RESUMO
As use of human immunodeficiency virus (HIV) integrase strand transfer inhibitors (INSTI) increases and formulations are being developed for maintenance therapies and chemoprophylaxis, assessing virus suppression under INSTI-based regimens in prevention-relevant biologic compartments, such as the male genital tract, is timely. We used cell-source marker virion immunocapture to examine amplification of particle RNA then assessed the phylogenetic relatedness of seminal and blood viral sequences from men with HIV who were prescribed INSTI-based regimens. Seminal plasma immunocaptures yielded amplifiable virion RNA from 13 of 24 (54%) men, and the sequences were primarily associated with markers indicative of macrophage and resident dendritic cell sources. Genetic distances were greatest (>2%) between seminal virions and circulating proviruses, pointing to ongoing low-level expression from tissue-resident cells. While the low levels in semen predict an improbable likelihood of transmission, viruses with large genetic distances are expressed under potent INSTI therapy and have implications for determining epidemiologic linkages if adherence is suboptimal.
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Infecções por HIV , Inibidores de Integrase de HIV , Sêmen , Sêmen/virologia , Humanos , Masculino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacologia , Inibidores de Integrase de HIV/uso terapêutico , Adulto , Filogenia , RNA Viral/genética , HIV-1/genética , HIV-1/efeitos dos fármacos , Vírion/metabolismo , Pessoa de Meia-IdadeRESUMO
BACKGROUND: With an unplanned pregnancy rate of 50% or more in many countries, there is an urgent need for contraceptives that are more accessible and acceptable. To meet the growing demand for new contraceptives, ZabBio developed ZB-06, a vaginal film containing HC4-N, a human contraceptive antibody that inactivates sperm. OBJECTIVE: This study aimed to assess the potential contraceptive activity of the ZB-06 film using a surrogate assessment for contraceptive efficacy, the postcoital test. We also assessed clinical safety of film use among healthy heterosexual couples. Serum, cervical mucus, and vaginal fluid HC4-N antibody concentrations and sperm agglutination potency were determined after single film use. Changes in the concentration of soluble proinflammatory cytokines and vaginal Nugent score after film use were measured as subclinical safety endpoints. STUDY DESIGN: This was a phase 1, first-in-woman, open-label, proof-of-concept, postcoital test and safety study. RESULTS: A total of 20 healthy women were enrolled in the study, and 8 heterosexual couples completed all study visits. The product was safe for both female participants and their male sexual partners. The postcoital test performed on ovulatory cervical mucus at baseline (no product use) revealed a mean of 25.9 (±30.6) progressively motile sperm per high-power field. After use of a single ZB-06 film before intercourse, this number dropped to 0.04 (±0.06) progressively motile sperm per high-power field (P<.0001). At the follow-up postcoital test visit approximately 1 month later (no product use), a mean of 47.4 (±37.4) progressively motile sperm per high-power field was observed, indicating contraceptive reversibility. CONCLUSION: A single dose of the ZB-06 film applied before intercourse was safe and met efficacy surrogate benchmarks of excluding progressively motile sperm from ovulatory cervical mucus. These data indicate that ZB-06 is a viable contraceptive candidate warranting further development and testing.
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Dispositivos Anticoncepcionais Femininos , Espermicidas , Gravidez , Humanos , Masculino , Feminino , Anticoncepcionais , Espermicidas/farmacologia , Sêmen , VaginaRESUMO
BACKGROUND: MB66 film is a multipurpose prevention technology (MPT) product with monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N). The mAbs were produced by transient expression in Nicotiana benthamiana (N). We conducted a Phase I clinical trial to assess the safety, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66 when used intravaginally. METHODS AND FINDINGS: The clinical trial enrolled healthy reproductive-aged, sexually abstinent women. In Segment A, 9 women received a single MB66 film which was inserted into the vaginal posterior fornix by a clinician. In Segment B, 29 women were randomly assigned to MB66 (Active) or Placebo film groups and were instructed to insert 1 film vaginally for 7 consecutive days. Visits and clinical sampling occurred predose and at various time points after single and repeated film doses. The primary endpoint was number of adverse events (AEs) Grade 2 or higher related to product use. Secondary endpoints included film dissolution rate, Nugent score (a Gram stain scoring system to diagnose bacterial vaginosis), vaginal pH, post-use survey results, cytokine concentrations in cervicovaginal lavage (CVL) specimens (assessed by Luminex assay), mAb concentrations in vaginal fluid collected from 4 sites (assessed by ELISA), and HIV and HSV neutralization activity of CVL samples ex vivo (assessed by TZM-bl and plaque reduction assay, respectively). The product was generally safe and well tolerated, with no serious AEs recorded in either segment. The AEs in this study were primarily genitourinary in nature with the most commonly reported AE being asymptomatic microscopic hematuria. There were no differences in vaginal pH or Nugent scores or significant increases in levels of proinflammatory cytokines for up to 7 days after film insertion in either segment or between Active and Placebo groups. Acceptability and willingness to use the product were judged to be high by post-use surveys. Concentrations of VRC01-N and HSV8-N in vaginal secretions were assessed over time to generate pharmacokinetic curves. Antibody levels peaked 1 hour postdosing with Active film (median: 35 µg/mL) and remained significantly elevated at 24 hours post first and seventh film (median: 1.8 µg/mL). Correcting for sample dilution (1:20), VRC01-N concentrations ranged from 36 to 700 µg/mL at the 24-hour time point, greater than 100-fold the IC50 for VRC01 (0.32 µg/mL); HSV8-N concentrations ranged from 80 to 601 µg/mL, well above the IC50 of 0.1 µg/m. CVL samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo. Study limitations include the small size of the study cohort, and the fact that no samples were collected between 24 hours and 7 days for pharmacokinetic evaluation. CONCLUSIONS: Single and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable. Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were significantly elevated and thus could provide protection for at least 24 hours postdose. However, further research is needed to evaluate the efficacy of MB66 film in women at risk for HIV and HSV infection. Additional antibodies could be added to this platform to provide protection against other sexually transmitted infections (STIs) and contraception. TRIAL REGISTRATION: ClinicalTrials.gov NCT02579083.
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Anticorpos Monoclonais/uso terapêutico , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Administração Intravaginal , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Amplamente Neutralizantes/metabolismo , Anticorpos Amplamente Neutralizantes/uso terapêutico , Feminino , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Profilaxia Pré-Exposição/métodos , Vagina/virologia , Adulto JovemRESUMO
Sexually transmitted infections are highly prevalent, and over 40% of pregnancies are unplanned. We are producing new antibody-based multipurpose prevention technology products to address these problems and fill an unmet need in female reproductive health. We used a Nicotiana platform to manufacture monoclonal antibodies against two prevalent sexually transmitted pathogens, HIV-1 and HSV-2, and incorporated them into a vaginal film (MB66) for preclinical and Phase 1 clinical testing. These tests are now complete and indicate that MB66 is effective and safe in women. We are now developing an antisperm monoclonal antibody to add contraceptive efficacy to this product. The antisperm antibody, H6-3C4, originally isolated by Shinzo Isojima from the blood of an infertile woman, recognizes a carbohydrate epitope on CD52g, a glycosylphosphatidylinositol-anchored glycoprotein found in abundance on the surface of human sperm. We engineered the antibody for production in Nicotiana; the new antibody which we call "human contraception antibody," effectively agglutinates sperm at concentrations >10 µg/ml and maintains activity under a variety of physiological conditions. We are currently seeking regulatory approval for a Phase 1 clinical trial, which will include safety and "proof of principle" efficacy endpoints. Concurrently, we are working with new antibody production platforms to bring the costs down, innovative antibody designs that may produce more effective second-generation antibodies, and delivery systems to provide extended protection.
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Anticorpos Monoclonais , Anticoncepção/métodos , Saúde Reprodutiva , Feminino , Humanos , MasculinoRESUMO
Background: Condylomata acuminata (anogenital warts [AGWs]) are prevalent in human immunodeficiency virus (HIV)-infected individuals and sexually active populations at risk for HIV acquisition and have been associated with HIV transmission. We compared AGW specimens to control tissue specimens for abundance, types, and location of HIV target cells and for susceptibility to HIV infection in vitro, to provide biologic evidence that AGWs facilitate HIV transmission. Methods: We used immunohistologic staining to identify HIV target cells in AGW and control specimens. We also inoculated HIV in vitro into AGW and control specimens from HIV-negative men and assessed infection by means of TZM-bl and p24 assays. Results: CD1a+ dendritic cells, CD4+ T cells, and macrophages were significantly more abundant in the epidermis of AGW specimens than control specimens. These HIV target cells also often appeared in large focal accumulations in the dermis of AGW specimens. Two of 8 AGW specimens versus 0 of 8 control specimens showed robust infection with HIV in vitro. Conclusions: Compared with normal skin, AGWs contain significantly higher concentrations of HIV target cells that may be susceptible to HIV infection. Condylomata may thus promote HIV transmission, especially in the setting of typical lesion vascularity and friability. Prevention or treatment of AGWs may decrease the sexual transmission of HIV.
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Condiloma Acuminado/patologia , Condiloma Acuminado/virologia , Infecções por HIV/transmissão , Adulto , Idoso , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos , Condiloma Acuminado/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Granulócitos , Células HEK293 , Proteína do Núcleo p24 do HIV , Infecções por HIV/virologia , HIV-1 , Humanos , Antígenos CD15 , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/virologia , Receptores CXCR4 , Pele/imunologia , Pele/patologia , Adulto JovemRESUMO
BACKGROUND: Obstetrics and gynecology departments receive the smallest amount of National Institutes of Health research funding and have significantly lower application success rates compared to pediatric, internal medicine, and surgery departments. The development of mentored early career development training grants (K awards) has been one strategy implemented by the National Institutes of Health to help aspiring physician-scientists establish independent research careers. OBJECTIVE: The purpose of this study is to describe the cohort of obstetrics and gynecology physician-scientists who were K08, K12, and K23 recipients from 1988 through 2015 and to identify predictors of success in obtaining independent federal funding, as defined by acquisition of an R01, R21, R34, U01, U54, P01, or P50 award. We hypothesized that sex, subspecialty, type of K award, and dual MD/PhD would impact success rates. STUDY DESIGN: K08, K12, and K23 recipients from 1988 through 2015 were identified from the National Institutes of Health Research Portfolio Online Reporting Tools, the office of the National Institutes of Health Freedom of Information Act, and the website of the Reproductive Scientist Development Program. Data were stratified by sex, educational degree, subspecialty, and type of K award. Data were analyzed using the Pearson χ2 and Fisher exact tests. The Kaplan-Meier estimator was used to determine rates of conversion to independent funding over time. RESULTS: A total of 388 K recipients were identified. Women accounted for 66% of K awards while men accounted for 34%. Among K recipients, 82% were MDs, while 18% were MD/PhDs. K12 awards accounted for 82% of all K awards, while K08 and K23 awards accounted for 10% and 8%, respectively. Subspecialists in maternal-fetal medicine and reproductive endocrinology and infertility received the highest proportion of K awards, followed by generalists and gynecologic oncologists. Altogether, the 3 subspecialty groups accounted for 68% of all K awards. R01 awards made up the bulk of independent funding. Among recipients who received their first K award between 1988 and 2009, 63 of 288 (22%) were successful at obtaining an R01. Rates of R21 (n = 22), U01 (n = 15), U54 (n = 12), P01 (n = 5), R34 (n = 1), and P50 (n = 1) acquisition ranged from 0.35-7.6%. In all, 118 K scholars (41%) were successful at achieving independent funding of any type compared to 1219 of 7535 (16.2%) obstetrics and gynecology non-K scholars. K08 recipients received the largest proportion of R01 awards compared to K12 and K23 recipients (32% vs 20%; P = .12), while 21% of K12 recipients and 17% of K23 recipients achieved an R01. There were no differences in the rates of independent funding success among K12 programs. K23 recipients were more likely to obtain an R21 (22% vs 6%, P = .008) compared to K12 and K08 recipients. The mean time to R01 acquisition was 6.8 years, while the mean time to independent funding of any type was 6.4 years. There were no significant differences in independent funding success rates by sex, educational degree, or subspecialty, although generalists received the highest proportion of R01 awards (29%). CONCLUSION: Mentored early career development K programs enable aspiring obstetrics and gynecology physician-scientists to achieve higher rates of National Institutes of Health-based independent research funding compared to non-K recipients.
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Financiamento Governamental/economia , Ginecologia , Obstetrícia , Médicos , Pesquisadores , Apoio à Pesquisa como Assunto/economia , Pesquisa Biomédica/economia , Feminino , Humanos , Masculino , Mentores , National Institutes of Health (U.S.) , Estados UnidosRESUMO
Human seminal plasma contains factors that can regulate the female immune system and potentially promote reproductive fitness. Adverse effects on fertility and pregnancy may occur when seminal plasma provides insufficient, excessive, or altered signals or when the female partner is incapable of receiving these signals.
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Genitália Feminina/fisiopatologia , Sêmen/fisiologia , Feminino , Genitália Feminina/imunologia , Humanos , Inflamação/fisiopatologia , MasculinoRESUMO
Human immunodeficiency virus (HIV)-infected leukocytes have been detected in genital secretions from HIV-infected men and women and may play an important role in the sexual transmission of HIV. However, they have been largely overlooked in studies on mechanisms of HIV transmission and in the design and testing of HIV vaccine and microbicide candidates. This article describes the characteristics and quantities of leukocytes in male and female genital secretions under various conditions and also reviews evidence for the involvement of HIV-infected cells in both horizontal and vertical cell-associated HIV transmission. Additional research is needed in this area to better target HIV prevention strategies.
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Genitália Feminina/virologia , Genitália Masculina/virologia , HIV/fisiologia , Feminino , Doenças dos Genitais Femininos/fisiopatologia , Doenças dos Genitais Masculinos/fisiopatologia , Genitália Feminina/metabolismo , Genitália Masculina/metabolismo , Infecções por HIV/virologia , Humanos , Transmissão Vertical de Doenças Infecciosas , Leucócitos/fisiologia , Leucócitos/virologia , Masculino , Sêmen/virologiaRESUMO
The high incidence of HIV and other sexually transmitted infections (STIs), and an unmet need for modern contraception resulting in a high unintended pregnancy rate, are major problems in reproductive health. The concept of multipurpose prevention technology (MPT) was introduced following the failure of several leading microbicide candidates to prevent human immunodeficiency virus type 1 (HIV-1) transmission in large clinical trials in the early 2000s. MPTs are defined as products designed to simultaneously prevent at least two of the following conditions: unintended pregnancy, HIV-1, or other major STIs. The goal of contraceptive MPT products (cMPTs) is to provide contraception and protection against one or more major STI pathogen (eg, HIV-1, herpes simplex virus (HSV) type 2, Neisseria gonorrhoeae (gonorrhea), Treponema pallidum (syphilis), Trichomonas vaginalis, Chlamydia trachomatis (Chlamydia). This new field has great potential and will benefit from lessons learned from the early microbicide trials. The cMPT field includes candidates representing various categories with different mechanisms of action including pH modifiers, polyions, microbicidal peptides, monoclonal antibodies, and other peptides that target specific reproductive and infectious processes. More preclinical research is being conducted to ensure minimal side effects and maximum efficacy in vivo. Effective proven and novel candidates are being combined to maximize efficacy, minimize side effects, and avoid drug resistance. More attention is being paid to acceptability and new delivery systems. cMPTs have a very promising future if adequate resources can be mobilized to sustain the effort from preclinical research to clinical trials to bring effective, acceptable, and affordable products to market.
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Monoclonal antibodies (mAbs) are currently being produced for a number of clinical applications including contraception and the prevention of sexually transmitted infections (STIs). Combinations of contraceptive and anti-STI mAbs, including antibodies against HIV-1 and HSV-2, provide a powerful and flexible approach for highly potent and specific multipurpose prevention technology (MPT) products with desirable efficacy, safety and pharmacokinetic profiles. MAbs can be administered systemically by injection, or mucosally via topical products (e.g., films, gels, rings) which can be tailored for vaginal, penile or rectal administration to address the needs of different populations. The MPT field has faced challenges with safety, efficacy, production and cost. Here, we review the state-of-the-art of mAb MPTs that tackle these challenges with innovative strategies in mAb engineering, manufacturing, and delivery that could usher in a new generation of safe, efficacious, cost-effective, and scalable mAb MPTs.
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High rates of unintended pregnancies worldwide indicate a need for more accessible and acceptable methods of contraception. We have developed a monoclonal antibody, the Human Contraception Antibody (HCA), for use by women in vaginal films and rings for contraception. The divalent F(ab')2 region of HCA binds to an abundant male reproductive tract-specific antigen, CD52g, and potently agglutinates sperm. Certain other antibody activities mediated by the Fc region such as mucus trapping, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) could have beneficial or negative effects. The purpose of this study was to document HCA Fc effector functions and determine whether an engineered variant of HCA with a modified Fc region, HCA-LALAPG, retains desirable contraceptive activity while minimizing Fc-mediated effects. Fab and Fc functions were compared between HCA and HCA-LALAPG. Fab activity was assessed using sperm agglutination and modified swim-up ("sperm escape") assays. Fc functions were assessed by CDC (sperm immobilization), ADCP, and cervical mucus penetration assays. HCA and HCA-LALAPG showed equivalent activity in assays of Fab function. In the assays of Fc function, HCA supported strong CDC, ADCP, and sperm trapping in cervical mucus whereas HCA-LALAPG demonstrated little to no activity. HCA and the HCA-LALAPG variant were both highly effective in the sperm agglutination assays but differed in Fc mediated functions. Use of the HCA-LALAPG variant for contraception in women could reduce antibody-mediated inflammation and antigen presentation but may have reduced contraceptive efficacy due to much weaker sperm trapping in mucus and complement-dependent sperm immobilization activity.
Assuntos
Sêmen , Aglutinação Espermática , Gravidez , Humanos , Masculino , Feminino , Aglutinação Espermática/genética , Anticorpos Monoclonais , Anticoncepcionais , Anticoncepção , Citotoxicidade Celular Dependente de AnticorposRESUMO
BACKGROUND: Self-administered swabs are used to sample vaginal contents for a variety of clinical purposes including detection of sexually transmitted infections, condom breakage, and vaginal product use. The goal of this study was to determine whether a quantitative glycogen assay can be used to assess whether a swab has been exposed to the vagina to assure study compliance. STUDY DESIGN: Buccal, skin, or vaginal samples were tested to determine whether a commercial quantitative glycogen assay can differentiate vaginal specimens. In addition, archived remnant de-identified vaginal swabs from clinical trials were tested. Periodic acid-Schiff stain was used to identify glycogen-positive cells as a confirmation test. RESULTS: Glycogen concentrations in eluates of vaginal swabs from reproductive-aged women were significantly higher than those from unused swabs (mean ± SE, 964 ± 135 µg/mL vs. 14.7 ± 2.5 µg/mL, P < 0.001) and swabs exposed to buccal and finger/hand epithelia (40.3 ± 4.8 and 18.5 ± 5.4 µg/mL, P < 0.001). Glycogen concentrations were lower and more variable in vaginal swabs from older perimenopausal/menopausal women (mean ± SE, 235 ± 123, P < 0.01). Semen and sample storage longer than 1 year did not affect glycogen detection. Using a cutoff of 100 µg/mL of glycogen, 30 of 30 vaginal swabs from reproductive-aged women versus 0 of 28 control swabs were positive, for an assay sensitivity of 1 (95% confidence interval, 0.86-1) and specificity of 1 (95% confidence interval, 0.85-1). Periodic acid-Schiff stain correlated with soluble glycogen results but was less specific. CONCLUSIONS: The quantitative glycogen assay provides a simple and inexpensive method to validate the use of self-administered swabs for sampling vaginal contents in clinical studies.
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Glicogênio/análise , Mãos/microbiologia , Mucosa Bucal/microbiologia , Infecções Sexualmente Transmissíveis/microbiologia , Vagina/microbiologia , Esfregaço Vaginal/métodos , Adulto , Fatores Etários , Feminino , Humanos , Valor Preditivo dos Testes , Kit de Reagentes para Diagnóstico/estatística & dados numéricos , Sensibilidade e Especificidade , Infecções Sexualmente Transmissíveis/diagnóstico , Manejo de EspécimesRESUMO
Objective: To determine whether infertility diagnoses differ between Black ethnic subgroups. Design: Retrospective review. Setting: an urban safety-net hospital. Patients: Women seeking infertility care between 2005 and 2015. Interventions: Charts of women with infertility and polycystic ovary syndrome (International Classification of Diseases, Ninth Revision diagnoses) were reviewed to confirm diagnoses. Data were stratified by race and subsequently by ethnicity to evaluate the differences in infertility diagnoses between Black American, Black Haitian, and Black African women. White American women were used as the comparison group. Main Outcome Measures: Infertility diagnoses between Black ethnic subgroups and White women. Results: A total of 358 women met the inclusion criteria, including 99 Black American, 110 Black Haitian, 61 Black African, and 88 White American women. Anovulation/polycystic ovary syndrome was the most common diagnosis in each ethnic group, accounting for 40% of infertility among White American, 57% among Black American, 25% among Black Haitian, and 21% among Black African women. There were no significant differences in the individual infertility diagnoses between Black and White women. Between ethnic subgroups, multivariate analysis showed significantly higher odds of infertility because of anovulation/polycystic ovary syndrome in Black American women compared with Black African women (odds ratio [OR], 4.9; 95% confidence interval [CI], 1.4-17.0). Compared with Black African women, higher odds of tubal factor infertility were observed in Black American (OR, 4.7; 95% CI, 1.16-18.7) and Black Haitian women (OR, 4.0; 95% CI, 1.1-14.0). Conclusions: Infertility diagnoses were not homogeneous across Black ethnic groups. Studies examining infertility should specify the ethnic subgroups within a race because this may affect results.
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BACKGROUND: Approximately 40% of human pregnancies are unintended, indicating a need for more acceptable effective contraception methods. New antibody production systems make it possible to manufacture reagent-grade human monoclonal antibodies (mAbs) for clinical use. We used the Nicotiana platform to produce a human antisperm mAb and tested its efficacy for on-demand topical contraception. METHODS: Heavy and light chain variable region DNA sequences of a human IgM antisperm antibody derived from an infertile woman were inserted with human IgG1 constant region sequences into an agrobacterium and transfected into Nicotiana benthamiana. The product, an IgG1 mAb ["Human Contraception Antibody" (HCA)], was purified on Protein A columns, and QC was performed using the LabChip GXII Touch protein characterization system and SEC-HPLC. HCA was tested for antigen specificity by immunofluorescence and western blot assays, antisperm activity by sperm agglutination and complement dependent sperm immobilization assays, and safety in a human vaginal tissue (EpiVaginal™) model. FINDINGS: HCA was obtained at concentrations ranging from 0.4 to 4 mg/ml and consisted of > 90% IgG monomers. The mAb specifically reacted with a glycan epitope on CD52g, a glycoprotein produced in the male reproductive tract and found in abundance on sperm. HCA potently agglutinated sperm under a variety of relevant physiological conditions at concentrations ≥ 6.25 µg/ml, and mediated complement-dependent sperm immobilization at concentrations ≥ 1 µg/ml. HCA and its immune complexes did not induce inflammation in EpiVaginal™ tissue. INTERPRETATION: HCA, an IgG1 mAb with potent sperm agglutination and immobilization activity and a good safety profile, is a promising candidate for female contraception. FUNDING: This research was supported by grants R01 HD095630 and P50HD096957 from the National Institutes of Health.
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Anticorpos Monoclonais/imunologia , Antígeno CD52/imunologia , Anticoncepção Imunológica/métodos , Espermatozoides/imunologia , Vacinas Anticoncepcionais/imunologia , Especificidade de Anticorpos , Feminino , Humanos , MasculinoRESUMO
Transition into daylight savings time (DST) has studied negative impacts on health, but little is known regarding impact on fertility. This retrospective cohort study evaluates DST impact on pregnancy and pregnancy loss rates in 1,654 autologous in vitro fertilization cycles (2009 to 2012). Study groups were identified based on the relationship of DST to embryo transfer. Pregnancy rates were similar in Spring and Fall (41.4%, 42.2%). Pregnancy loss rates were also comparable between Spring and Fall (15.5%, 17.1%), but rates of loss were significantly higher in Spring when DST occurred after embryo transfer (24.3%). Loss was marked in patients with a history of prior spontaneous pregnancy loss (60.5%).
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Aborto Espontâneo , Ritmo Circadiano , Fertilização in vitro , Adulto , Feminino , Humanos , Gravidez , Estudos RetrospectivosRESUMO
: Passive immunization, the transfer of antibodies to a nonimmune individual to provide immunological protection, has been used for over 100 years to prevent and treat human infectious diseases. The introduction of techniques to produce human mAbs has revolutionized the field, and a large number of human mAbs have been licensed for the treatment of cancer, autoimmune and inflammatory diseases. With the recent discovery and production of highly potent broadly neutralizing and other multifunctional antibodies to HIV, mAbs are now being considered for HIV therapy and prophylaxis. In this review, we briefly present recent advances in the anti-HIV mAb field and outline strategies for the selection, engineering and production of human mAbs, including the modification of their structure for optimized stability and function. We also describe results from nonhuman primate studies and phase 1 clinical trials that have tested the safety, tolerability, pharmacokinetics, and efficacy of mAb-based HIV prevention strategies, and discuss the future of parenteral and topical mAb administration for the prevention of HIV transmission.
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Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Anti-HIV/efeitos dos fármacos , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Imunização Passiva , Profilaxia Pré-Exposição/métodos , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Administração Tópica , Animais , Anticorpos Monoclonais/administração & dosagem , Feminino , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Humanos , Imunização Passiva/métodos , Reto/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Resultado do Tratamento , Vagina/virologiaRESUMO
OBJECTIVE: Preejaculatory fluid, a viscous, lubricating secretion expressed by penile urethral glands during sexual excitement, may play a role in the sexual transmission of HIV-1. The urethra has been shown to be an important site of HIV infection in men and male macaques, and preejaculatory fluid and urethral swabs from HIV-1-infected men often contain HIV. Recent studies have shown that HAART reduces but does not eliminate seminal HIV shedding in infected men, and that the penile urethra remains a site of persistent simian immunodeficiency virus infection in HAART-treated macaques. The objective of this study was to determine whether HIV-infected men on stable HAART continue to shed HIV into preejaculatory secretions. DESIGN: Single-center prospective study. METHODS: Sixty HIV-infected men on HAART were recruited to provide preejaculatory fluid, semen, and blood for HIV RNA quantification by reverse transcription-PCR. RESULTS: Eight men had detectable HIV in blood; of these four had HIV in semen (range: 40-96â000âcopies/ml), and one had HIV in preejaculate (2400âcopies/sample). Fifty-two men had undetectable HIV RNA in blood; of these 10 (19.2%) had HIV RNA in semen (range: 59-800âcopies/ml) whereas none (0%) had HIV RNA in preejaculate (Pâ=â0.004). CONCLUSIONS: This study documents for the first time high levels of HIV RNA in preejaculate fluid. However, none of the men on stable HAART with undetectable blood viral load had HIV RNA in preejaculate, even though many had detectable HIV in semen. The urethral glands do not appear to be a principal source of HIV in men on suppressive HAART.
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Antirretrovirais/uso terapêutico , Secreções Corporais/virologia , Ejaculação , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Eliminação de Partículas Virais , Adulto , Animais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/análise , Resposta Viral Sustentada , Adulto JovemRESUMO
BACKGROUND: Episomal 2-long terminal repeat (LTR) HIV-1 cDNA, a by-product of HIV-1 infection, is used in clinical trials as a marker for ongoing viral replication. It would be useful to employ 2-LTR cDNA to monitor cryptic HIV-1 infection in the genital tract of men on antiretroviral therapy (ART) to predict the evolution of sexually transmissible drug-resistant HIV-1, but studies thus far have failed to detect this marker in semen. The objectives of this study were: 1) to use a technique that maximizes DNA recovery from HIV-1 infected white blood cells in semen to determine if episomal 2-LTR cDNA is detectable in semen of ART-naïve men with other evidence of genital tract HIV-1 infection, and 2) to compare levels of HIV-1 2-LTR cDNA, RNA, and proviral DNA in semen from HIV-1+ men on ART. RESULTS: Using a somatic cell DNA extraction technique, 2-LTR cDNA was detected by PCR/ELISA in 4 out of 8 semen samples from ART-naïve men selected for other signs of seminal HIV-1 infection (positive controls). Southern blot and DNA sequencing confirmed that the amplified sequences were HIV-1 2-LTR cDNA; copy numbers ranged from 55 to 504 copies/sample. Two semen samples from a cohort of 22 HIV-1-infected men on dual nucleoside therapy, one with and one without detectable seminal HIV-1 RNA, were 2-LTR cDNA positive (336 and 8,560 copies/sample). Following addition of indinavir to the therapy regimen, no semen samples from 21 men with controlled peripheral and seminal viral loads were 2-LTR cDNA positive at 1 and 6 month time points, despite the persistence of HIV-1 proviral DNA+ semen cells and seminal cytomegalovirus (CMV) shedding in some cases. However, one individual who failed indinavir therapy and later developed distinct protease inhibitor (PI) drug resistance mutations in semen, maintained elevated levels of HIV-1 RNA and 2-LTR cDNA in semen. CONCLUSION: 2-LTR HIV-1 cDNA is detectable in semen of HIV-1-infected men. Two men on ART had 2-LTR HIV-1 cDNA in semen, suggesting that this marker may prove to be useful to monitor HIV-1 infection in the genital tract of men on ART to predict the evolution of drug resistance mutations in semen.
RESUMO
Cervical cytobrushes provide a tool to sample endocervical T cells for assessment of local immunity. However, most previous studies in HIV-seropositive women have excluded samples containing blood and hence have analyzed selected populations of patients. As determined by multiple-parameter flow cytometric analysis of T lymphocytes from two sequential cytobrushes and concurrently collected blood samples, this study found a minimal effect of blood contamination on cervical T cell phenotypic parameters in normal women. The consequences of blood in endocervical samples will ultimately depend on the design and objective of each study, but these data suggest studies could be more inclusive and should not automatically discard samples that contain red blood cells.
Assuntos
Colo do Útero/imunologia , Imunidade Celular , Linfócitos T/imunologia , Feminino , Citometria de Fluxo , HumanosRESUMO
OBJECTIVE: To determine whether conversion of gonadotropin/IUI cycles at high risk of high-order multiple pregnancies to IVF yields a pregnancy rate high enough to warrant the added intervention. DESIGN: Case-control study. SETTING: Brigham and Women's Hospital assisted reproductive technology program. PATIENT(S): Seventy-seven patients converted from gonadotropin/IUI to IVF, 77 consecutive age and attempt number-matched controls (sequential controls [SCs]), and 77 consecutive age-, attempt-, and E(2)-matched controls (E(2) controls [ECs]). INTERVENTION(S): Gonadotropin/IUI cycles with exuberant responses were converted to IVF (cases) to avoid cycle cancellation and high-order multiple pregnancies. MAIN OUTCOME MEASURE(S): Pregnancy rates, delivery rates, E(2) levels, follicle and oocyte number, and fertilization and implantation rates. RESULT(S): Compared with SCs and ECs, cases had more follicles (16.3 +/- 0.6 vs. 13.3 +/- 0.9 and 14.4 +/- 0.9) and higher E(2) at hCG administration (1,951 +/- 93 vs. 1,568 +/- 96 and 1,939 +/- 89 pg/mL). Delivery rates among the three groups (45.5% vs. 32.5% and 39.0%) did not differ significantly. Despite the transfer of fewer embryos in cases than in controls (2.5 +/- 0.1 vs. 3.1 +/- 0.1 and 2.9 +/- 0.1), three triplet pregnancies occurred in cases and three in controls. CONCLUSION(S): Conversion of high responder gonadotropin/IUI patients to IVF is an effective alternative to cycle cancellation and offers a delivery rate as high or higher per cycle than that of planned IVF. Sample size limited the statistical power of the study.