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1.
Science ; 364(6439): 480-484, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31048489

RESUMO

Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies network theory to HIV protein structure data to quantitate the topological importance of individual amino acid residues. Mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes presented by protective human leukocyte antigen (HLA) class I alleles. Moreover, CD8+ T cell targeting of highly networked epitopes distinguished individuals who naturally control HIV, even in the absence of protective HLA alleles. This approach thereby provides a mechanistic basis for immune control and a means to identify CD8+ T cell epitopes of topological importance for rational immunogen design, including a T cell-based HIV vaccine.


Assuntos
Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Síndrome de Imunodeficiência Adquirida/prevenção & controle , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , HIV-1/imunologia , Alelos , Sequência Conservada , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Mutação , Proteoma/genética , Proteoma/imunologia , Replicação Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana
2.
Lancet HIV ; 5(1): e35-e44, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28978417

RESUMO

BACKGROUND: HIV incidence among young women in sub-Saharan Africa remains high and their inclusion in vaccine and cure efforts is crucial. We aimed to establish a cohort of young women detected during Fiebig stage I acute HIV infection in whom treatment was initiated immediately after diagnosis to advance research in this high-risk group. METHODS: 945 women aged 18-23 years in KwaZulu-Natal, South Africa, who were HIV uninfected and sexually active consented to HIV-1 RNA testing twice a week and biological sampling and risk assessment every 3 months during participation in a 48-96 week life-skills and job-readiness programme. We analysed the effect of immediate combination antiretroviral therapy (ART) on viraemia and immune responses, sexual risk behaviour, and the effect of the socioeconomic intervention. FINDINGS: 42 women were diagnosed with acute HIV infection between Dec 1, 2012, and June 30, 2016, (incidence 8·2 per 100 person-years, 95% CI 5·9-11·1), of whom 36 (86%) were diagnosed in Fiebig stage I infection with a median initial viral load of 2·97 log10 copies per mL (IQR 2·42-3·85). 23 of these 36 women started ART at a median of 1 day (1-1) after detection, which limited the median peak viral load to 4·22 log10 copies per mL (3·27-4·83) and the CD4 nadir to 685 cells per µL (561-802). ART also suppressed viral load (to <20 copies per mL) within a median of 16 days (12-26) and, in 20 (87%) of 23 women, prevented seroconversion, as shown with western blotting. 385 women completed the 48 week socioeconomic intervention, of whom 231 were followed up for 1 year. 202 (87%) of these 231 women were placed in jobs, returned to school, or started a business. INTERPRETATION: Frequent HIV screening combined with a socioeconomic intervention facilitated sampling and risk assessment before and after infection. In addition to detection of acute infection and immediate treatment, we established a cohort optimised for prevention and cure research. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases, International AIDS Vaccine Initiative, Wellcome Trust, Howard Hughes Medical Institute.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Feminino , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Humanos , Masculino , Estudos Prospectivos , Fatores Socioeconômicos , África do Sul , Carga Viral , Adulto Jovem
3.
Immunity ; 46(1): 29-37, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28087240

RESUMO

Elevated inflammation in the female genital tract is associated with increased HIV risk. Cervicovaginal bacteria modulate genital inflammation; however, their role in HIV susceptibility has not been elucidated. In a prospective cohort of young, healthy South African women, we found that individuals with diverse genital bacterial communities dominated by anaerobes other than Gardnerella were at over 4-fold higher risk of acquiring HIV and had increased numbers of activated mucosal CD4+ T cells compared to those with Lactobacillus crispatus-dominant communities. We identified specific bacterial taxa linked with reduced (L. crispatus) or elevated (Prevotella, Sneathia, and other anaerobes) inflammation and HIV infection and found that high-risk bacteria increased numbers of activated genital CD4+ T cells in a murine model. Our results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells. These findings might be leveraged to reduce HIV acquisition in women living in sub-Saharan Africa.


Assuntos
Colo do Útero/microbiologia , Infecções por HIV/microbiologia , Vagina/microbiologia , Animais , Bactérias Anaeróbias , Linfócitos T CD4-Positivos/imunologia , Estudos de Coortes , Feminino , Citometria de Fluxo , Humanos , Lactobacillus , Camundongos , Microbiota/imunologia , Prevotella , África do Sul
4.
J Infect Dis ; 214(4): 612-6, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27357340

RESUMO

Humanized mice reconstituted with a human immune system can be mucosally infected with human immunodeficiency virus (HIV), opening up the possibility of studying HIV transmission in a small-animal model. Here we report that passive immunization with the broadly neutralizing antibody b12 protected humanized mice against repetitive intravaginal infection in a dose-dependent manner. In addition, treatment with the antibody PGT126, which is more potent in vitro, was more efficacious in vivo and provided sterilizing protection. Our results demonstrate that humanized mice can be used as a small-animal model to study the efficacy and mechanism of broadly neutralizing antibody protection against HIV acquisition.


Assuntos
Anticorpos Neutralizantes/administração & dosagem , Modelos Animais de Doenças , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , Imunização Passiva/métodos , Animais , Relação Dose-Resposta Imunológica , Feminino , Camundongos , Camundongos SCID , Resultado do Tratamento
5.
Open Forum Infect Dis ; 3(1): ofw036, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27006961

RESUMO

Prolonged neutropenia is generally thought to be the major factor for invasive pulmonary aspergillosis (IPA). In the present study, we characterize the frequency, severity, and duration of neutropenia that immediately precedes IPA. Prolonged neutropenia was identified in only one third of all IPA cases and occurred exclusively in hematologic patients.

6.
Cell Host Microbe ; 19(3): 311-22, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26962942

RESUMO

Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.


Assuntos
Síndrome de Imunodeficiência Adquirida/microbiologia , Síndrome de Imunodeficiência Adquirida/virologia , Bactérias/isolamento & purificação , Microbioma Gastrointestinal , Microbiota , Vírus/isolamento & purificação , Síndrome de Imunodeficiência Adquirida/complicações , Síndrome de Imunodeficiência Adquirida/imunologia , Antirretrovirais/uso terapêutico , Bactérias/classificação , Bactérias/genética , Linfócitos T CD4-Positivos/imunologia , Variação Genética , Enteropatia por HIV/etiologia , Voluntários Saudáveis , Humanos , Filogenia , Uganda , Vírus/classificação , Vírus/genética
7.
Lancet Infect Dis ; 16(4): 441-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26723758

RESUMO

BACKGROUND: The use of injectable progestin-only contraceptives has been associated with increased risk of HIV acquisition in observational studies, but the biological mechanisms of this risk remain poorly understood. We aimed to assess the effects of progestins on HIV acquisition risk and the immune environment in the female genital tract. METHODS: In this prospective cohort, we enrolled HIV-negative South African women aged 18-23 years who were not pregnant and were living in Umlazi, South Africa from the Females Rising through Education, Support, and Health (FRESH) study. We tested for HIV-1 twice per week to monitor incident infection. Every 3 months, we collected demographic and behavioural data in addition to blood and cervical samples. The study objective was to characterise host immune determinants of HIV acquisition risk, including those associated with injectable progestin-only contraceptive use. Hazard ratios (HRs) were estimated using Cox proportional hazards methods. FINDINGS: Between Nov 19, 2012, and May 31, 2015, we characterised 432 HIV-uninfected South African women from the FRESH study. In this cohort, 152 women used injectable progestin-only contraceptives, 43 used other forms of contraception, and 222 women used no method of long-term contraception. Women using injectable progestin-only contraceptives were at substantially higher risk of acquiring HIV (12·06 per 100 person-years, 95% CI 6·41-20·63) than women using no long-term contraception (3·71 per 100 person-years, 1·36-8·07; adjusted hazard ratio [aHR] 2·93, 95% CI 1·09-7·868, p=0·0326). HIV-negative injectable progestin-only contraceptive users had 3·92 times the frequency of cervical HIV target cells (CCR5+ CD4 T cells) compared with women using no long-term contraceptive (p=0·0241). Women using no long-term contraceptive in the luteal phase of the menstrual cycle also had a 3·25 times higher frequency of cervical target cells compared with those in the follicular phase (p=0·0488), suggesting that a naturally high progestin state had similar immunological effects to injectable progestin-only contraceptives. INTERPRETATION: Injectable progestin-only contraceptive use and high endogenous progesterone are both associated with increased frequency of activated HIV targets cells at the cervix, the site of initial HIV entry in most women, providing a possible biological mechanism underlying increased HIV acquisition in women with high progestin exposure. FUNDING: The Bill and Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases.


Assuntos
Anticoncepcionais Femininos/efeitos adversos , Infecções por HIV/etiologia , HIV-1/efeitos dos fármacos , Progestinas/efeitos adversos , Adolescente , Estudos de Coortes , Anticoncepção/métodos , Anticoncepcionais Femininos/administração & dosagem , Feminino , Infecções por HIV/epidemiologia , Humanos , Incidência , Injeções , Progestinas/administração & dosagem , Modelos de Riscos Proporcionais , Estudos Prospectivos , Risco , África do Sul/epidemiologia , Adulto Jovem
8.
Immunity ; 42(5): 965-76, 2015 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-25992865

RESUMO

Colonization by Lactobacillus in the female genital tract is thought to be critical for maintaining genital health. However, little is known about how genital microbiota influence host immune function and modulate disease susceptibility. We studied a cohort of asymptomatic young South African women and found that the majority of participants had genital communities with low Lactobacillus abundance and high ecological diversity. High-diversity communities strongly correlated with genital pro-inflammatory cytokine concentrations in both cross-sectional and longitudinal analyses. Transcriptional profiling suggested that genital antigen-presenting cells sense gram-negative bacterial products in situ via Toll-like receptor 4 signaling, contributing to genital inflammation through activation of the NF-κB signaling pathway and recruitment of lymphocytes by chemokine production. Our study proposes a mechanism by which cervicovaginal microbiota impact genital inflammation and thereby might affect a woman's reproductive health, including her risk of acquiring HIV.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Lactobacillus/imunologia , Vagina/imunologia , Vagina/microbiologia , Adolescente , Adulto , África , Bactérias/genética , Bactérias/imunologia , Biodiversidade , Citocinas/imunologia , Feminino , Humanos , Lactobacillus/genética , RNA Ribossômico 16S/genética , Análise de Sequência , África do Sul , Adulto Jovem
9.
J AIDS HIV Res ; 5(2): 59-64, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23626920

RESUMO

This research aimed to study the effect of premarital sex on sexually transmitted infections (STIs) and high risk behaviors among women in sub-Saharan Africa. It included 1393 women randomly selected from the Moshi urban district of northern Tanzania. Participants' demographic and socio-demographic characteristics, alcohol use, condom use, number of partners, symptoms of STIs and age at first sex and marriage were obtained. Moreover, blood and urine samples were tested for HIV-1, HSV-2, syphilis, chlamydia, gonorrhea, trichomonas and Mycoplasma genitalium infections. The average duration of premarital sex in the study participants was 1.66 years (SD of 2.61 years). Women with longer duration of premarital sex had higher odds of HIV-1, HSV-2 and other STIs. Moreover, women with longer duration of premarital sex were more likely to report multiple sexual partners. These findings highlight the importance of a lengthy period of premarital sex as a public health issue. STIs prevention programs in sub-Saharan Africa should address factors leading to a longer period of premarital sex in women.

10.
Eur J Immunol ; 41(9): 2729-40, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21630248

RESUMO

Acute HIV infection is marked by dramatic viral replication associated with preferential replication within secondary lymphoid tissues, such as lymph nodes (LNs), that is rapidly but incompletely contained to a viral setpoint. Accumulating evidence supports a role for natural killer (NK) cells in the early control of HIV infection; however, little is known about the location of their antiviral control. Given that HIV replicates profusely in LNs during early infection, we sought to define whether changes occurred in the NK cell infiltrate within these sites during the first year of HIV infection. Surprisingly, NK cell numbers and distribution were unaltered during early HIV infection. LN NK cells expressed decreased inhibitory receptors, were more highly activated, and expressed elevated TRAIL, potentially conferring a superior capacity for NK cells to become activated and control infection. Most noticeably, KIR(+) NK cells were rarely detected in the LN during HIV infection, associated with diminished migratory capacity in the setting of reduced expression of CX3CR1 and CXCR1. Thus, incomplete control of HIV viral replication during early disease may be due to the inefficient recruitment of KIR(+) NK cells to this vulnerable site, providing HIV a niche where it can replicate unabated by early NK-cell-mediated innate pressure.


Assuntos
Infecções por HIV/imunologia , HIV/fisiologia , Evasão da Resposta Imune , Células Matadoras Naturais/metabolismo , Adulto , Idoso , Receptor 1 de Quimiocina CX3C , Movimento Celular/imunologia , Células Cultivadas , Regulação da Expressão Gênica/imunologia , HIV/patogenicidade , Infecções por HIV/virologia , Humanos , Imunidade Inata , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Linfonodos/patologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8A/metabolismo , Receptores KIR/genética , Receptores KIR/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Replicação Viral
11.
Genet Med ; 13(4): 305-13, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20921895

RESUMO

PURPOSE: Leftover newborn spots can provide a powerful research tool as a population-wide DNA bank. Some provinces/states store them for more than 20 years; however, parents are usually not informed of the retention of leftover newborn spots. To examine the opinions of Canadian geneticists regarding permission for leftover newborn spots storage for research purposes and the associated risks, a web-based survey was distributed to all members of the Canadian College of Medical Geneticists with a valid e-mail address (n = 209) and completed by 78 respondents (37%). RESULTS: The majority of respondents (73%) favored opt-out notification for retention of samples that would be held for longer than 2 years. For research on multifactorial conditions using leftover newborn spots originally banked without parental permission, geneticists favored different types of permission depending on the level of identifiable information attached to samples. Thirty-eight percent were concerned that information pamphlets that state that leftover newborn spots will be stored and may be "a source of DNA for research" would lead to a decreased participation in newborn screening. Twenty-eight percent believed that group stigma or family anxiety was likely to result from using nonidentified leftover newborn spots to study multifactorial conditions. CONCLUSION: The concerns of this knowledgeable cohort supports the critical importance of public engagement about both the potential risks and societal benefits associated with the use of leftover newborn spots in research as policy for leftover newborn spots is developed.


Assuntos
Pesquisa em Genética/ética , Triagem Neonatal/ética , Consentimento dos Pais/ética , Atitude Frente a Saúde , Bancos de Sangue/economia , Bancos de Sangue/normas , Doadores de Sangue/ética , Canadá , Bases de Dados Genéticas , Testes Diagnósticos de Rotina , Ética Clínica , Humanos , Recém-Nascido
12.
J Acquir Immune Defic Syndr ; 47(4): 506-13, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18176319

RESUMO

OBJECTIVES: To examine the effect of a 15-session coping group intervention compared with a 15-session therapeutic support group intervention among HIV-positive men and women with a history of childhood sexual abuse (CSA) on sexual transmission risk behavior. DESIGN: A randomized controlled behavioral intervention trial with 12-month follow-up. METHODS: A diverse sample of 247 HIV-positive men and women with histories of CSA was randomized to 1 of 2 time-matched group intervention conditions. Sexual behavior was assessed at baseline; immediately after the intervention; and at 4-, 8-, and 12-month follow-up periods (5 assessments). Changes in frequency of unprotected anal and vaginal intercourse by intervention condition were examined using generalized linear mixed models for all partners, and specifically for HIV-negative or serostatus unknown partners. RESULTS: Participants in the HIV and trauma coping intervention condition decreased their frequency of unprotected sexual intercourse more than participants in the support intervention condition for all partners (P < 0.001; d = 0.38, 0.32, and 0.38 at the 4-, 8-, and 12-month follow-up periods, respectively) and for HIV-negative and serostatus unknown partners (P < 0.001; d = 0.48, 0.39, and 0.04 at the 4-, 8-, and 12-month follow-up periods, respectively). CONCLUSION: A group intervention to address coping with HIV and CSA can be effective in reducing transmission risk behavior among HIV-positive men and women with histories of sexual trauma.


Assuntos
Síndrome de Imunodeficiência Adquirida/prevenção & controle , Adaptação Psicológica , Abuso Sexual na Infância/psicologia , Infecções por HIV/prevenção & controle , Síndrome de Imunodeficiência Adquirida/psicologia , Síndrome de Imunodeficiência Adquirida/transmissão , Adulto , Criança , Feminino , Infecções por HIV/psicologia , Infecções por HIV/transmissão , Educação em Saúde/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde) , Comportamento Sexual/psicologia , Parceiros Sexuais
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