Genotypic and Phenotypic Diversity of the Replication-Competent HIV Reservoir in Treated Patients.

In HIV infection, viral rebound after treatment discontinuation is considered to originate predominantly from viral genomes integrated in resting CD4 T lymphocytes. Replication-competent proviral genomes represent a minority of the total HIV DNA. While the quantification of the HIV reservoir has been extensively studied, the diversity of genomes that compose the reservoir was less explored.

Neighborhood racial discrimination and the development of major depression.

This study examined the impact of neighborhood racial discrimination on the development of major depressive disorder (MDD) in a sample of African American women. Participants were 499 women from Georgia and Iowa with no history of MDD who were followed for 9 to 11 years. Several neighborhood characteristics (community social disorder, community cohesion, and community racism) and individual characteristics (negative life events, financial strain, personal outlook, religious involvement, relationship quality, negative affectivity, and individual experiences of racism) were employed as predictors of whether or not the women met criteria for MDD during this period of time.

Initial elevation bias in subjective reports.

People's reports of their thoughts, feelings, and behaviors are used in many fields of biomedical and social science. When these states have been studied over time, researchers have often observed an unpredicted and puzzling decrease with repeated assessment. When noted, this pattern has been called an "attenuation effect," suggesting that the effect is due to bias in later reports.

Genetically Intact but Functionally Impaired HIV-1 Env Glycoproteins in the T-Cell Reservoir.

HIV-infected subjects under antiretroviral treatment (ART) harbor a persistent viral reservoir in resting CD4 T cells, which accounts for the resurgence of HIV replication after ART interruption. A large majority of HIV reservoir genomes are genetically defective, but even among intact proviruses few seem able to generate infectious virus. To understand this phenomenon, we examined the function and expression of HIV envelope glycoproteins reactivated from the reservoir of four HIV-infected subjects under suppressive ART.

United and Divided by Stress: How Stressors Differentially Influence Social Support in African American Couples Over Time.

The factors that allow people to be good support providers in relationships are not fully understood. We examined how support providers' stressful experiences (financial strain and racial discrimination) differentially influence their supportiveness, using longitudinal data from two samples of African American couples. Among couples that provided observational data ( N = 163 couples), providers who experienced high chronic financial strain behaved less supportively toward their partners, while those who experienced frequent racial discrimination behaved more supportively over a 2-year period.

Single-dose pharmacokinetics and pharmacodynamics of oral tenofovir and emtricitabine in blood, saliva and rectal tissue: a sub-study of the ANRS IPERGAY trial.

Objectives: In the ANRS IPERGAY pre-exposure prophylaxis (PrEP) trial, a single dose of tenofovir disoproxil fumarate and emtricitabine was taken orally 2-24 h before sexual intercourse. A sub-study was conducted to assess the pharmacokinetics of tenofovir and emtricitabine in blood, saliva and rectal tissue following this initial oral intake.

Methods: Plasma, PBMC, saliva and rectal tissue sampling was performed over 24 h in 12 seronegative men before enrolment in the ANRS IPERGAY trial, following a single dose of 600 mg tenofovir disoproxil fumarate/400 mg emtricitabine.

Modifiable causes of premature death in middle-age in Western Europe: results from the EPIC cohort study.

Background: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death.

Methods: We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment.

Cell-to-cell infection by HIV contributes over half of virus infection.

Cell-to-cell viral infection, in which viruses spread through contact of infected cell with surrounding uninfected cells, has been considered as a critical mode of virus infection. However, since it is technically difficult to experimentally discriminate the two modes of viral infection, namely cell-free infection and cell-to-cell infection, the quantitative information that underlies cell-to-cell infection has yet to be elucidated, and its impact on virus spread remains unclear. To address this fundamental question in virology, we quantitatively analyzed the dynamics of cell-to-cell and cell-free human immunodeficiency virus type 1 (HIV-1) infections through experimental-mathematical investigation.

Quantifying the Antiviral Effect of IFN on HIV-1 Replication in Cell Culture.

Type-I interferons (IFNs) induce the expression of hundreds of cellular genes, some of which have direct antiviral activities. Although IFNs restrict different steps of HIV replication cycle, their dominant antiviral effect remains unclear. We first quantified the inhibition of HIV replication by IFN in tissue culture, using viruses with different tropism and growth kinetics.

Microtubule-associated proteins 1 (MAP1) promote human immunodeficiency virus type I (HIV-1) intracytoplasmic routing to the nucleus.

After cell entry, HIV undergoes rapid transport toward the nucleus using microtubules and microfilaments. Neither the cellular cytoplasmic components nor the viral proteins that interact to mediate transport have yet been identified. Using a yeast two-hybrid screen, we identified four cytoskeletal components as putative interaction partners for HIV-1 p24 capsid protein: MAP1A, MAP1S, CKAP1, and WIRE.

Circulating biomarkers of one-carbon metabolism in relation to renal cell carcinoma incidence and survival.

Background: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival.

Methods: The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs.

Impact of the HIV integrase genetic context on the phenotypic expression and in vivo emergence of raltegravir resistance mutations.

Objectives: HIV resistance to the integrase inhibitor raltegravir in treated patients is characterized by distinct resistance pathways. We hypothesize that differences in the in vivo dynamics of HIV resistance to raltegravir are due to the genetic context of the integrase present at baseline.

Patients And Methods: We studied four patients whose viruses evolved towards different resistance pathways.

Pressure from TRIM5α contributes to control of HIV-1 replication by individuals expressing protective HLA-B alleles.

The expression of certain HLA class I alleles, including HLA-B*27 and HLA-B*57, is associated with better control of human immunodeficiency virus type 1 (HIV-1) infection, but the mechanisms responsible are not fully understood. We sought evidence that pressure from the human restriction factor TRIM5α (hTRIM5α) could contribute to viral control. The hTRIM5α sensitivity of viruses from both HLA-B*57-positive (HLA-B*57(+)) and HLA-B*27(+) patients who spontaneously controlled viral replication, but not viruses from viremic patients expressing these alleles, was significantly greater than that of viruses from patients not expressing these protective HLA-B alleles.

Dietary intake of acrylamide and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Background: In 1994, acrylamide (AA) was classified as a probable human carcinogen by the International Agency for Research on Cancer. In 2002, AA was discovered at relatively high concentrations in some starchy, plant-based foods cooked at high temperatures.

Patients And Methods: A prospective analysis was conducted to evaluate the association between the dietary intake of AA and ductal adenocarcinoma of the exocrine pancreatic cancer (PC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using Cox regression modeling.

Host cell factors in HIV replication: partners and opponents.

Cycles of virus replication within the cell are often presented in a simplistic manner, viruses being considered as intracellular parasites simply diverting the cellular machinery for their own benefit. Accumulated knowledge on the relationship between the human immunodeficiency virus (HIV) and host cells illustrate the complexity of these relationships. Some cellular factors are partners of the virus and are essential for the proper performance of the multiplication cycle, whereas other factors are adversaries with antiviral activity, called restriction factors.

High level of susceptibility to human TRIM5α conferred by HIV-2 capsid sequences.

Background: HIV-2, which was transmitted to humans from a distant primate species (sooty mangabey), differs remarkably from HIV-1 in its infectivity, transmissibility and pathogenicity. We have tested the possibility that a greater susceptibility of HIV-2 capsid (CA) to the human restriction factor TRIM5α (hTRIM5α) could contribute to these differences.

Results: We constructed recombinant clones expressing CA from a variety of HIV-2 viruses in the context of HIV-1 NL4-3-luciferase.

Delaying reverse transcription does not increase sensitivity of HIV-1 to human TRIM5α.

Background: Because uncoating of the capsid is linked to reverse transcription, modifications that delay this process lead to the persistence in the cytoplasm of capsids susceptible to recognition by the human restriction factor TRIM5α (hTRIM5α). It is unknown, however, if increasing the time available for capsid-hTRIM5α interactions would actually render viruses more sensitive to hTRIM5α.

Results: Viral sensitivity to hTRIM5α was evaluated by comparing their replication in human U373-X4 cells in which hTRIM5α activity had or had not been inhibited by overexpression of human TRIM5γ.

Tea consumption and incidence of type 2 diabetes in Europe: the EPIC-InterAct case-cohort study.

Background: In previous meta-analyses, tea consumption has been associated with lower incidence of type 2 diabetes. It is unclear, however, if tea is associated inversely over the entire range of intake. Therefore, we investigated the association between tea consumption and incidence of type 2 diabetes in a European population.

Counteraction of tetherin antiviral activity by two closely related SIVs differing by the presence of a Vpu gene.

In different primate lentiviruses, three proteins (Vpu, Env and Nef) have been shown to have anti-tetherin activities. SIVden is a primate lentivirus harbored by a Cercopithecus denti (C. denti) whose genome code for a Vpu gene.

Gag cytotoxic T lymphocyte escape mutations can increase sensitivity of HIV-1 to human TRIM5alpha, linking intrinsic and acquired immunity.

Although laboratory-adapted HIV-1 strains are largely resistant to the human restriction factor TRIM5α (hTRIM5α), we have recently shown that some viruses carrying capsid (CA) sequences from clinical isolates can be more sensitive to this restriction factor. In this study we evaluated the contribution to this phenotype of CA mutations known to be associated with escape from cytotoxic T lymphocyte (CTL) responses. Recombinant viruses carrying HIV-1 CA sequences from NL4-3 and three different clinical isolates were prepared, along with variants in which mutations associated with CTL resistance were modified by site-directed mutagenesis, and the infectivities of these viruses in target cells expressing hTRIM5α and cells in which TRIM5α activity had been inhibited by overexpression of TRIM5γ were compared.

Modulation of TRIM5alpha activity in human cells by alternatively spliced TRIM5 isoforms.

TRIM5α is a restriction factor that can block an early step in the retroviral life cycle by recognizing and causing the disassembly of incoming viral capsids, thereby preventing the completion of reverse transcription. Numerous other isoforms of human TRIM5 exist, and isoforms lacking a C-terminal SPRY domain can inhibit the activity of TRIM5α. Thus, TRIM5α activity in a given cell type could be dependent on the relative proportions of TRIM5 isoforms expressed, but little information concerning the relative expression of TRIM5 isoforms in human cells is available.

Strain-specific differences in the impact of human TRIM5alpha, different TRIM5alpha alleles, and the inhibition of capsid-cyclophilin A interactions on the infectivity of HIV-1.

HIV-1 infectivity is strongly restricted by TRIM5α from certain primate species but has been described as being only marginally susceptible to human TRIM5α. In this study, we evaluated the effects of the modulation of human TRIM5α activity (pretreatment of target cells with alpha interferon, expression of a pre-miRNA targeting TRIM5α, and/or overexpression of TRIM5γ), the inhibition of cyclophilin A (CypA)-CA interactions, and the expression of different allelic variants of human TRIM5α on the infectivity of a series of recombinant viruses carrying different patient-derived Gag-protease sequences. We show that HIV-1 displays virus-specific differences in its sensitivity to human TRIM5α and in its sensitivity to different TRIM5α alleles.