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1.
Nat Commun ; 10(1): 2737, 2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31227699

RESUMEN

Little is known about the genotypic make-up of HIV-1 DNA genomes during the earliest stages of HIV-1 infection. Here, we use near-full-length, single genome next-generation sequencing to longitudinally genotype and quantify subtype C HIV-1 DNA in four women identified during acute HIV-1 infection in Durban, South Africa, through twice-weekly screening of high-risk participants. In contrast to chronically HIV-1-infected patients, we found that at the earliest phases of infection in these four participants, the majority of viral DNA genomes are intact, lack APOBEC-3G/F-associated hypermutations, have limited genome truncations, and over one year show little indication of cytotoxic T cell-driven immune selections. Viral sequence divergence during acute infection is predominantly fueled by single-base substitutions and is limited by treatment initiation during the earliest stages of disease. Our observations provide rare longitudinal insights of HIV-1 DNA sequence profiles during the first year of infection to inform future HIV cure research.


Asunto(s)
ADN Viral/genética , Evolución Molecular , Genoma Viral/genética , Infecciones por VIH/virología , VIH-1/genética , Enfermedad Aguda , Adulto , Fármacos Anti-VIH/uso terapéutico , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estudios Longitudinales , Mutación , Estudios Prospectivos , Sudáfrica , Carga Viral , Adulto Joven
2.
Sci Transl Med ; 11(493)2019 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-31118290

RESUMEN

Sustained viremia after acute HIV infection is associated with profound CD4+ T cell loss and exhaustion of HIV-specific CD8+ T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak viremia. Immediate treatment of Fiebig stages I and II infection led to a rapid decline in viral load and diminished magnitude of HIV-specific (tetramer+) CD8+ T cell responses compared to untreated donors. There was a strong positive correlation between cumulative viral antigen exposure before full cART-induced suppression and immune responses measured by MHC class I tetramers, IFN-γ ELISPOT, and CD8+ T cell activation. HIV-specific CD8+ T responses of early treated individuals were characterized by increased CD127 and BCL-2 expression, greater in vitro IFN-γ secretion, and enhanced differentiation into effector memory (Tem) cells. Transcriptional analysis of tetramer+ CD8+ T cells from treated persons revealed reduced expression of genes associated with activation and apoptosis, with concurrent up-regulation of prosurvival genes including BCL-2, AXL, and SRC Early treatment also resulted in robust HIV-specific CD4+ T cell responses compared to untreated HIV-infected individuals. Our data show that limiting acute viremia results in enhanced functionality of HIV-specific CD4+ and CD8+ T cells, preserving key antiviral properties of these cells.

3.
Lancet HIV ; 6(4): e259-e268, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30885693

RESUMEN

Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research.

4.
J Virol ; 93(2)2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30381486

RESUMEN

Heterosexual transmission of human immunodeficiency virus type 1 (HIV-1) is associated with a significant bottleneck in the viral quasispecies population, yet the timing of that bottleneck is poorly understood. We characterized HIV-1 diversity in the blood and female genital tract (FGT) within 2 weeks after detection of infection in three women enrolled in a unique prospective cohort in South Africa. We assembled full-length HIV-1 genomes from matched cervicovaginal lavage (CVL) samples and plasma. Deep sequencing allowed us to identify intrahost single-nucleotide variants (iSNVs) and to characterize within-sample HIV-1 diversity. Our results demonstrated very little HIV-1 diversity in the FGT and plasma by the time viremia was detectable. Within each subject, the consensus HIV-1 sequences were identical in plasma and CVL fluid. No iSNV was present at >6% frequency. One subject had 77 low-frequency iSNVs across both CVL fluid and plasma, another subject had 14 iSNVs in only CVL fluid from the earliest time point, and the third subject had no iSNVs in CVL fluid or plasma. Overall, the small amount of diversity that we detected was greater in the FGT than in plasma and declined over the first 2 weeks after viremia was detectable, compatible with a very early HIV-1 transmission bottleneck. To our knowledge, our study represents the earliest genomic analysis of HIV-1 in the FGT after transmission. Further, the use of metagenomic sequencing allowed us to characterize other organisms in the FGT, including commensal bacteria and sexually transmitted infections, highlighting the utility of the method to sequence both HIV-1 and its metagenomic environment.IMPORTANCE Due to error-prone replication, HIV-1 generates a diverse population of viruses within a chronically infected individual. When HIV-1 is transmitted to a new individual, one or a few viruses establish the new infection, leading to a genetic bottleneck in the virus population. Understanding the timing and nature of this bottleneck may provide insight into HIV-1 vaccine design and other preventative strategies. We examined the HIV-1 population in three women enrolled in a unique prospective cohort in South Africa who were followed closely during the earliest stages of HIV-1 infection. We found very little HIV-1 diversity in the blood and female genital tract during the first 2 weeks after virus was detected in the bloodstream. These results are compatible with a very early HIV-1 population bottleneck, suggesting the need to study the HIV-1 population in the female genital tract before virus is detectable in the bloodstream.


Asunto(s)
Infecciones por VIH/sangre , VIH-1/genética , Metagenómica/métodos , Análisis de Secuencia de ARN/métodos , Vagina/virología , Femenino , Infecciones por VIH/virología , VIH-1/clasificación , Humanos , Filogenia , Estudios Prospectivos , Cuasiespecies , ARN Viral/genética , Sudáfrica , Adulto Joven
6.
Lancet HIV ; 5(1): e35-e44, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28978417

RESUMEN

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.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Femenino , Infecciones por VIH/virología , VIH-1/genética , VIH-1/fisiología , Humanos , Masculino , Estudios Prospectivos , Factores Socioeconómicos , Sudáfrica , Carga Viral , Adulto Joven
7.
Front Immunol ; 8: 1104, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28943879

RESUMEN

Immunological events in acute HIV-1 infection before peak viremia (hyperacute phase) may contribute to the development of broadly cross-neutralizing antibodies. Here, we used pre-infection and acute-infection peripheral blood mononuclear cells and plasma samples from 22 women, including 10 who initiated antiretroviral treatment in Fiebig stages I-V of acute infection to study B cell subsets and B-cell associated cytokines (BAFF and CXCL13) kinetics for up to ~90 days post detection of plasma viremia. Frequencies of B cell subsets were defined by flow cytometry while plasma cytokine levels were measured by ELISA. We observed a rapid but transient increase in exhausted tissue-like memory, activated memory, and plasmablast B cells accompanied by decline in resting memory cells in untreated, but not treated women. B cell subset frequencies in untreated women positively correlated with viral loads but did not predict emergence of cross-neutralizing antibodies measured 12 months post detection of plasma viremia. Plasma BAFF and CXCL13 levels increased only in untreated women, but their levels did not correlate with viral loads. Importantly, early CXCL13 but not BAFF levels predicted the later emergence of detectable cross-neutralizing antibodies at 12 months post detection of plasma viremia. Thus, hyperacute HIV-1 infection is associated with B cell subset changes, which do not predict emergence of cross-neutralizing antibodies. However, plasma CXCL13 levels during hyperacute infection predicted the subsequent emergence of cross-neutralizing antibodies, providing a potential biomarker for the evaluation of vaccines designed to elicit cross-neutralizing activity or for natural infection studies to explore mechanisms underlying development of neutralizing antibodies.

8.
J Clin Invest ; 127(7): 2689-2696, 2017 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-28628034

RESUMEN

HIV-1 causes a chronic, incurable disease due to its persistence in CD4+ T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4+ T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4+ T cells, and subsets of functionally polarized memory CD4+ T cells. This approach identified multiple sets of independent, near-full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4+ T cells harboring intact HIV-1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4+ T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4+ T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4+ T cells.


Asunto(s)
Genoma Viral/inmunología , VIH-1/fisiología , Células TH1/inmunología , Células TH1/virología , Latencia del Virus/inmunología , Adulto , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad
9.
Immunity ; 46(1): 29-37, 2017 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-28087240

RESUMEN

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.


Asunto(s)
Cuello del Útero/microbiología , Infecciones por VIH/microbiología , Vagina/microbiología , Animales , Bacterias Anaerobias , Linfocitos T CD4-Positivos/inmunología , Estudios de Cohortes , Femenino , Citometría de Flujo , Humanos , Lactobacillus , Ratones , Microbiota/inmunología , Prevotella , Sudáfrica
10.
South Afr J HIV Med ; 18(1): 775, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29568643

RESUMEN

The gap in HIV testing remains significant and new modalities such as HIV self-testing (HIVST) have been recommended to reach key and under-tested populations. In December 2016, the World Health Organization (WHO) released the Guidelines on HIV Self-Testing and Partner Notification: A Supplement to the Consolidated Guidelines on HIV Testing Services (HTS) and urged member countries to develop HIVST policy and regulatory frameworks. In South Africa, HIVST was included as a supplementary strategy in the National HIV Testing Services Policy in 2016, and recently, guidelines for HIVST were included in the South African National Strategic Plan for HIV, sexually transmitted infections and tuberculosis 2017-2022. This document serves as an additional guidance for the National HIV Testing Services Policy 2016, with specific focus on HIVST. It is intended for policy advocates, clinical and non-clinical HTS providers, health facility managers and healthcare providers in private and public health facilities, non-governmental, community-based and faith-based organisations involved in HTS and outreach, device manufacturers, workplace programmes and institutes of higher education.

11.
Immunity ; 44(2): 391-405, 2016 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-26850658

RESUMEN

Innate lymphoid cells (ILCs) play a central role in the response to infection by secreting cytokines crucial for immune regulation, tissue homeostasis, and repair. Although dysregulation of these systems is central to pathology, the impact of HIV-1 on ILCs remains unknown. We found that human blood ILCs were severely depleted during acute viremic HIV-1 infection and that ILC numbers did not recover after resolution of peak viremia. ILC numbers were preserved by antiretroviral therapy (ART), but only if initiated during acute infection. Transcriptional profiling during the acute phase revealed upregulation of genes associated with cell death, temporally linked with a strong IFN acute-phase response and evidence of gut barrier breakdown. We found no evidence of tissue redistribution in chronic disease and remaining circulating ILCs were activated but not apoptotic. These data provide a potential mechanistic link between acute HIV-1 infection, lymphoid tissue breakdown, and persistent immune dysfunction.


Asunto(s)
Infecciones por VIH/inmunología , VIH-1/inmunología , Interferón gamma/metabolismo , Intestinos/patología , Linfocitos/inmunología , Enfermedad Aguda , Antivirales/administración & dosificación , Apoptosis/efectos de los fármacos , Apoptosis/genética , Movimiento Celular , Células Cultivadas , Enfermedad Crónica , Estudios de Cohortes , Regulación de la Expresión Génica , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunidad Innata , Interferón gamma/genética , Intestinos/virología , Linfocitos/efectos de los fármacos , Linfocitos/virología , Factores de Tiempo , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Carga Viral/inmunología
12.
Lancet Infect Dis ; 16(4): 441-8, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26723758

RESUMEN

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.


Asunto(s)
Anticonceptivos Femeninos/efectos adversos , Infecciones por VIH/etiología , VIH-1/efectos de los fármacos , Progestinas/efectos adversos , Adolescente , Estudios de Cohortes , Anticoncepción/métodos , Anticonceptivos Femeninos/administración & dosificación , Femenino , Infecciones por VIH/epidemiología , Humanos , Incidencia , Inyecciones , Progestinas/administración & dosificación , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Riesgo , Sudáfrica/epidemiología , Adulto Joven
13.
Immunity ; 43(3): 591-604, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26362266

RESUMEN

CD8(+) T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) T cell response, with limited bystander activation of non-HIV memory CD8(+) T cells. HIV-specific CD8(+) T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8(+) T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Activación de Linfocitos/inmunología , Carga Viral/inmunología , Adolescente , Apoptosis/inmunología , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Femenino , Citometría de Flujo , Infecciones por VIH/sangre , Infecciones por VIH/diagnóstico , Infecciones por VIH/virología , VIH-1/genética , VIH-1/inmunología , VIH-1/fisiología , Humanos , Cinética , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Viral/genética , ARN Viral/inmunología , Factores de Tiempo , Viremia/diagnóstico , Viremia/inmunología , Adulto Joven , Receptor fas/inmunología , Receptor fas/metabolismo
15.
Immunity ; 42(5): 965-76, 2015 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-25992865

RESUMEN

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.


Asunto(s)
Interacciones Huésped-Patógeno/inmunología , Lactobacillus/inmunología , Vagina/inmunología , Vagina/microbiología , Adolescente , Adulto , África , Bacterias/genética , Bacterias/inmunología , Biodiversidad , Citocinas/inmunología , Femenino , Humanos , Lactobacillus/genética , ARN Ribosómico 16S/genética , Análisis de Secuencia , Sudáfrica , Adulto Joven
16.
J Infect Dis ; 204 Suppl 4: S1102-9, 2011 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-21996692

RESUMEN

Clinical and logistic systems to support the timely diagnosis of tuberculosis are currently not preventing large numbers of tuberculosis deaths in South Africa. Context-appropriate systems for the diagnosis of tuberculosis are entirely dependent on effective and responsive management of human resources and an uninterrupted supply of clinical materials. Attention to these components of the tuberculosis program is urgently needed before new diagnostic technologies can be expected to impact on tuberculosis mortality in resource constrained settings.


Asunto(s)
Tuberculosis/diagnóstico , Adulto , Niño , Técnicas de Laboratorio Clínico , Prestación de Atención de Salud , Países en Desarrollo , Humanos , Laboratorios de Hospital/organización & administración , Laboratorios de Hospital/provisión & distribución , Personal de Laboratorio Clínico/organización & administración , Personal de Laboratorio Clínico/provisión & distribución , Sudáfrica , Esputo/microbiología
18.
Curr HIV/AIDS Rep ; 6(4): 217-23, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19849965

RESUMEN

Among an estimated 33 million individuals who are infected with HIV worldwide, only 10% are aware of their status. HIV testing is the cornerstone to preventing further transmission and to caring for those infected, particularly as access to treatment improves in resource-limited settings. However, efforts to expand testing through facilities-based testing have not achieved adequate testing coverage, prompting efforts to reach more individuals through strategies such as home-based HIV testing. Home testing is showing promising early results in some high-prevalence, resource-limited settings. This article reviews the mechanisms and literature to date of this door-to-door approach.


Asunto(s)
Infecciones por VIH/diagnóstico , Recursos en Salud , Accesibilidad a los Servicios de Salud , Juego de Reactivos para Diagnóstico , Autocuidado , Infecciones por VIH/economía , Infecciones por VIH/psicología , Humanos , Factores Sexuales , Factores Socioeconómicos
19.
J Virol ; 83(19): 10234-44, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19605475

RESUMEN

A broad Gag-specific CD8(+) T-cell response is associated with effective control of adult human immunodeficiency virus (HIV) infection. The association of certain HLA class I molecules, such as HLA-B*57, -B*5801, and -B*8101, with immune control is linked to mutations within Gag epitopes presented by these alleles that allow HIV to evade the immune response but that also reduce viral replicative capacity. Transmission of such viruses containing mutations within Gag epitopes results in lower viral loads in adult recipients. In this study of pediatric infection, we tested the hypothesis that children may tend to progress relatively slowly if either they themselves possess one of the protective HLA-B alleles or the mother possesses one of these alleles, thereby transmitting a low-fitness virus to the child. We analyzed HLA type, CD8(+) T-cell responses, and viral sequence changes for 61 mother-child pairs from Durban, South Africa, who were monitored from birth. Slow progression was significantly associated with the mother or child possessing one of the protective HLA-B alleles, and more significantly so when the protective allele was not shared by mother and child (P = 0.007). Slow progressors tended to make CD8(+) T-cell responses to Gag epitopes presented by the protective HLA-B alleles, in contrast to progressors expressing the same alleles (P = 0.07; Fisher's exact test). Mothers expressing the protective alleles were significantly more likely to transmit escape variants within the Gag epitopes presented by those alleles than mothers not expressing those alleles (75% versus 21%; P = 0.001). Reversion of transmitted escape mutations was observed in all slow-progressing children whose mothers possessed protective HLA-B alleles. These data show that HLA class I alleles influence disease progression in pediatric as well as adult infection, both as a result of the CD8(+) T-cell responses generated in the child and through the transmission of low-fitness viruses by the mother.


Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/patología , VIH-1/metabolismo , Antígenos HLA/metabolismo , Linfocitos T CD8-positivos/metabolismo , Progresión de la Enfermedad , Epítopos , Femenino , Productos del Gen gag/química , Antígenos HLA-B/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Madres , Replicación Viral
20.
AIDS Res Hum Retroviruses ; 24(2): 265-70, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18284325

RESUMEN

Multiple HIV-1-specific cytokine and proliferative responses by CD4(+) T cells have not been studied in acutely infected infants. Using an intracellular cytokine staining assay, 34 untreated clade C HIV-1-infected infants (2-102 days old) were assessed for IFN-gamma, 28/34 for IL-2, and 26/34 for TNF-alpha responses to all HIV-1 proteins. Responses were detected in 29%, 36%, and 15% of infants, respectively. Twelve of the original 34 infants were then studied longitudinally for 14 months to determine the effect of viral load on IFN-gamma Gag-specific responses: seven infants were treated for 1 year, stopped treatment, and resumed when CD4% was < 20 and five infants were treated only when the CD4% was <20. Following treatment cessation, there was an immediate increase in viral load followed by an increase in the magnitude of CD4(+) Gag-specific responses. Despite this, the majority of infants (54%) had to restart treatment by 24 months of age, indicating that the immune responses were antigen driven but not associated with protection. Among untreated infants HIV-specific CD4(+) responses were detected sporadically indicating a dysfunctional immune response in the face of constant exposure to high levels of viremia.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Animales , Recuento de Linfocito CD4 , Proliferación Celular , Células Cultivadas , Humanos , Lactante , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Estudios Longitudinales , Factor de Necrosis Tumoral alfa/biosíntesis , Carga Viral
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