the griffithsin anti-HIV microbicide and placebo gels on the rectal mucosal proteome and microbiome in non-human primates.
Girard L , Birse K , Holm JB , Gajer P , Humphrys MS , Garber D , Guenthner P , Noel-Romas L , Abou M , McCorrister S , Westmacott G , Wang L , Rohan LC , Matoba N , McNicholl J , Palmer KE , Ravel J , Burgener AD . Sci Rep 2018 8 (1) 8059 Topical microbicides are being explored as an HIV prevention method for individuals who practice receptive anal intercourse. In vivo studies of these microbicides are critical to confirm safety. Here, we evaluated the impact of a rectal microbicide containing the antiviral lectin, Griffithsin (GRFT), on the rectal mucosal proteome and microbiome. Using a randomized, crossover placebo-controlled design, six rhesus macaques received applications of hydroxyethylcellulose (HEC)- or carbopol-formulated 0.1% GRFT gels. Rectal mucosal samples were then evaluated by label-free tandem MS/MS and 16 S rRNA gene amplicon sequencing, for proteomics and microbiome analyses, respectively. Compared to placebo, GRFT gels were not associated with any significant changes to protein levels at any time point (FDR < 5%), but increased abundances of two common and beneficial microbial taxa after 24 hours were observed in HEC-GRFT gel (p < 2E-09). Compared to baseline, both placebo formulations were associated with alterations to proteins involved in proteolysis, activation of the immune response and inflammation after 2 hours (p < 0.0001), and increases in beneficial Faecalibacterium spp. after 24 hours in HEC placebo gel (p = 4.21E-15). This study supports the safety profile of 0.1% GRFT gel as an anti-HIV microbicide and demonstrates that current placebo formulations may associate with changes to rectal proteome and microbiota. |
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. |
Daily and nondaily oral preexposure prophylaxis in men and transgender women who have sex with men: The Human Immunodeficiency Virus Prevention Trials Network 067/ADAPT Study
Grant RM , Mannheimer S , Hughes JP , Hirsch-Moverman Y , Loquere A , Chitwarakorn A , Curlin ME , Li M , Amico KR , Hendrix CW , Anderson PL , Dye BJ , Marzinke MA , Piwowar-Manning E , McKinstry L , Elharrar V , Stirratt M , Rooney JF , Eshleman SH , McNicholl JM , van Griensven F , Holtz TH . Clin Infect Dis 2018 66 (11) 1712-1721 Background: Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. Methods: At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time-driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self-report, drug concentrations, and electronic drug monitoring. Results: From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of >/=2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time-driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. Conclusions: Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment. Clinical Trials Registration: NCT01327651. |
Repeated administration of high-dose depot medroxyprogesterone acetate does not alter SHIVSF162p3 viral kinetics and tenofovir pharmacokinetics when delivered via intravaginal rings
Srinivasan P , Zhang J , Dinh CT , Teller RS , McNicholl JM , Kiser PF , Herold BC , Smith JM . J Med Primatol 2017 46 (4) 129-136 BACKGROUND: Intravaginal rings (IVR) for HIV prevention will likely be used by women on depot medroxyprogesterone acetate (DMPA) hormonal contraception. We used pigtailed macaques to evaluate the effects of DMPA on tenofovir disoproxil fumarate (TDF) IVR pharmacokinetics and viral shedding. METHODS: Mucosal tenofovir (TFV) levels were compared in SHIVSF162p3 -negative DMPA-treated (n=4) and normally cycling (n=6) macaques receiving TDF IVRs. Plasma viremia and vaginal shedding were determined in groups of SHIVSF162p3 -positive DMPA-treated (n=6) and normally cycling (n=5) macaques. RESULTS: Similar median vaginal fluid TFV concentrations were observed in the DMPA-treated and cycling macaques over 4 weeks (1.2x105 and 1.1.x105 ng/mL, respectively). Median plasma viremia and vaginal shedding AUC of the DMPA-treated (2.73x107 and 8.15x104 copies/mL, respectively) and cycling macaques (3.98x107 and 1.47x103 copies/mL, respectively) were statistically similar. CONCLUSIONS: DMPA does not affect TDF IVR pharmacokinetics or SHIV shedding. |
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. |
Development of a rectal sexually transmitted infection (STI) model in Rhesus macaques using Chlamydia trachomatis serovars E and L2
Henning TR , Morris M , Ellis S , Kelley K , Phillips C , Ritter J , Jones T , Nachamkin E , Chen CY , Hong J , Kang J , Patton D , McNicholl J , Papp J , Kersh EN . J Med Primatol 2017 46 (5) 218-227 BACKGROUND: Rectal STI coinfection models enhance the understanding of rectal HIV transmission risk factors. MATERIALS AND METHODS: Rhesus macaques (n=9) were exposed to one of three rectal Chlamydia trachomatis (CT) challenges: C. trachomatis L2 (CT-L2 ); C. trachomatis serovar E (CT-E), followed by CT-L2 ; or CT-E, treatment/clearance, then CT-L2 . Infections were monitored by PCR. Weekly blood and rectal secretion/lavage samples were collected for cytokine analyzes and/or epithelial sloughing, occult, and overt blood determinations. RESULTS: Chlamydial infections were successfully established in each animal, with varying degrees of persistence. Mucosal IL-1beta was upregulated in animals consecutively infected with CT-E then CT-L2 (P=.05). Epithelial sloughing was also significantly increased post-infection in this group (P=.0003). CONCLUSIONS: This study demonstrates successful rectal infection of rhesus macaques with CT-E and CT-L2 and describes measures of assessing rectal inflammation and pathology. Different infection strategies yield varying inflammatory and pathologic outcomes, providing well-described models for future SIV/SHIV susceptibility studies. |
Risk of non-targeted infectious disease hospitalizations among U.S. children following inactivated and live vaccines, 2005-2014
Bardenheier BH , McNeil MM , Wodi AP , McNicholl J , DeStefano F . Clin Infect Dis 2017 65 (5) 729-737 Background: Recent studies have shown that some vaccines have beneficial effects that could not be explained solely by the prevention of their respective targeted disease(s). Methods: We used the MarketScan(R) United States (US) Commercial Claims Databases from 2005-2014 to assess the risk of hospital admission for non-targeted infectious diseases in children from 16 through 24 months according to the last vaccine type (live and/or inactivated). We included children continuously enrolled within a month of birth through 15 months who received at least three doses of Diphtheria-Tetanus-acellular Pertussis vaccine by end of 15 months of age. We used Cox regression to estimate hazard ratios (HRs), stratifying by birthdate to control for age, year and seasonality, and adjusting for sex, chronic diseases, prior hospitalizations, number of outpatient visits, region of residence, urban/rural area of domicile, prematurity, low birth weight, and mother's age. Results: 311,663 children were included. In adjusted analyses, risk of hospitalization for non-targeted infections from ages 16 through 24 months was reduced for those who received live vaccine alone compared with inactivated alone or concurrent live and inactivated vaccines (HR 0.50, 95% CI 0.43, 0.57 and HR 0.78, 95% CI 0.67, 0.91, respectively), and for those who received live and inactivated vaccines concurrently compared with inactivated only (HR 0.64, 95% CI 0.58, 0.70). Conclusions: We found lower risk of non-targeted infectious disease hospitalizations from 16 through 24 months among US children whose last vaccine received was live compared with inactivated vaccine, as well as concurrent receipt compared with inactivated vaccine. |
Analysis of false-negative HIV rapid tests performed on oral fluid in three international clinical research studies
Curlin ME , Gvetadze R , Leelawiwat W , Martin M , Rose C , Niska RW , Segolodi TM , Choopanya K , Tongtoyai J , Holtz TH , Samandari T , McNicholl JM . Clin Infect Dis 2017 64 (12) 1663-1669 Objective: The OraQuick Advance Rapid HIV-1/2 Test is a point-of-care test capable of detecting HIV-specific antibodies in blood and oral fluid. To understand test performance and factors contributing to false-negative (FN) results in longitudinal studies, we examined results of participants enrolled in the TDF2 study, the Bangkok Tenofovir Study, and the Bangkok MSM Cohort Study (BMCS), three separate clinical studies of high-risk, HIV-negative persons conducted in Botswana and Thailand. Design: Retrospective observational analysis. Methods: We compared oral fluid OraQuick (OFOQ) results among participants becoming HIV-infected to results obtained retrospectively using enzyme immunoassay and nucleic acid amplification tests on stored specimens. We categorized negative OFOQ results as true-negative or false-negative relative to NAAT and/or EIA, and determined the delay in OFOQ conversion relative to the estimated time of infection. We used generalized estimating equations to examine the association between FN results and participant, clinical and testing-site factors. Results: Two-hundred and thirty-three FN OFOQ results occurred in 80 of 287 seroconverting individuals. Estimated OFOQ conversion delay ranged from 14.5-547.5 (median 98.5) days. Delayed OFOQ conversion was associated with clinical site and test operator (p<0.05), pre-exposure prophylaxis (p=0.01), low plasma viral load (p<0.02) and time to kit expiration (p<0.01). Participant age, gender, and HIV subtype were not associated with FN results. Long OFOQ conversion delay time was associated with antiretroviral exposure and low PVL. Conclusions: Failure of OFOQ to detect HIV-1 infection was frequent, and multifactorial in origin. In longitudinal trials, negative oral fluid results should be confirmed by testing blood samples. |
Topical tenofovir protects against vaginal SHIV infection in macaques co-infected with chlamydia trachomatis and trichomonas vaginalis
Makarova N , Henning T , Taylor A , Dinh C , Lipscomb J , Aubert R , Hanson D , Phillips C , Papp J , Mitchell J , McNicholl J , Garcia-Lerma GJ , Heneine W , Kersh E , Dobard C . AIDS 2017 31 (6) 745-752 BACKGROUND: Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV), two prevalent sexual transmitted infections, are known to increase HIV risk in women and could potentially diminish pre-exposure prophylaxis (PrEP) efficacy, particularly for topical interventions that rely on local protection. We investigated in macaques whether co-infection with CT/TV reduces protection by vaginal TFV gel. METHODS: Vaginal TFV gel dosing previously shown to provide 100% or 74% protection when applied either 30 minutes or 3 days before SHIV challenge was assessed in pigtailed macaques co-infected with CT/TV and challenged twice-weekly with SHIV162p3 for up to 10 weeks (2 menstrual cycles). Three groups of six macaques received either placebo or 1% TFV gel 30 minutes or 3 days before each SHIV challenge. We additionally assessed TFV and TFV-diphosphate (TFV-DP) concentrations in plasma and vaginal tissues in CT/TV co-infected (n = 4) and uninfected (n = 4) macaques. RESULTS: CT/TV co-infections were maintained during the SHIV challenge period. All macaques that received placebo gel were SHIV-infected after a median of 7 challenges (1 menstrual cycle). In contrast, no infections were observed in macaques treated with TFV gel 30 minutes before SHIV challenge (p < 0.001). Efficacy was reduced to 60% when TFV gel was applied 3 days before SHIV challenge (p = 0.07). Plasma TFV and TFV-DP concentrations in tissues and vaginal lymphocytes were significantly higher in CT/TV co-infected compared to CT/TV uninfected macaques. CONCLUSIONS: Our findings in this model suggest that CT/TV co-infection may have little or no impact on the efficacy of highly effective topical TFV modalities and highlight a significant modulation of TFV pharmacokinetics. |
Factors associated with the uptake of and adherence to HIV pre-exposure prophylaxis in people who have injected drugs: an observational, open-label extension of the Bangkok Tenofovir Study
Martin M , Vanichseni S , Suntharasamai P , Sangkum U , Mock PA , Chaipung B , Worrajittanon D , Leethochawalit M , Chiamwongpaet S , Kittimunkong S , Gvetadze RJ , McNicholl JM , Paxton LA , Curlin ME , Holtz TH , Samandari T , Choopanya K . Lancet HIV 2016 4 (2) e59-e66 BACKGROUND: Results of the randomised, double-blind, placebo-controlled Bangkok Tenofovir Study (BTS) showed that taking tenofovir daily as pre-exposure prophylaxis (PrEP) can reduce the risk of HIV infection by 49% in people who inject drugs. In an extension to the trial, participants were offered 1 year of open-label tenofovir. We aimed to examine the demographic characteristics, drug use, and risk behaviours associated with participants' uptake of and adherence to PrEP. METHODS: In this observational, open-label extension of the BTS (NCT00119106), non-pregnant, non-breastfeeding, HIV-negative BTS participants, all of whom were current or previous injecting drug users at the time of enrolment in the BTS, were offered daily oral tenofovir (300 mg) for 1 year at 17 Bangkok Metropolitan Administration drug-treatment clinics. Participant demographics, drug use, and risk behaviours were assessed at baseline and every 3 months using an audio computer-assisted self-interview. HIV testing was done monthly and serum creatinine was assessed every 3 months. We used logistic regression to examine factors associated with the decision to take daily tenofovir as PrEP, the decision to return for at least one PrEP follow-up visit, and greater than 90% adherence to PrEP. FINDINGS: Between Aug 1, 2013, and Aug 31, 2014, 1348 (58%) of the 2306 surviving BTS participants returned to the clinics, 33 of whom were excluded because they had HIV (n=27) or grade 2-4 creatinine results (n=6). 798 (61%) of the 1315 eligible participants chose to start open-label PrEP and were followed up for a median of 335 days (IQR 0-364). 339 (42%) participants completed 12 months of follow-up; 220 (28%) did not return for any follow-up visits. Participants who were 30 years or older (odds ratio [OR] 1.8, 95% CI 1.4-2.2; p<0.0001), injected heroin (OR 1.5, 1.1-2.1; p=0.007), or had been in prison (OR 1.7, 1.3-2.1; p<0.0001) during the randomised trial were more likely to choose PrEP than were those without these characteristics. Participants who reported injecting heroin or being in prison during the 3 months before open-label enrolment were more likely to return for at least one open-label follow-up visit than those who did not report injecting heroin (OR 3.0, 95 % CI 1.3-7.3; p=0.01) or being in prison (OR 2.3, 1.4-3.7; p=0.0007). Participants who injected midazolam or were in prison during open-label follow-up were more likely to be greater than 90% adherent than were those who did not inject midazolam (OR 2.2, 95% CI 1.2-4.3; p=0.02) or were not in prison (OR 4.7, 3.1-7.2; p<0.0001). One participant tested positive for HIV, yielding an HIV incidence of 2.1 (95% CI 0.05-11.7) per 1000 person-years. No serious adverse events related to tenofovir use were reported. INTERPRETATION: More than 60% of returning, eligible BTS participants started PrEP, which indicates that a substantial proportion of PWID who are knowledgeable about PrEP might be interested in taking it. Participants who had injected heroin or been in prison were more likely to choose to take PrEP, suggesting that participants based their decision to take PrEP, at least in part, on their perceived risk of incident HIV infection. FUNDING: US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration. |
Combining biomedical preventions for HIV: Vaccines with pre-exposure prophylaxis, microbicides or other HIV preventions
McNicholl JM . Hum Vaccin Immunother 2016 12 (12) 0 Biomedical preventions for HIV, such as vaccines, microbicides or pre-exposure prophylaxis (PrEP) with antiretroviral drugs, can each only partially prevent HIV-1 infection in most human trials. Oral PrEP is now FDA approved for HIV-prevention in high risk groups, but partial adherence reduces efficacy. If combined as biomedical preventions (CBP) an HIV vaccine could provide protection when PrEP adherence is low and PrEP could prevent vaccine breakthroughs. Other types of PrEP or microbicides may also be partially protective. When licensed, first generation HIV vaccines are likely to be partially effective. Individuals at risk for HIV may receive an HIV vaccine combined with other biomedical preventions, in series or in parallel, in clinical trials or as part of standard of care, with the goal of maximally increasing HIV prevention. In human studies, it is challenging to determine which preventions are best combined, how they interact and how effective they are. |
Increases in endogenous or exogenous progestins promote virus-target cell interactions within the non-human primate female reproductive tract
Carias AM , Allen SA , Fought AJ , Kotnik Halavaty K , Anderson MR , Jimenez ML , McRaven MD , Gioia CJ , Henning TR , Kersh EN , Smith JM , Pereira LE , Butler K , McNicholl SJ , Hendry RM , Kiser PF , Veazey RS , Hope TJ . PLoS Pathog 2016 12 (9) e1005885 Currently, there are mounting data suggesting that HIV-1 acquisition in women can be affected by the use of certain hormonal contraceptives. However, in non-human primate models, endogenous or exogenous progestin-dominant states are shown to increase acquisition. To gain mechanistic insights into this increased acquisition, we studied how mucosal barrier function and CD4+ T-cell and CD68+ macrophage density and localization changed in the presence of natural progestins or after injection with high-dose DMPA. The presence of natural or injected progestins increased virus penetration of the columnar epithelium and the infiltration of susceptible cells into a thinned squamous epithelium of the vaginal vault, increasing the likelihood of potential virus interactions with target cells. These data suggest that increasing either endogenous or exogenous progestin can alter female reproductive tract barrier properties and provide plausible mechanisms for increased HIV-1 acquisition risk in the presence of increased progestin levels. |
A depot medroxyprogesterone acetate dose that models human use and its effect on vaginal SHIV acquisition risk
Butler K , Ritter JM , Ellis S , Morris MR , Hanson DL , McNicholl JM , Kersh EN . J Acquir Immune Defic Syndr 2016 72 (4) 363-71 INTRODUCTION: Hormonal contraception with depot medroxyprogesterone acetate (DMPA) may increase HIV acquisition risk, but observational human studies are inconclusive, and animal models can help investigate this risk. In this study, we test the impact of a low DMPA dose, designed to resemble human contraceptive use, on Simian-Human Immunodeficiency Virus (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, whereas 11 were untreated controls. For comparison, women receive 150 mg (approximately 2 mg/kg) every 3 months. We exposed monkeys to 20 suboptimal 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 to 8.3). Ovulation was suppressed, and the vaginal epithelium was thinned after DMPA treatment in all animals (mean, 30 and 219 mm 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 Simian Immunodeficiency Virus (SIV) or SHIV acquisition. |
Topical delivery of tenofovir disoproxil fumarate and emtricitabine from pod-intravaginal rings protects macaques from multiple SHIV exposures
Srinivasan P , Moss JA , Gunawardana M , Churchman SA , Yang F , Dinh CT , Mitchell JM , Zhang J , Fanter R , Miller CS , Butkyavichene I , McNicholl JM , Smith TJ , Baum MM , Smith JM . PLoS One 2016 11 (6) e0157061 Topical preexposure prophylaxis (PrEP) against HIV has been marginally successful in recent clinical trials with low adherence rates being a primary factor for failure. Controlled, sustained release of antiretroviral (ARV) drugs may help overcome these low adherence rates if the product is protective for extended periods of time. The oral combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is currently the only FDA-approved ARV drug for HIV PrEP. A novel pod-intravaginal ring (IVR) delivering TDF and FTC at independently controlled rates was evaluated for efficacy at preventing SHIV162p3 infection in a rigorous, repeat low-dose vaginal exposure model using normally cycling female pigtailed macaques. Six macaques received pod-IVRs containing TDF (65 mg) and FTC (68 mg) every two weeks, and weekly vaginal exposures to 50 TCID50 of SHIV162p3 began one week after the first pod-IVR insertion. All pod-IVR-treated macaques were fully protected throughout the study (P = 0.0002, Log-rank test), whereas all control animals became infected with a median of 4 exposures to infection. The topical, sustained release of TDF and FTC from the pod-IVR maintained protective drug levels in macaques over four months of virus exposures. This novel and versatile delivery system has the capacity to deliver and maintain protective levels of multiple drugs and the protection observed here warrants clinical evaluation of this pod-IVR design. |
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