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Longitudinal Human Immunodeficiency Virus Type 1 Load in the Italian Seroconversion Study: Correlates and Temporal Trends of Virus Load
Abstract and Figures
A prospective study of 149 human immunodeficiency virus type 1 (HIV-1) seroconverters was conducted to describe trends and
correlates of HIV-1 load after seroconversion and over time. HIV-1 load was quantified from frozen sera by reverse transcriptase-polymerase
chain reaction. High early virus load was associated with lower CD4 cell counts and male sex but not with age at seroconversion
or injection drug use. Early virus load predicted progression to clinical AIDS and AIDS/<200 CD4 cells/μL. Virus load exhibited a decline of 52% by 18 months after seroconversion then increased 23% annually (95% confidence interval,
13%–33%). Men and those developing AIDS during follow-up had higher virus loads over the course of disease. Persons who developed
AIDS had a steeper virus load slope than those who were AIDS-free (P = .01). In long-term follow-up, virus load exhibited a gradual and sustained increase over time. Virus load and annual increase
are strong predictors of disease progression.
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... Usage du préservatif: PpreservatifSon efficacité dépend de sa fréquence d'utilisation (toujours, parfois et jamais comme décrit dans(121,122).Tableau 2 Variables conditionnant la probabilité de transmissionTout individu infecté peut être transmetteur, à l'exception des individus au stade SIDA de la maladie qui ne font plus de contact dans le modèle. Nous avons considéré que le diagnostic de ce stade suivait d'un mois la déclaration de la maladie.Pendant les trois premiers mois, la charge virale monte vite pour décroitre vers la première valeur de la CV au stade chronique en 3 mois (124-126)(127,128).Pour la phase chronique de la maladie, il existe une grande variété de données et de publications sur l'évolution naturelle de la charge virale(129,130). Notre modèle est basé sur l'article d'Hubert et al.(131). ...
La notion de réseaux de contacts est majeure en épidémiologie des maladies transmissibles. Les données de réseaux peuvent être utilisées 1) à des fins analytiques, dans l’objectif d’intégrer des variables liée au réseau dans le risque d’acquérir une pathologie, 2) à des fins de simulation, afin d’évaluer l’importance des variables de réseaux dans un processus épidémique et 3) à des fins de redressement de données épidémiologiques issues d’échantillons non représentatifs échantillonnés au sein d’un réseau. L’étude des réseaux et leur impact dans l’évolution d’une épidémie a pris son essor avec l’apparition du VIH. Ce virus se transmet essentiellement par voie sexuelle en suivant les liens formant un réseau de contacts dit sexuels. Après avoir dressé le panorama bibliographique sur l’utilisation des variables de réseaux dans l’analyse du risque de la transmission du VIH nous développons deux travaux utilisant la modélisation et la simulation de réseaux de contacts sexuels dans des populations d’hommes ayant des rapports sexuels avec des hommes (HSH). Le premier travail détaille l’usage des réseaux dans la simulation de l’épidémie liée au VIH et leur impact sur l’effet des mesures de prévention. A partir des données de l’étude PREVAGAY portant sur les hommes ayant des rapports sexuels avec des hommes visitant des lieux de rencontre parisiens, des réseaux de contacts sexuels réalistes ont été développés. Des processus épidémiques ont été générés dans ces réseaux et comparés à des réseaux théoriques. Nous démontrons que la structure du réseau influe non seulement sur l’évolution de la courbe épidémique mais également sur l’efficacité des mesures de prévention individuelles telles que la prophylaxie de préexposition. Son efficacité peut être doublée selon les caractéristiques réseaux des individus entrant dans ce type de programme de prévention. Ce travail confirme la nécessité de colliger des données de réseau en France en vue de préciser le modèle développé. Le deuxième travail généralise une méthode d’estimation de la prévalence du VIH réseaux à partir de données d’observation partielle et utilisant la modélisation de réseaux. Cet outil était antérieurement peu applicable aux données réelles. Il démontre la robustesse de la méthode face aux biais classiquement retrouvés dans les données récoltées par échantillonnage orientés par les pairs (respondent driven sampling (RDS). L’application de cette méthode d’estimation a été comparée aux méthodes historiques d’estimation à partir de données réelles issues d’une étude de type RDS réalisé chez les HSH vivant dans les grandes zones urbaines au Brésil. Le travail confirme l’inquiétante prévalence de l’infection par le VIH dans cette population malgré de grandes disparités territoriales. Il ouvre vers d’éventuelles comparaisons de données historiques en vue de comprendre l’évolution de l’épidémie liée au VIH au Brésil. L’ensemble de ce travail suggère que les caractéristiques des réseaux peuvent être utilisées à des fins d’intervention dans le but de mettre en œuvre des politiques de préventions rapidement efficientes.
... Biological sex also affects various aspects of HIV infection and progression [10,11], such as plasma viral load [12][13][14] and immune activation. For example, levels of plasma HIV RNA proximal to seroconversion are higher in men than women [15][16][17][18][19][20][21], although these differences attenuate with disease progression. In contrast, women exhibit higher T-cell activation [22], interferon-a production after toll-like receptor 7 stimulation [22,23] and expression of interferon-stimulated genes when matched by level of plasma viraemia [24]. ...
Introduction
Sex-specific differences affect multiple aspects of HIV infection, yet few studies have quantified HIV levels in tissues from women. Since an HIV functional cure will likely require a major reduction of infected cells from most tissues, we measured total and intact HIV DNA and the HIV transcription profile in blood, gut, genital tract and liver from HIV-positive antiretroviral therapy (ART) -treated women.
Methods
Peripheral blood mononuclear cells (PBMC) and biopsies from the gastrointestinal (ileum, colon, rectosigmoid +/- liver) and genital (ectocervix, endocervix and endometrium) tracts were collected from 6 ART-treated (HIV RNA < 200 copies/mL) women. HIV DNA (total and intact) and levels of read-through, initiated (total), 5’elongated, polyadenylated and multiply spliced HIV transcripts were measured by droplet digital PCR. Immunophenotyping of cells was performed using Cytometry by time of flight (CyTOF).
Results
We detected total HIV DNA in all tissues and intact HIV DNA in blood, ileum, colon, rectosigmoid and ectocervix. Initiated HIV transcripts per provirus were higher in PBMC and endometrium than in ileum, colon, rectosigmoid, ectocervix or endocervix, and higher in the rectum than either ileum or colon. 5’Elongated HIV transcripts per provirus were comparable in PBMC and endometrium, but higher than in gut or cervical samples. Polyadenylated and multiply spliced HIV transcripts were detected in PBMC (6/6 and 3/6 individuals respectively), but rarely in the tissues.
Conclusions
These results suggest tissue-specific differences in the mechanisms that govern HIV expression, with lower HIV transcription in most tissues than blood. Therapies aimed at disrupting latency, such as latency-reversing or latency-silencing agents, will be required to penetrate into multiple tissues and target different blocks to HIV transcription.
... Il ne s'agit que d'une stabilité apparente car la réplication virale est particulièrement active dans les tissus lymphoïdes et de nombreuses cellules CD4 sont détruites chaque jour (environ 1 milliard) mais rapidement remplacées par l'organisme. Si le niveau de CV reste stable ou augmente peu, le taux de LT CD4 diminue à une vitesse variant entre 49 et 109/mm 3 par an (Drylewicz et al. 2008 ;Lyles et al. 1999). Par ailleurs, plus le nadir de CV (qui correspond au niveau de CV le plus bas atteint à l'issue de la PIV) est élevé, plus la décroissance du nombre de LT CD4 est rapide (J. ...
L’absence de virémie VIH détectable chez 3 enfants après l’arrêt du traitement antirétroviral suggère qu’une thérapie très précoce pourrait amener à une cure fonctionnelle. L’objectif principal est de caractériser de manière qualitative et quantitative le réservoir viral ainsi que les anticorps anti-VIH chez des enfants en suppression virologique afin d’identifier les facteurs associés à leur diminution. Il s’agit d’une étude prospective transversale incluant 97 enfants, au CHU Gabriel Touré (Bamako, Mali). Ils avaient un âge médian de 9,8 ans et de 3,3 ans à la mise en route du traitement avec une durée médiane de traitement de 5,4 années. Le taux médian d’ADN-VIH était de 445 copies/106 PBMCs, la médiane d’activité des anticorps anti-gp41 était de 0,29 DO et le niveau médian des anticorps anti-VIH était 14,1 S/CO. Nous avons montré une prévalence élevée de la résistance au VIH dans l'ADN. Huit séroréversions VIH ont été identifiées. Une activité basse des anticorps anti-gp41 était associée à un plus jeune âge d’initiation du traitement et avec un faible niveau d’anticorps anti-VIH. Un faible niveau d’anticorps anti-VIH était associée à une initiation précoce du traitement. Une proportion significative d'enfants VHIV en suppression virologique ayant commencé une thérapie avant l'âge de 2 ans ont cessé de produire et/ou ont progressivement perdu les anticorps anti-VIH.
... A growing body of data has demonstrated that women exhibit more robust immune responses to both primary viral infections and vaccination compared to men (2,3). In HIV-1 specifically, several studies have reported that chronically infected women have significantly lower plasma viremia than men, although the reason for this discrepancy has yet to be identified (5)(6)(7)(8)(9)(10). In addition, a study comparing men and women chronically infected with HIV-1 found that infected women had a higher proportion of activated (CD38 ϩ HLA-DR ϩ ) CD8 ϩ T cells, but not CD4 ϩ T cells, prior to antiretroviral therapy (ART) initiation, suggesting higher levels of detrimental immune activation (11). ...
Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4 ⁺ T cell loss than men. These profound differences are influenced by 17β-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.
Biological sex has wide-ranging impacts on HIV infection spanning differences in acquisition risk, the pathogenesis of untreated infection, impact of chronic treated disease and prospects for HIV eradication or functional cure. This chapter summarizes the scope of these differences and discusses several features of the immune response thought to contribute to the clinical outcomes.
Many statistical and computational models have been developed to investigate the complexity of HIV dynamics in the immune response. Most of the models described viral replication as a system of differential equations, where the solution of parameters is not easy to obtain. A model of HIV replication where infected cells undergo through a truncated logistic distribution is proposed. An infected cell is modelled as an individual entity with certain states and properties. Three simulation approaches are used for implementing the model, conditional distribution, truncated population mean approaches and sample mean. Simulation results give insights into the details of HIV replication dynamics inside the cell at the protein level. Therefore the model can be used for future studies of HIV intracellular replication. It will also promote a better understanding of the HIV/AIDS transmission dynamics, the study will also add to the existing body of knowledge on the mathematical application in the field of epidemiology.
Background
Immune activation is a significant contributor to HIV pathogenesis and disease progression. In virally-suppressed individuals on ART, low-level immune activation has been linked to several non-infectious comorbid diseases. However, studies have not been systematically performed in sub-Saharan Africa and thus the impact of demographics, ART and regional endemic co-infections on immune activation is not known. We therefore comprehensively evaluated in a large multinational African cohort markers for immune activation and its distribution in various settings.
Methods
2747 specimens from 2240 people living with HIV (PLWH) and 477 without HIV from the observational African Cohort Study (AFRICOS) were analyzed for 13 immune parameters. Samples were collected along with medical history, sociodemographic and comorbidity data at 12 HIV clinics across 5 programs in Uganda, Kenya, Tanzania and Nigeria. Data were analyzed with univariate and multivariate methods such as random forests and principal component analysis.
Findings
Immune activation was markedly different between PLWH with detectable viral loads, and individuals without HIV across sites. Among viremic PLWH, we found that all immune parameters were significantly correlated with viral load except for IFN-α. The overall inflammatory profile was distinct between men and women living with HIV, in individuals off ART and with HIV viremia. We observed stronger differences in the immune activation profile with increasing viremia. Using machine learning methods, we found that geographic differences contributed to unique inflammatory profiles. We also found that among PLWH, age and the presence of infectious and/or noninfectious comorbidities showed distinct inflammatory patterns, and biomarkers may be used to predict the presence of some comorbidities.
Interpretation
Our findings show that chronic immune activation in HIV-1 infection is influenced by HIV viral load, sex, age, region and ART use. These predictors, as well as associations among some biomarkers and coinfections, influence biomarkers associated with noncommunicable diseases.
Funding
This work was supported by the President's Emergency Plan for AIDS Relief via a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense [W81XWH-11-2-0174, W81XWH-18-2-0040]. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25. This article was prepared while Michael A. Eller was employed at Henry M. Jackson Foundation for the Advancement of Military Medicine for the U.S. Military HIV Research Program. The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. The opinions expressed in this article are the author's own, and do not reflect the view of the National Institutes of Health, the U.S. Department of Health and Human Services, or the U.S. government.
Objective:
Despite lower plasma HIV RNA levels, women progress faster to AIDS than men. The reasons for these differences are not clear but might be a consequence of an elevated inflammatory response in women.
Methods:
We investigated sex differences in cytokine profiles by measuring the concentrations of 36 cytokine/chemokines by Luminex in blood of women and men (sex at birth) with chronic HIV infection under suppressive therapy. We initially performed a principal component analysis to see if participants clustered by sex, and then fit a partial least squares discriminant analysis (PLS-DA) model where we used cytokines to predict sex at birth. The significance of the difference in nine cytokines with VIP greater than 1 was tested using Wilcoxon test-rank. Further, potential confounding factors were tested by multivariate linear regression models.
Results:
Overall, we predicted sex at birth in the PLS-DA model with an error rate of approximately 13%. We identified five cytokines, which were significantly higher in women compared with men, namely the pro-inflammatory chemokines CXCL1 (Gro-α), CCL5 (RANTES), CCL3 (MIP-1α), CCL4 (MIP-1β), as well as the T-cell homeostatic factor IL-7. The effect of sex remained significant after adjusting for CD4+, age, ethnicity, and race for all cytokines, except for CCL3 and race.
Conclusion:
The observed sex-based differences in cytokines might contribute to higher immune activation in women compared with men despite suppressive therapy. Increased levels of IL-7 in women suggest that homeostatic proliferation may have a differential contribution to HIV reservoir maintenance in female and male individuals. Our study emphasizes the importance of sex-specific studies of viral pathogenesis.
Objectives:
To determine whether rate of development of AIDS is affected by category of exposure to HIV and whether the more rapid development found in older subjects persists for each exposure category.
Design:
Longitudinal study of people with known date of seroconversion to HIV.
Setting:
16 HIV treatment centres throughout Italy.
Subjects:
1199 people infected with HIV through use of injected drugs, homosexual sex, or heterosexual sex.
Main outcome measures:
AIDS as defined by 1987 definition of Centers for Disease Control (including and excluding neoplasms) and by 1993 European definition.
Results:
225 subjects (18.8%) progressed to AIDS (Centers for Disease Control 1987 definition) during median follow up of 5.8 years. Univariate analyses showed more rapid progression to AIDS for older subjects compared with younger subjects and for homosexual men compared with other exposure categories. The age effect was of similar size in each exposure category and in men and women. In a bivariate model with age and exposure categories simultaneously included as covariates, differences by exposure category disappeared for use of injected drugs and heterosexual sex compared with homosexual sex (relative hazards 1.02 (95% confidence interval 0.71 to 1.45) and 1.07 (0.70 to 1.64) respectively), while the age effect remained (relative hazard 1.55 (1.32 to 1.83) for 10 year increase in age). Analyses using the other definitions for AIDS did not appreciably change these results.
Conclusions:
There was no evidence of differences in rate of development of AIDS by exposure category, while there was a strong tendency for more rapid development in older subjects for all three groups. This supports the view that external cofactors do not play major role in AIDS pathogenesis but that age is of fundamental importance.
The natural variability of quantitative virologic measures among human immunodeficiency virus (HIV) type 1-infected persons
was prospectively studied in 29 untreated persons with >600 CD4 cells/µL and in 15 persons receiving zidovudine monotherapy
who had 400–550 CD4 cells/µL at study entry. Cell- and plasma-associated infectious HIV-1, provirus, and virion RNA were determined
monthly as were numbers of CD4 and CD8 cells. HIV-1 replication varied widely among subjects with similar CD4 cell counts.
The within-individual variability was significantly less than the variability between subjects for all virologic measures.
Plasma virion HIV-1 RNA levels had the least variability. A mathematical model was devised to assess whether a potential therapeutic
intervention significantly alters peripheral HIV-1 load. The model indicated that three measurements of plasma RNA would be
outside the 95th percentile for the expected change in an individual due to natural variability. This approach can be used
to accurately assess a therapeutic intervention among persons with low plasma HIV-1 titers.
Background: The rate of disease progression among persons infected with human immunodeficiency virus type 1 (HIV-1) varies widely, and the relative prognostic value of markers of disease activity has not been defined. Objective: To compare clinical, serologic, cellular, and virologic markers for their ability to predict progression to the acquired immunodeficiency syndrome (AIDS) and death during a 10-year period. Design: Prospective, multicenter cohort study. Setting: Four university-based clinical centers participating in the Multicenter AIDS Cohort Study. Patients: 1604 men infected with HIV-1. Measurements: The markers compared were oral candidiasis (thrush) or fever; serum neopterin levels; serum β 2 -microglobulin levels; number and percentage of CD3 + , CD4 + , and CD8 + lymphocytes; and plasma viral load, which was measured as the concentration of HIV-1 RNA found using a sensitive branched-DNA signal-amplification assay. Results: Plasma viral load was the single best predictor of progression to AIDS and death, followed (in order of predictive strength) by CD4 + lymphocyte count and serum neopterin levels, serum β 2 -microglobulin levels, and thrush or fever. Plasma viral load discriminated risk at all levels of CD4 + lymphocyte counts and predicted their subsequent rate of decline. Five risk categories were defined by plasma HIV-1 RNA concentrations: 500 copies/mL or less, 501 to 3000 copies/mL, 3001 to 10 000 copies/mL, 10 001 to 30 000 copies/mL, and more than 30 000 copies/mL. Highly significant (P < 0.001) differences in the percentages of participants who progressed to AIDS within 6 years were seen in the five risk categories: 5.4%, 16.6%, 31.7%, 55.2%, and 80.0%, respectively. Highly significant (P < 0.001) differences in the percentages of participants who died of AIDS within 6 years were also seen in the five risk categories: 0.9%, 6.3%, 18.1%, 34.9%, and 69.5%, respectively. A regression tree incorporating both HIV-1 RNA measurements and CD4 + lymphocyte counts provided better discrimination of outcome than did either marker alone; use of both variables defined categories of risk for AIDS within 6 years that ranged from less than 2% to 98%. Conclusions: Plasma viral load strongly predicts the rate of decrease in CD4 + lymphocyte count and progression to AIDS and death, but the prognosis of HIV-infected persons is more accurately defined by combined measurement of plasma HIV-1 RNA and CD4 + lymphocytes.
