京都大学 / 新制・課程博士 / 博士(医学) / 甲第23072号 / 医博第4699号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 浅野 雅秀, 教授 福田 和彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Disgust is an important adaptive mechanism in protection against disease. Disgust sensitivity is very variable between individuals and, according to the compensatory prophylaxis hypothesis (CPH), should be adjusted to individual's vulnerability to disease. The beginning of pregnancy is associated with a number of changes in the immune system and thus disgust sensitivity is expected to be increased. The aim of this thesis was to test the CPH in relation to longitudinal changes in disgust during pregnancy and after birth, as well as in comparison with non-pregnant control sample of women. Another aim was to observe the maladaptive role of disgust, specifically the relationship between trait anxiety and disgust. Against the set expectations, disgust was observed to increase during pregnancy in the animal reminder domain of disgust. However, the function of this domain in protection against disease has been criticized. These changes were only observed in pregnancies with a male fetus. In line with the CPH predictions, it was shown that women who reported having recent health problems also had higher disgust. Similarly, the results showed a possible protective role of mothers' increased disgust in the beginning of pregnancy, which was related to new-borns having a higher 10 minute APGAR score. When...

Fléau mondial depuis des millénaires, la tuberculose (TB) a régressé dans la deuxième moitié du 20ème siècle avant de connaitre une résurgence à partir des années 1980 à la faveur de la pandémie du VIH. Les deux maladies se potentialisent mutuellement et forment un « couple infernal ». En Afrique, la TB est la première cause de mortalité des adultes infectés par le VIH, quel que soit leur niveau d’immunité. Une des mesures pour lutter contre la TB associée au VIH est la chimioprophylaxie, consistant à traiter une infection tuberculeuse latente pour prévenir l’évolution vers une TB maladie. La mieux évaluée, consiste à prescrire 6 à 12 mois de monothérapie d’isoniazide (Isoniazid Preventive Therapy, IPT). Depuis 1993, l’OMS recommande la prescription de 6 mois d’IPT chez toutes les personnes infectées par le VIH sans signe de TB active. Malgré des preuves scientifiques solides à l’appui de cette recommandation, l’utilisation de l’IPT est toujours restée faible. Avant notre travail, trois raisons expliquaient cette faiblesse : (i) la crainte qu’une chimioprophylaxie mal appliquée ne favorise l’émergence de résistances ; (ii) le fait que les essais avaient démontré l’efficacité de l’IPT pour réduire l’incidence de TB, pas pour réduire la mortalité ; (iii) le fait que les essais d’IPT avaient eu lieu en majorité avant l’ère des antirétroviraux (ARV), chez des personnes très immunodéprimées. Les ARV permettant également de réduire le risque de TB en faisant régresser l’immunodépression, certains considéraient que l’IPT était devenue inutile. Dans cette thèse nous faisons d’abord un rappel des connaissances essentielles sur l’infection par le VIH, la TB, l’association TB/VIH, et le concept de chimioprophylaxie antituberculeuse. Puis nous exposons les résultats de l’analyse du suivi prolongé de l’essai randomisé Temprano ANRS 12136, qui s’est déroulé entre 2008 et 2015. Cet essai a suivi 2056 adultes infectés par le VIH dans 9 centres de soins à Abidjan. Les participants qui avaient des CD4 élevés (moyenne 477/mm3) étaient randomisés en 4 bras pour étudier deux interventions : 6 mois d’IPT (reçu vs. non reçu) et ARV (début immédiat vs. début différé). Les participants ont été suivis pendant 4,9 ans en moyenne. 89% d’entre eux ont débuté des ARV. Pendant le suivi, il y a eu 86 décès, 34 dans le groupe avec IPT (probabilité à 6 ans : 4,1% ; IC95% 2,9–5,7) et 52 dans le groupe sans IPT (probabilité à 6 ans: 6,9% ; 5,1–9,2). Le Hazard ratio de décès dans le groupe avec IPT par rapport à l’autre groupe était 0,63 (95% CI 0,41-0,97). Il n’y avait pas d’interaction entre IPT et ARV précoce, ni entre IPT et le temps. Ces résultats ont été publiés dans The Lancet Global Health. Enfin nous discutons ces résultats avec ceux des essais d’IPT précédents, dans une revue critique de la littérature analysant les données d’efficacité et de tolérance, les déterminants de l’efficacité, et les risques de résistance. Nous montrons que l’essai Temprano complète et élargit le spectre des connaissances, et que les preuves scientifiques accumulées depuis 1993 jusqu’à l’essai Temprano inclus suggèrent que les ARV modifient certains paramètres de l’IPT qu’on pensait solidement établis. Avant l’ère des ARV on considérait que l’efficacité de l’IPT était forte chez les personnes avec IDR positive mais très faible voire inexistante chez les personnes avec IDR négative, qu’il y avait une perte d’efficacité de l’IPT au cours du temps et que l’IPT n’avait pas d’effet sur la mortalité. Avec les ARV, on voit que l’IPT est efficace quel que soit le résultat des tests tuberculiniques, que cette efficacité est prolongée, et qu’elle se traduit non seulement par une réduction de la TB mais aussi de la mortalité. L’IPT reste donc une intervention d’une grande actualité à l’ère des ARV. Ces résultats devraient convaincre les pays jusque-là réticents à appliquer les recommandations de l’OMS. / Tuberculosis (TB) has been a worldwide scourge for millennia. It has regressed in the second half of the 20th century before resurging in the 1980s because of the HIV pandemic. Both diseases potentiate each other and form a "cursed duet". In Africa, TB is the leading cause of mortality among HIV-infected adults, regardless of their level of immunity. One of the measures to fight HIV-associated TB is chemoprophylaxis, which consists in treating latent TB infection to prevent the progression to TB disease. The most evaluated chemoprophylaxis, referred to as "Isoniazid Preventive Therapy" (IPT), consists in prescribing 6 to 12 months of isoniazid monotherapy. Since 1993, WHO recommends the prescription of 6 months of IPT in all HIV-infected persons who do not have evidence of active TB. Despite strong scientific evidence to support this recommendation, the use of IPT has remained low. Before our work, there were three reasons for this:(i) people feared that chemoprophylaxis might favor the emergence of resistance to TB drug; (ii) the IPT trials demonstrated the effectiveness of IPT in reducing TB incidence, not in reducing mortality; (iii) most IPT trials took place before the antiretroviral treatment (ART) era, in highly immunocompromised individuals. As ART also reduces the risk of TB by decreasing immunosuppression, some people considered that IPT had become useless. In this work, we first go over the basic knowledge about HIV infection, TB, the combination of the two diseases, and the concept of antituberculous chemoprophylaxis. Then we present the results of the long-term follow-up of the Temprano ANRS 12136 randomized trial, which took place between 2008 and 2015. This trial followed 2056 HIV infected adults in 9 care centers in Abidjan. Participants with high CD4 counts (mean: 477 cells/mm3) were randomized into 4 arms to study two interventions: 6 months of IPT (received vs. not received) and early ART (immediate initiation vs. delayed initiation). Participants were followed for an average of 4.9 years. Eighty nine percent of participants received ART. During follow-up, there were 86 deaths, 34 in patients randomized to IPT (6-year probability: 4.1%, 95% CI 2.9-5.7) and 52 in those randomized to no-IPT (6-year probability: 6.9%, 5.1-9.2). The Hazard ratio of deaths among those randomized to IPT compared to others was 0.63 (95% CI 0.41-0.97). There was no interaction between IPT and early ART, nor between IPT and time. These results were published in The Lancet Global Health. Finally, we discuss these results with those of previous IPT trials, after reviewing all available randomized-controlled evidence on efficacy, safety, efficacy determinants and risks of resistance. We show that the Temprano trial complements and widens the spectrum of evidence accumulated since 1993 and that ART modifies some key parameters of IPT previously thought to be strongly established. Prior to the ART era, evidence suggested that the efficacy of IPT was high in people with positive Tuberculin Skin Test (TST) but very low in those with negative TST; that there was a loss of IPT efficacy over time; and that IPT had no effect on mortality. With ART, IPT appears to be effective regardless of TST results, have prolonged efficacy, and reduce not only TB but also mortality. IPT remains a very topical intervention in the ART era. These results should convince IPT-reluctant countries to implement WHO recommendations.

BACKGROUND: Although the total number of new documented HIV diagnoses annually decreased from 2008-2018, the rate of decrease started to slow in 2013, and substantial variation exists across at-risk groups. People who inject drugs (PWID) account for 9% of new diagnoses annually, with increasing incidence in this population starting in 2015. Among PWID, 34% of new HIV diagnoses occurred in individuals who were also classified as men who have sex with men (MSM), indicating that MSM-PWID have elevated HIV risk. Data on MSM-PWID are scarce, and programmatic and advocacy efforts in HIV prevention do not specifically target MSM-PWID, with no CDC-recommended interventions existing for this population. OBJECTIVE: We sought to characterize the complex, intersecting and unique HIV risks faced by MSM-PWID, including perceptions of HIV risk and attitudes toward antiretroviral pre-exposure prophylaxis (PrEP) among MSM-PWID in urban and non-urban areas of Massachusetts and Rhode Island. METHODS: We recruited PWID through community-based organizations (CBOs; e.g. syringe service programs) in 18 urban centers and smaller cities and towns across Massachusetts and Rhode Island. Participants completed semi-structured interviews exploring substance use behaviors and HIV prevention needs. This in-depth analysis focused on describing the experiences and HIV prevention needs and attitudes of nine participants in the sample who reported a sexual orientation other than “heterosexual.” RESULTS: Most participants identified as cisgender, bisexual men. However, the context of their sexual behaviors varied, with some participants only engaging in same-sex behavior during sex work. The relationship between identity and behavior is explored in the context of reported risk behavior. All participants engaged in at least one behavior that increased risk of HIV acquisition, including syringe sharing, inconsistent condom use, and sex work. Participants also described heightened risk when these behaviors overlapped, particularly within contexts of “sex parties” that some individuals described. At the same time, experiences of isolation and exclusion were common in the sample, indicating a potential vulnerability in this population. HIV risk perception varied among participants, but was not consistently aligned with the behaviors described. Many participants did not perceive needing HIV prevention services “yet,” indicating that they did not view their risk to be high enough to warrant prevention services. Alternatively, some described needing to prioritize daily survival and mental health over HIV prevention efforts. Although knowledge of PrEP was low, acceptability of PrEP was high in this sample, and several participants provided specific suggestions for improving the feasibility of PrEP. CONCLUSION: Data from this study illustrate the HIV risks and prevention needs of this at-risk population and highlight mechanisms to engage them in preventative care. Our main findings are (1) participants had low knowledge of PrEP, but were largely enthusiastic after learning about it from interviewers, (2) varying identity related to same-sex behavior among men who have sex with men and inject drugs may play a role in shaping HIV risk and prevention needs, (3) specific healthcare and prevention service needs of this population emerged, including reducing risk at sex parties and improving access to non-stigmatizing mental health services. An in-depth understanding of the ways in which sexual orientation and gender identity shape HIV risk and prevention needs remains crucial in providing treatment and prevention services to MSM-PWID.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Pre-exposure prophylaxis (PrEP) has limited availability across Latin America, though access is increasing. We explored PrEP uptake in Mexico via an online survey completed by Spanish-speaking, Hornet geosocial networking application (GSN app) users without HIV (n = 2020). Most (81.3%) had heard of PrEP, 3.5% were current users, and 34.2% intended to take PrEP within six months. Current PrEP use was associated with PrEP eligibility (aOR 26.07 [95%CI 13.05–52.09], p < 0.001), recent STI testing (aOR 3.79 [95%CI 1.10–13.11], p = 0.035), and recent chemsex (aOR 3.02 [95%CI 1.02–8.93], p = 0.046). Recent STI testing was associated with hearing about PrEP from a doctor (aOR 3.26 [95%CI 1.98–5.36], p < 0.001), and those who lived in large cities were less likely to have learned about PrEP via Hornet (aOR 0.52 [95%CI 0.32–0.85], p = 0.009). Interventions to increase PrEP uptake in Mexico should build upon existing health networks and utilize GSN apps for PrEP information dissemination, particularly in less populated areas. / University of California / Revisión por pares

Following rabies virus (RABV) exposure, a combination of thorough wound washing, multiple-dose vaccine administration and the local infiltration of rabies immune globulin (RIG) are essential components of modern post-exposure prophylaxis (PEP). Although modern cell-culture-based rabies vaccines are increasingly used in many countries, RIG is much less available. The prohibitive cost of polyclonal serum RIG products has prompted a search for alternatives and design of anti-RABV monoclonal antibodies (MAbs) that can be manufactured on a large scale with a consistent potency and lower production costs. Robust in vitro neutralization activity has been demonstrated for the CL184 MAb cocktail, a 1:1 protein mixture of two human anti-RABV MAbs (CR57/CR4098), against a large panel of RABV isolates. In this study, we used a hamster model to evaluate the efficacy of experimental PEP against a lethal challenge. Various doses of CL184 and commercial rabies vaccine were assessed for the ability to protect against lethal infection with representatives of four distinct bat RABV lineages of public health relevance: silver-haired bat (Ln RABV); western canyon bat (Ph RABV); big brown bat (Ef-w1 RABV) and Mexican free-tailed bat RABV (Tb RABV). 42–100% of animals survived bat RABV infection when CL184 (in combination with the vaccine) was administered. A dose-response relationship was observed with decreasing doses of CL184 resulting in increasing mortality. Importantly, CL184 was highly effective in neutralizing and clearing Ph RABV in vivo, even though CR4098 does not neutralize this virus in vitro. By comparison, 19–95% survivorship was observed if human RIG (20 IU/kg) and vaccine were used following challenge with different bat viruses. Based on our results, CL184 represents an efficacious alternative for RIG. Both large-scale and lower cost production could ensure better availability and affordability of this critical life-saving biologic in rabies enzootic countries and as such, significantly contribute to the reduction of human rabies deaths globally.

Patients with human immunodeficiency virus (HIV)/AIDS live a far different life today compared with those who were infected in the 1980s and 1990s. Antiretroviral therapy has evolved from a once poorly tolerated, heavy pill burden to the availability of many once-daily single-tablet regimens. The improvements in therapy have necessitated the need to be cognizant of comorbidities as well as drug-drug interactions. Despite the tremendous advances in therapy, newer therapies are in the pipeline and continue to emerge, making care for patients burdened by HIV perhaps easier than it has ever been.

Unwanted pregnancies and sexually transmitted infections (STIs) are major health concerns of women worldwide. These concerns have prompted efforts to develop Multipurpose Prevention Technologies (MPTs), which simultaneously provide contraception and prevent STIs, including HIV. LL-37, the only human cathelicidin and an effective spermicide on human sperm, has broad antimicrobial activity including in vitro activity against HIV. 17BIPHE2 is a truncated LL-37 peptide, engineered to contain 5 unnatural residues, thus limiting its protease degradation within vaginal fluid. Hence, this antimicrobial peptide (AMP) represents a promising MPT agent. It was therefore hypothesized that these peptides would be inhibitors of HIV infection in cell lines, PBMC, and CD4+ T cells. In the chronically infected ACH-2 cell line, there was significant reduction in p24 production when cells were treated with 17BIPHE2, but not LL-37. When 17BIPHE2 was pre-incubated with HIV prior to infection and present during infection, viral replication decreased in the TZM-bl reporter cell line, but this result was not recapitulated in the primary activated cells, PBMCs nor isolated CD4+ T cells. Conversely, pre-incubation of 17BIPHE2 with target cells prior to infection significantly inhibited HIV infection in a dose-dependent manner. Therefore, 17BIPHE2 may act on the cell or on the virus/cell interaction rather than on the virus itself to inhibit HIV infection.

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