Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated

Many HIV-1 envelope-reactive antibodies shortly after HIV-1 transmission may arise from crow-reactive memory B cells previously stimulated by non-HIV-1 host or microbial antigen

Analysis of Genetic Linkage of HIV From Couples Enrolled in the HIV Prevention Trials Network 052 Trial

Background. The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early initiation of antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) transmission from HIV-infected adults (index participants) to their HIV-uninfected sexual partners. We analyzed HIV from 38 index-partner pairs and 80 unrelated index participants (controls) to assess the linkage of seroconversion events

Computational Methods to Study Diversification in Pathogens, and Invertebrate and Vertebrate Immune Systems

<p>Pathogens and host immune systems use strikingly similar methods of diversification. Mechanisms such as point mutations and recombination help pathogens escape the host immune system and similar mechanisms help the host immune system attack rapidly evolving pathogens. Understanding the interplay between pathogen and immune system evolution is crucial to effective drug and vaccine development. In this thesis we employ various computational methods to study diversification in a pathogen, an invertebrate and a vertebrate immune system.</p> <p>First, we develop a technique for phylogenetic inference in the presence of recombination based on the principle of minimum description length, which assigns a cost-the description length-to each network topology given the observed sequence data. We show that the method performs well on simulated data and demonstrate its application on HIV <italic>env</italic> gene sequence data from 8 human subjects.</p> <p>Next, we demonstrate via phylogenetic analysis that the evolution of repeats in an immune-related gene family in <italic>Strongylocentrotus purpuratus</italic> is the result of recombination and duplication and/or deletion. These results support the evidence suggesting that invertebrate immune systems are highly complex and may employ similar mechanisms for diversification as higher vertebrates.</p> <p>Third, we develop a probabilistic model of the immunoglobulin (Ig) rearrangement process and a Bayesian method for estimating posterior probabilities for the comparison of multiple plausible rearrangements. We validate the software using various datasets and in all tests, SoDA2 performed better than other available software.</p> <p>Finally, we characterize the somatic population genetics of the nucleotide sequences of >1000 recombinant Ig pairs derived from the blood of 5 acute HIV-1 infected (AHI) subjects. We found that the Ig genes from the 20 day AHI PC showed extraordinary clonal relatedness among themselves; a single clone comprised of 52 members, with observed and inferred precursor antibodies specific for HIV-1 Env gp41. Antibodies from AHI patients show a decreased CDR3H length and an increased mutation frequency when compared to influenza vaccinated individuals. The high mutation frequency is coupled with a comparatively low synonymous to non-synonymous mutation ratio in the heavy chain. Our results may suggest presence of positive antigenic selection in previously triggered non-HIV-1 memory B cells in AHI.</p> <p>Taken together, the studies presented in this thesis provide methods to study diversification in pathogens, and invertebrate and vertebrate immune systems.</p>Dissertatio

Use of a Mobile App to Augment Psychotherapy in a Community Psychiatric Clinic: Feasibility and Fidelity Trial.

BACKGROUND: Even though 1 in 5 Americans experience some form of mental illness each year, 80% have been shown to discontinue psychotherapy prematurely. The traditional psychotherapy service delivery model, consisting of isolated clinical sessions, lacks the ability to keep patients engaged outside clinical sessions. Newer digital mental health platforms can address the clinical need for a robust tool that tracks mental well-being and improves engagement in patients with depressive symptoms. OBJECTIVE: The primary goals of this feasibility study were to (1) assess compliance among providers and their patients with a digital mental health platform protocol, and (2) examine the usability and fidelity of a mobile app through structured participant feedback. METHODS: A sample of 30 participants was recruited for a 5-week study from a community-based mental health clinic in Baltimore, Maryland, USA. Inclusion criteria were: aged 18 years or older, having access to a smartphone, and having at least mild-to-moderate depression and/or anxiety as measured by the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scales, respectively. Eligible participants were randomized into one of two study arms: (1) the intervention arm or (2) the waitlist control arm. Participants in the intervention arm were asked to download the Rose app and were prompted to complete clinical assessments (PHQ-9 and GAD-7) every other week, daily mood and anxiety Likert scales, and daily journal entries. The participants in the waitlist arm served as controls for the study and completed the clinical assessments only. Both arms engaged in weekly psychotherapy sessions, with participant in-app input informing the psychotherapy process of the intervention arm, while those in the waitlist control arm continued their standard care. Outcomes of interest included adherence to completion of in-app assessments and usability of the Rose mobile app assessed through the modified Mobile Application Rating Scale. RESULTS: Over the study period, a sample of 30 participants used the Rose app 2834 times to complete clinical assessments. On average, 70% (21; 95% CI 61.14%-77.41%) of participants completed mood and anxiety daily check-ins and journal entries 5 days per week. Nearly all participants (29/30, 97%) completed all PHQ-9 and GAD-7 in-app scales during the study. Subjective impressions showed that 73% (22/30) of participants found the mobile app to be engaging and in line with their needs, and approximately 70% (21/30) of participants reported the app functionality and quality of information to be excellent. Additionally, more than two-thirds of the participants felt that their knowledge and awareness of depression and anxiety management improved through using the app. CONCLUSIONS: Steady compliance and high app ratings showcase the utility of the Rose mobile mental health app in augmenting the psychotherapy process for patients with mood disorders and improving mental health knowledge. Future studies are needed to further examine the impact of Rose on treatment outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04200170; https://clinicaltrials.gov/ct2/show/NCT04200170

The Role of Viral Introductions in Sustaining Community-Based HIV Epidemics in Rural Uganda: Evidence from Spatial Clustering, Phylogenetics, and Egocentric Transmission Models

<div><p>Background</p><p>It is often assumed that local sexual networks play a dominant role in HIV spread in sub-Saharan Africa. The aim of this study was to determine the extent to which continued HIV transmission in rural communities—home to two-thirds of the African population—is driven by intra-community sexual networks versus viral introductions from outside of communities.</p><p>Methods and Findings</p><p>We analyzed the spatial dynamics of HIV transmission in rural Rakai District, Uganda, using data from a cohort of 14,594 individuals within 46 communities. We applied spatial clustering statistics, viral phylogenetics, and probabilistic transmission models to quantify the relative contribution of viral introductions into communities versus community- and household-based transmission to HIV incidence. Individuals living in households with HIV-incident (<i>n</i> = 189) or HIV-prevalent (<i>n</i> = 1,597) persons were 3.2 (95% CI: 2.7–3.7) times more likely to be HIV infected themselves compared to the population in general, but spatial clustering outside of households was relatively weak and was confined to distances <500 m. Phylogenetic analyses of <i>gag</i> and <i>env</i> genes suggest that chains of transmission frequently cross community boundaries. A total of 95 phylogenetic clusters were identified, of which 44% (42/95) were two individuals sharing a household. Among the remaining clusters, 72% (38/53) crossed community boundaries. Using the locations of self-reported sexual partners, we estimate that 39% (95% CI: 34%–42%) of new viral transmissions occur within stable household partnerships, and that among those infected by extra-household sexual partners, 62% (95% CI: 55%–70%) are infected by sexual partners from outside their community. These results rely on the representativeness of the sample and the quality of self-reported partnership data and may not reflect HIV transmission patterns outside of Rakai.</p><p>Conclusions</p><p>Our findings suggest that HIV introductions into communities are common and account for a significant proportion of new HIV infections acquired outside of households in rural Uganda, though the extent to which this is true elsewhere in Africa remains unknown. Our results also suggest that HIV prevention efforts should be implemented at spatial scales broader than the community and should target key populations likely responsible for introductions into communities.</p><p><i>Please see later in the article for the Editors' Summary</i></p></div