Biomarker reveals HIV's hidden reservoir.

Determining the total amount of HIV DNA in people undergoing antiretroviral therapy could accelerate the development of novel therapies and potential cures for HIV infection

Roadblocks to translational challenges on viral pathogenesis.

Distinct roadblocks prevent translating basic findings in viral pathogenesis into therapies and implementing potential solutions in the clinic. An ongoing partnership between the Volkswagen Foundation and Nature Medicine resulted in an interactive meeting in 2012, as part of the "Herrenhausen Symposia" series. Current challenges for various fields of viral research were recognized and discussed with a goal in mind--to identify solutions and propose an agenda to address the translational barriers. Here, some of the researchers who participated at the meeting provide a concise outlook at the most pressing unmet research and clinical needs, identifying these key obstacles is a necessary step towards the prevention and cure of human viral diseases

The end of HIV: Still a very long way to go, but progress continues.

In an Editorial accompanying PLOS Medicine's Special Issue on Advances in Prevention, Treatment and Cure of HIV/AIDS, Guest Editors Steven Deeks, Sharon Lewin, and Linda-Gail Bekker discuss priorities in the field and the content of the issue

Mitral Annular and Coronary Artery Calcification Are Associated with Mortality in HIV-Infected Individuals.

BackgroundHIV infection increases cardiovascular risk. Coronary artery calcification (CAC) and mitral annular calcification (MAC) identify patients at risk for cardiovascular disease (CVD). The purpose of this study was to examine the association between MAC, CAC and mortality in HIV-infected individuals.Methods and resultsWe studied 152 asymptomatic HIV-infected individuals with transthoracic echocardiography (TTE) and computed tomography (CT). MAC was identified on TTE using standardized criteria. Presence of CAC, CAC score and CAC percentiles were determined using the modified Agatston criteria. Mortality data was obtained from the Social Security and National Death Indices (SSDI/NDI). The median age was 49 years; 87% were male. The median duration of HIV was 16 years; 84% took antiretroviral therapy; 64% had an undetectable viral load. CVD risk factors included hypertension (35%), smoking (62%) and dyslipidemia (35%). Twenty-five percent of individuals had MAC, and 42% had CAC. Over a median follow-up of 8 years, 11 subjects died. Subjects with CAC had significantly higher mortality compared to those with MAC only or no MAC. The Harrell's C-statistic of CAC was 0.66 and increased to 0.75 when MAC was added (p = 0.05). MAC, prior CVD, age and HIV viral load were independently associated with higher age- and gender-adjusted CAC percentiles in an adjusted model (p < 0.05 for all).ConclusionIn HIV patients, the presence of MAC, traditional risk factors and HIV viral load were independently associated with CAC. Presence of CAC and MAC may be useful in identifying HIV-infected individuals at higher risk for death

Cortisol patterns are associated with T cell activation in HIV.

ObjectiveThe level of T cell activation in untreated HIV disease is strongly and independently associated with risk of immunologic and clinical progression. The factors that influence the level of activation, however, are not fully defined. Since endogenous glucocorticoids are important in regulating inflammation, we sought to determine whether less optimal diurnal cortisol patterns are associated with greater T cell activation.MethodsWe studied 128 HIV-infected adults who were not on treatment and had a CD4(+) T cell count above 250 cells/µl. We assessed T cell activation by CD38 expression using flow cytometry, and diurnal cortisol was assessed with salivary measurements.ResultsLower waking cortisol levels correlated with greater T cell immune activation, measured by CD38 mean fluorescent intensity, on CD4(+) T cells (r = -0.26, p = 0.006). Participants with lower waking cortisol also showed a trend toward greater activation on CD8(+) T cells (r = -0.17, p = 0.08). A greater diurnal decline in cortisol, usually considered a healthy pattern, correlated with less CD4(+) (r = 0.24, p = 0.018) and CD8(+) (r = 0.24, p = 0.017) activation.ConclusionsThese data suggest that the hypothalamic-pituitary-adrenal (HPA) axis contributes to the regulation of T cell activation in HIV. This may represent an important pathway through which psychological states and the HPA axis influence progression of HIV

History-Adjusted Marginal Structural Models to Estimate Time-Varying Effect Modification

Much of epidemiology and clinical medicine is focused on the estimation of treatments or interventions administered over time. In such settings of longitudinal treatment, time-dependent confounding is often an important source of bias. Marginal structural models are a powerful tool for estimating the causal effect of a treatment using observational data, particularly when time-dependent confounding is present. Recent statistical work presented a generalization of marginal structural models, called history-adjusted marginal structural models. Unlike standard marginal structural models, history-adjusted marginal structural models can be used to estimate modification of treatment effects by time-varying covariates. Estimation of time-dependent causal effect modification is frequently of great practical relevance. For example, clinical researchers are often interested in how the prognostic significance of a biomarker for treatment response can change over time. This article provides a practical introduction to the implementation and interpretation of history-adjusted marginal structural models. The method is illustrated using a clinical question drawn from the treatment of HIV infection. Observational cohort data from San Francisco, California, collected between 2000 and 2004, are used to estimate the effect of time until switching antiretroviral therapy regimen among patients receiving a non-suppressive regimen, and how this effect differs depending on CD4 T cell count

Tissue memory CD4+ T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection.

The primary reservoir for HIV is within memory CD4+ T cells residing within tissues, yet the features that make some of these cells more susceptible than others to infection by HIV is not well understood. Recent studies demonstrated that CCR5-tropic HIV-1 efficiently enters tissue-derived memory CD4+ T cells expressing CD127, the alpha chain of the IL7 receptor, but rarely completes the replication cycle. We now demonstrate that the inability of HIV to replicate in these CD127-expressing cells is not due to post-entry restriction by SAMHD1. Rather, relative to other memory T cell subsets, these cells are highly prone to undergoing latent infection with HIV, as revealed by the high levels of integrated HIV DNA in these cells. Host gene expression profiling revealed that CD127-expressing memory CD4+ T cells are phenotypically distinct from other tissue memory CD4+ T cells, and are defined by a quiescent state with diminished NFκB, NFAT, and Ox40 signaling. However, latently-infected CD127+ cells harbored unspliced HIV transcripts and stimulation of these cells with anti-CD3/CD28 reversed latency. These findings identify a novel subset of memory CD4+ T cells found in tissue and not in blood that are preferentially targeted for latent infection by HIV, and may serve as an important reservoir to target for HIV eradication efforts