Current Estimates for HIV-1 Production Imply Rapid Viral Clearance in Lymphoid Tissues

It has recently been estimated that a single HIV-1 infected cell produces between and more than viral particles over its life span. Since body-wide estimates of the ratio of free virus to productively infected cells are smaller than and much smaller than , individual virions must be cleared rapidly. This seems difficult to reconcile with the fact that most of the total body virus is trapped on follicular dendritic cells where it can survive for many months. It has also been difficult to reconcile the vast difference in the rates at which the virus is cleared from the blood in rhesus macaques and in chronically infected patients. Here we attempt to reconcile these seemingly contradictory observations by considering the virion clearance rate in various organs and the virion exchange rates between them. The main results are that the per capita clearance rate of free virus in lymphoid tissue should be fast, the virion exchange rate between lymphoid tissue and the blood should be slow, and the comparatively slow previous estimates for the virion clearance rate from the blood correspond to the rate of virion efflux from the blood to other organs where the virus is ultimately cleared

Topical microbicides to prevent the transmission of HIV: formulation gaps and challenges

The efforts of the topical microbicide field to identify a safe and effective topical microbicide were realized in July of 2010 with the reporting of the results of the Centre for the AIDS Programme of Research in South Africa 004 trial. In this trial, a 1% tenofovir gel was found to reduce women’s risk for HIV acquisition by 39% compared to placebo. To understand the impact of this trial on future microbicide development, we must view it from the historical perspective of previous phases 2 and 3 clinical trials with detergents and sulfated polyanions. This knowledge and emerging information must then be parlayed into the next steps needed to create a safe, effective, and acceptable topical microbicide. This review will look at the lessons learned from preclinical and clinical development of topical microbicides, focusing on two significant future challenges: (1) topical microbicide formulation safety and (2) the critical role that adherence to product use has in determining safety and efficacy in clinical trials and ultimately commercial viability of the licensed product. In addition to framing these issues within our current understanding of formulation and prevention of HIV acquisition, recent advances in our understanding of the mechanism of HIV transmission and how it informs on future formulation strategies will be briefly discussed

Physical activity as a treatment for depression: the TREAD randomised trial protocol

Depression is one of the most common reasons for consulting a General Practitioner (GP) within the UK. Whilst antidepressants have been shown to be clinically effective, many patients and healthcare professionals would like to access other forms of treatment as an alternative or adjunct to drug therapy for depression. A recent systematic review presented some evidence that physical activity could offer one such option, although further investigation is needed to test its effectiveness within the context of the National Health Service.The aim of this paper is to describe the protocol for a randomised, controlled trial (RCT) designed to evaluate an intervention developed to increase physical activity as a treatment for depression within primary care

Rectal Transmission of Transmitted/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice

Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1(JRCSF) or the MSM-derived transmitted/founder (T/F) virus HIV-1(THRO) within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1(JRCSF) and HIV-1(THRO), respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1(JRCSF) and 0% (0/6; log rank p = 0.02) for HIV-1(THRO). This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides

An initial psychometric evaluation and exploratory cross-sectional study of the Body Checking Questionnaire among Brazilian women

Body checking is considered an expression of an excessive preoccupation with appearance. The first aim of this study was to evaluate the psychometric properties of a Brazilian Portuguese version of the Body Checking Questionnaire (BCQ). Additionally, we wanted to examine the questionnaire’s associations with body avoidance behaviour, body mass index, dietary habits, and the intensity, frequency, and length of physical exercise. Finally, we also examined the differences between the total BCQ score and the individual BCQ factor scores. Differences between active and sedentary persons and between non-dieters and those on weight-loss diets were also analyzed. For the psychometric study, 546 female public university students from four different courses were surveyed. Two minor samples of university students and eating disorders women were also recruited. In the second part of the study, 403 women were recruited from weight-loss programs, gyms, and a university. All participants were verbally invited to participate in the research and voluntarily took part. Confirmatory factor analysis showed a good fit to the original model of the Brazilian BCQ that retained all 23 items. Satisfactory evidence of construct validity and internal consistency were also generated through analysis of factor loadings, t-values, Cronbach’s alpha, and construct reliability tests. The results also showed associations among body checking and body avoidance, body satisfaction, social anxiety, body mass index, and the frequency and intensity of physical exercise. Significant differences were found between non-dieters and weight-loss dieters for all BCQ factors and the total BCQ score. For physically active and sedentary persons, a significant difference was only observed for idiosyncratic checking behaviour. In conclusion, the BCQ appears to be a valid and reliable scale for Brazilian research, and the associations and differences found in this study suggest that women at gyms and especially in weight-loss programs should be targeted for future body checking studies

Semen May Harbor HIV Despite Effective HAART: Another Piece in the Puzzle

The risk of male-to-female intravaginal HIV-1 transmission is estimated at about 1 event per 200–2000 coital acts. The aim of this study was to assess the residual risk of HIV presence in semen in patients under HAART therapy.The study took place in France from October 2001 to March 2009. 394 paired blood and semen samples were provided from 332 HIV-1 infected men. The Roche Cobas AMPLICOR Monitor HIV assay was used to quantify HIV-1 RNA in blood and in seminal plasma. Three percent of 394 HIV-1 infected men enrolled in an assisted reproductive technology program harbored detectable HIV-1 RNA in semen, although they had no other sexually transmitted disease and their blood viral load was undetectable for at least 6 months under antiretroviral treatment.These data suggest that undetectable plasma HIV RNA means a lower risk of viral transmission through seminal fluid on a population level, but not necessarily at the level of the individual

Glycerol monolaurate prevents mucosal SIV transmission

Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection1, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission2–4. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)–rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry5,6. Here we show in this SIV–macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α (also known as CCL20), plasmacytoid dendritic cells and CCR5+ cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4+ T cells to fuel this obligate expansion. We then show that glycerol monolaurate—a widely used antimicrobial compound7with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines8—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to blockHIV-1 mucosal transmission

Lymphoid Tissue Damage in HIV-1 Infection Depletes Naïve T Cells and Limits T Cell Reconstitution after Antiretroviral Therapy

Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of naïve CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to naïve T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within naïve T cell populations increases significantly, resulting in progressive depletion of both naïve CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the naïve T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of naïve T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution