Within-talker and within-session stability of acoustic characteristics of conversational and clear speaking stylesa).

In speech production research, talkers often perform a speech task several times per recording session with different speaking styles or in different environments. For example, Lombard speech studies typically have talkers speak in several different noise conditions. However, it is unknown to what degree simple repetition of a speech task affects speech acoustic characteristics or whether repetition effects might offset or exaggerate effects of speaking style or environment. The present study assessed speech acoustic changes over four within-session repetitions of a speech production taskset performed with two speaking styles recorded in separate sessions: conversational and clear speech. In each style, ten talkers performed a set of three speech tasks four times. Speaking rate, median fundamental frequency, fundamental frequency range, and mid-frequency spectral energy for read sentences were measured and compared across test blocks both within-session and between the two styles. Results indicate that statistically significant changes can occur from one repetition of a speech task to the next, even with a brief practice set and especially in the conversational style. While these changes were smaller than speaking style differences, these findings support using a complete speech set for training while talkers acclimate to the task and to the laboratory environment.

Systematic Review of Literature on Vocal Demand Response: Understanding Physiology, Measurements, and Associated Factors.

PURPOSE: Considering the conceptual migration from vocal load and vocal loading to vocal demand and vocal demand response, this review of literature aimed to identify physiological explanations, reported measurements, and associated factors (vocal demands) reported in the literature when considering the phonatory response to a vocal demand. METHODS: A systematic review of literature, following the PRISMA Statement, was conducted using Web of Science, PubMed, Scopus, and ScienceDirect. Data were analyzed and presented in two parts. First, a bibliometric analysis, co-occurrence analysis, and content analysis were performed. Three criteria that got article inclusion were defined: (1) written in English, Spanish, and Portuguese; (2) published between 2009 and 2021; and (3) focused on vocal load and loading, vocal demand response, and voice assessment parameters. A total of 54 publications met the criteria and were included in this review. The second part included a conceptual framework based on the content analysis of three aspects of vocal demand response: (1) physiological explanations, (2) reported measurements, and (3) vocal demands. RESULTS AND CONCLUSION: As would be expected since vocal demand response is a relatively new term and not yet commonly used in literature when discussing way that the speakers respond to communicative scenarios, most of the studies reviewed (both historical and recent) still use the term of vocal load and vocal loading. Although there is a broad variety of literature discussing a wide range of vocal demands and voice parameters used to characterize the vocal demand response, results show that there is consistency across the studies. While vocal demand response is unique and intrinsic to the talker, associated factors that contribute to this response include both internal talker and external talker factors. Internal factors include muscle stiffness, viscosity in the phonatory system, vocal fold tissue damage, elevated sound pressure levels during occupational voice demands, extended periods of voice use, suboptimal body posture, difficulties in breathing technique, and sleep disturbances. Associated external factors include the working environment (noise, acoustics, temperature, humidity). In conclusion, although vocal demand response is intrinsic to the speaker, the speaker's response is affected by external vocal demands. However, due to the wide methods to evaluate vocal demand response, it has been difficult to establish its contribution to voice disorders in the general population and, specifically, among occupational voice users. This literature review identified commonly reported parameters and factors that may help clinicians and researchers define vocal demand response.

The C3/465 glycan hole cluster in BG505 HIV-1 envelope is the major neutralizing target involved in preventing mucosal SHIV infection.

Stabilized HIV-1 envelope (Env) trimers elicit tier 2 autologous neutralizing antibody (nAb) responses in immunized animals. We previously demonstrated that BG505 SOSIP.664.T332N gp140 (BG505 SOSIP) immunization of rhesus macaques (RM) provided robust protection against autologous intra-vaginal simian-human immunodeficiency virus (SHIV) challenge that was predicted by high serum nAb titers. Here, we show that nAb in these protected RM targeted a glycan hole proximal to residue 465 in gp120 in all cases. nAb also targeted another glycan hole at residues 241/289 and an epitope in V1 at varying frequencies. Non-neutralizing antibodies directed at N611-shielded epitopes in gp41 were also present but were more prevalent in RM with low nAb titers. Longitudinal analysis demonstrated that nAb broadened in some RM during sequential immunization but remained focused in others, the latter being associated with increases in nAb titer. Thirty-eight monoclonal antibodies (mAbs) isolated from a protected RM with an exceptionally high serum neutralization titer bound to the trimer in ELISA, and four of the mAbs potently neutralized the BG505 Env pseudovirus (PV) and SHIV. The four neutralizing mAbs were clonally related and targeted the 465 glycan hole to varying degrees, mimicking the serum. The data demonstrate that the C3/465 glycan hole cluster was the dominant neutralization target in high titer protected RM, despite other co-circulating neutralizing and non-neutralizing specificities. The isolation of a neutralizing mAb family argues that clonotype expansion occurred during BG505 SOSIP immunization, leading to high titer, protective nAb and setting a desirable benchmark for HIV vaccines.

Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype.

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, pDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.

Immediate Effects of Semi-Occluded Vocal Tract Exercises on Acoustic, Auditory-Perceptual, and Self-Perceptual Measures of Voice Production.

PURPOSE: This study examined the immediate acoustic, auditory-perceptual, and self-perceptual effects of two semi-occluded vocal tract exercises (SOVTs): straw phonation and straw phonation into a cup of water, delivered in a remote setting. METHOD: 36 participants (19 females and 17 males) completed a baseline battery of acoustic recordings, followed by one of two SOVTs, and an identical post-task battery. The procedure repeated itself to include the other SOVT. Participants were also asked to rate their self-perceived vocal effort and quality following each condition. Recordings were presented to three expert listeners for completion of auditory-perceptual analysis. RESULTS: Acoustically, a significant decrease in shimmer was noted following straw phonation. Auditory-perceptual analysis revealed a significant increase in the perception of strain following straw phonation into a cup of water. While no significant differences were found between SOVT tasks in self-perception of vocal effort, a significant increase in self-perception of vocal loudness was reported following straw phonation into a cup of water. CONCLUSIONS: SOVTs have a varied, yet significant short-term impact across acoustic, auditory-perceptual, and self-perceptual measures of voice production. Straw phonation provided consistently significant acoustic results, with nearly every variable improving to some degree. Results also support the notion that shimmer is an acoustic measure that is particularly susceptible to change following modest manipulation. These results, in addition to the auditory-perceptual and self-perceptual findings, have a direct impact on how SOVTs are being used clinically and may generalize to inform the way voice metrics are collected and analyzed.

Immediate and long-term effects of speech treatment targets and intensive dosage on Parkinson's disease dysphonia and the speech motor network: Randomized controlled trial.

This study compared acoustic and neural changes accompanying two treatments matched for intensive dosage but having two different treatment targets (voice or articulation) to dissociate the effects of treatment target and intensive dosage in speech therapies. Nineteen participants with Parkinsonian dysphonia (11 F) were randomized to three groups: intensive treatment targeting voice (voice group, n = 6), targeting articulation (articulation group, n = 7), or an untreated group (no treatment, n = 6). The severity of dysphonia was assessed by the smoothed cepstral peak prominence (CPPS) and neuronal changes were evaluated by cerebral blood flow (CBF) recorded at baseline, posttreatment, and 7-month follow-up. Only the voice treatment resulted in significant posttreatment improvement in CPPS, which was maintained at 7 months. Following voice treatment, increased activity in left premotor and bilateral auditory cortices was observed at posttreatment, and in the left motor and auditory cortices at 7-month follow-up. Articulation treatment resulted in increased activity in bilateral premotor and left insular cortices that were sustained at a 7-month follow-up. Activation in the auditory cortices and a significant correlation between the CPPS and CBF in motor and auditory cortices was observed only in the voice group. The intensive dosage resulted in long-lasting behavioral and neural effects as the no-treatment group showed a progressive decrease in activity in areas of the speech motor network out to a 7-month follow-up. These results indicate that dysphonia and the speech motor network can be differentially modified by treatment targets, while intensive dosage contributes to long-lasting effects of speech treatments.

HIV-1 variants are archived throughout infection and persist in the reservoir.

The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.

Infection with multiple HIV-1 founder variants is associated with lower viral replicative capacity, faster CD4+ T cell decline and increased immune activation during acute infection.

HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.

Genital Abnormalities, Hormonal Contraception, and Human Immunodeficiency Virus Transmission Risk in Rwandan Serodifferent Couples.

BACKGROUND: We explored the role of genital abnormalities and hormonal contraception in human immunodeficiency virus (HIV) transmission among heterosexual serodifferent couples in Rwanda. METHODS: From 2002 to 2011, HIV-serodifferent couples who were not using antiretroviral treatment were followed up, and sociodemographic and clinical data were collected, family planning provided, and HIV-negative partners retested. Couples were assessed for genital ulcers; nonulcerative genital sexually transmitted infection (STIs), including gonorrhea, chlamydia, and trichomoniasis; and non-STI vaginal infections, including bacterial vaginosis and candida. Multivariable models evaluated associations between covariates and HIV transmission genetically linked to the index partner. RESULTS: Among 877 couples in which the man was HIV positive, 37 linked transmissions occurred. Factors associated with women's HIV acquisition included genital ulceration in the female partner (adjusted hazard ratio, 14.1) and nonulcerative STI in the male partner (8.6). Among 955 couples in which the woman was HIV positive, 46 linked transmissions occurred. Factors associated with HIV acquisition in men included nonulcerative STI in the female partner (adjusted hazard ratio, 4.4), non-STI vaginal dysbiosis (7.1), and genital ulceration in the male partner (2.6). Hormonal contraception use was not associated with HIV transmission or acquisition. CONCLUSIONS: Our findings underscore the need for integrating HIV services with care for genital abnormalities. Barriers (eg, cost of training, demand creation, advocacy, and client education; provider time; and clinic space) to joint HIV/STI testing need to be considered and addressed.

Selective HLA restriction enables the evaluation and interpretation of immunogenic breadth at comparable levels to that observed with broader HLA distribution.

Existing approaches to identifying predictive T-cell epitopes have traditionally utilized either 2-digit HLA super-families or more commonly utilizing autologous HLA alleles to facilitate the predictions. However, the use of these criteria may not consider the HLA representation within any target population. Here we propose a modification to concept of utilizing autologous HLA whereby subsets of individuals are selected for their specific HLA allele profiles and the representation they provide within a given population. Using this selective approach to HLA selection and the linkages to specific individuals may enable the design of more targeted experimentalstrategies.

Direct identification of HLA-presented CD8 T cell epitopes from transmitted founder HIV-1 variants.

Cytotoxic T lymphocytes (CTLs) are a critical arm of the immune response to viral infections. The activation and expansion of antigen specific CTL requires recognition of peptide antigens presented on class I major histocompatibility complex molecules (MHC-1) of infected cells. Methods to identify presented peptide antigens that do not rely on the pre-existence of antigen specific CTL are critical to the development of new vaccines. We infected activated CD4+ T cells with two HIV-1 transmitted founder (TF) isolates and used high-resolution mass spectrometry (MS) to identify HIV peptides bound on MHC-1. Using this approach, we identified 14 MHC-1 bound peptides from across the two TF isolates. Assessment of predicted binding thresholds revealed good association of the identified peptides to the shared HLA alleles between the HIV+ donors and the naïve PBMC sample with three peptides identified through peptide sequencing inducing a CD8 T-cell response (p < 0.05). Direct infection of naïve CD4 cells by HIV TF isolates and sequencing of MHC-I presented peptides by HPLC-MS/MS enables identification of novel peptides that may be missed by alternative epitope mapping strategies and can provide valuable insight in to the first peptides presented by an HIV-infected CD4 cell in the first few days post infection.

A Stronger Innate Immune Response During Hyperacute Human Immunodeficiency Virus Type 1 (HIV-1) Infection Is Associated With Acute Retroviral Syndrome.

BACKGROUND: Acute retroviral syndrome (ARS) is associated with human immunodeficiency virus type 1 (HIV-1) subtype and disease progression, but the underlying immunopathological pathways are poorly understood. We aimed to elucidate associations between innate immune responses during hyperacute HIV-1 infection (hAHI) and ARS. METHODS: Plasma samples obtained from volunteers (≥18.0 years) before and during hAHI, defined as HIV-1 antibody negative and RNA or p24 antigen positive, from Kenya, Rwanda, Uganda, Zambia, and Sweden were analyzed. Forty soluble innate immune markers were measured using multiplexed assays. Immune responses were differentiated into volunteers with stronger and comparatively weaker responses using principal component analysis. Presence or absence of ARS was defined based on 11 symptoms using latent class analysis. Logistic regression was used to determine associations between immune responses and ARS. RESULTS: Of 55 volunteers, 31 (56%) had ARS. Volunteers with stronger immune responses (n = 36 [65%]) had increased odds of ARS which was independent of HIV-1 subtype, age, and risk group (adjusted odds ratio, 7.1 [95% confidence interval {CI}: 1.7-28.8], P = .003). Interferon gamma-induced protein (IP)-10 was 14-fold higher during hAHI, elevated in 7 of the 11 symptoms and independently associated with ARS. IP-10 threshold >466.0 pg/mL differentiated stronger immune responses with a sensitivity of 84.2% (95% CI: 60.4-96.6) and specificity of 100.0% (95% CI]: 90.3-100.0). CONCLUSIONS: A stronger innate immune response during hAHI was associated with ARS. Plasma IP-10 may be a candidate biomarker of stronger innate immunity. Our findings provide further insights on innate immune responses in regulating ARS and may inform the design of vaccine candidates harnessing innate immunity.

Elevated levels of inflammatory plasma biomarkers are associated with risk of HIV infection.

BACKGROUND: To determine if individuals, from HIV-1 serodiscordant couple cohorts from Rwanda and Zambia, who become HIV-positive have a distinct inflammatory biomarker profile compared to individuals who remain HIV-negative, we compared levels of biomarkers in plasma of HIV-negative individuals who either seroconverted (pre-infection) and became HIV-positive or remained HIV-negative (uninfected). RESULTS: We observed that individuals in the combined cohort, as well as those in the individual country cohorts, who later became HIV-1 infected had significantly higher baseline levels of multiple inflammatory cytokines/chemokines compared to individuals who remained HIV-negative. Genital inflammation/ulceration or schistosome infections were not associated with this elevated profile. Defined levels of ITAC and IL-7 were significant predictors of later HIV acquisition in ROC predictive analyses, whereas the classical Th1 and Th2 inflammatory cytokines such as IL-12 and interferon-γ or IL-4, IL-5 and Il-13 were not. CONCLUSIONS: Overall, the data show a significant association between increased plasma biomarkers linked to inflammation and immune activation and HIV acquisition and suggests that pre-existing conditions that increase systemic biomarkers represent a factor for increased risk of HIV infection.

Better Viral Control despite Higher CD4+ T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol.

The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4+ T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4+ T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4+ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4+ T cells in the acute phase was significantly correlated with plasma levels of 17ß-estradiol (E2). However, unlike in men, higher CD4+ T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4+ T cell loss, an effect that extends into the chronic phase of the disease.IMPORTANCE 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 17ß-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.

Differential Vpu-Mediated CD4 and Tetherin Downregulation Functions among Major HIV-1 Group M Subtypes.

Downregulation of BST-2/tetherin and CD4 by HIV-1 viral protein U (Vpu) promotes viral egress and allows infected cells to evade host immunity. Little is known however about the natural variability in these Vpu functions among the genetically diverse viral subtypes that contribute to the HIV-1 pandemic. We collected Vpu isolates from 332 treatment-naive individuals living with chronic HIV-1 infection in Uganda, Rwanda, South Africa, and Canada. Together, these Vpu isolates represent four major HIV-1 group M subtypes (A [n = 63], B [n = 84], C [n = 94], and D [n = 59]) plus intersubtype recombinants and uncommon strains (n = 32). The ability of each Vpu clone to downregulate endogenous CD4 and tetherin was quantified using flow cytometry following transfection into an immortalized T-cell line and compared to that of a reference Vpu clone derived from HIV-1 subtype B NL4.3. Overall, the median CD4 downregulation function of natural Vpu isolates was similar to that of NL4.3 (1.01 [interquartile range {IQR}, 0.86 to 1.18]), while the median tetherin downregulation function was moderately lower than that of NL4.3 (0.90 [0.79 to 0.97]). Both Vpu functions varied significantly among HIV-1 subtypes (Kruskal-Wallis P < 0.0001). Specifically, subtype C clones exhibited the lowest CD4 and tetherin downregulation activities, while subtype D and B clones were most functional for both activities. We also identified Vpu polymorphisms associated with CD4 or tetherin downregulation function and validated six of these using site-directed mutagenesis. Our results highlight the marked extent to which Vpu function varies among global HIV-1 strains, raising the possibility that natural variation in this accessory protein may contribute to viral pathogenesis and/or spread.IMPORTANCE The HIV-1 accessory protein Vpu enhances viral spread by downregulating CD4 and BST-2/tetherin on the surface of infected cells. Natural variability in these Vpu functions may contribute to HIV-1 pathogenesis, but this has not been investigated among the diverse viral subtypes that contribute to the HIV-1 pandemic. In this study, we found that Vpu function differs significantly among HIV-1 subtypes A, B, C, and D. On average, subtype C clones displayed the lowest ability to downregulate both CD4 and tetherin, while subtype B and D clones were more functional. We also identified Vpu polymorphisms that associate with functional differences among HIV-1 isolates and subtypes. Our study suggests that genetic diversity in Vpu may play an important role in the differential pathogenesis and/or spread of HIV-1.

CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection.

HIV-1 frequently escapes from CD8 T cell responses via HLA-I restricted adaptation, leading to the accumulation of adapted epitopes (AE). We previously demonstrated that AE compromise CD8 T cell responses during acute infection and are associated with poor clinical outcomes. Here, we examined the impact of AE on CD8 T cell responses and their biological relevance in chronic HIV infection (CHI). In contrast to acute infection, the majority of AE are immunogenic in CHI. Longitudinal analyses from acute to CHI showed an increased frequency and magnitude of AE-specific IFNγ responses compared to NAE-specific ones. These AE-specific CD8 T cells also were more cytotoxic to CD4 T cells. In addition, AE-specific CD8 T cells expressed lower levels of PD1 and CD57, as well as higher levels of CD28, suggesting a more activated and less exhausted phenotype. During CHI, viral sequencing identified AE-encoding strains as the dominant quasispecies. Despite increased CD4 T cell cytotoxicity, CD8 T cells responding to AE promoted dendritic cell (DC) maturation and CD4 T cell trans-infection perhaps explaining why AE are predominant in CHI. Taken together, our data suggests that the emergence of AE-specific CD8 T cell responses in CHI confers a selective advantage to the virus by promoting DC-mediated CD4 T cell trans-infection.

Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis.

Despite extensive research on the mechanisms of HLA-mediated immune control of HIV-1 pathogenesis, it is clear that much remains to be discovered, as exemplified by protective HLA alleles like HLA-B*81 which are associated with profound protection from CD4+ T cell decline without robust control of early plasma viremia. Here, we report on additional HLA class I (B*1401, B*57, B*5801, as well as B*81), and HLA class II (DQB1*02 and DRB1*15) alleles that display discordant virological and immunological phenotypes in a Zambian early infection cohort. HLA class I alleles of this nature were also associated with enhanced immune responses to conserved epitopes in Gag. Furthermore, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. Elevated LPS levels measured early in infection predicted accelerated CD4+ T cell decline, as well as immune activation and exhaustion. Taken together, these data suggest novel mechanisms for HLA-mediated immune control of HIV-1 pathogenesis that do not necessarily involve significant control of early viremia and point to microbial translocation as a direct driver of HIV-1 pathogenesis rather than simply a consequence.

Antiretroviral Therapy Use and HIV Transmission Among Discordant Couples in Nonresearch Settings in Kigali, Rwanda.

BACKGROUND: Antiretroviral therapy (ART) efficacy for HIV prevention among discordant couples has been demonstrated in clinical trials. Effectiveness outside of research settings is less well understood. METHODS: HIV-discordant couples were enrolled in couples' testing and follow-up at 20 government clinics in Kigali from 2010 to 2014. We performed viral linkage analysis on seroconverting couples to determine infection sources (intracouple vs. extracouple). Antiretroviral therapy use in index partners was collected at baseline and during follow-up by self-report with verification of government medical records. RESULTS: A total of 3777 HIV-discordant couples were identified and followed up at government health clinics. Fifty-four incident HIV infections were identified, of which 36 were confirmed linked to the index partner, 4 were unlinked, and 14 were unknown. Among the 50 linked or unknown transmission pairs, 38% occurred among couples in which the index partner was on ART (HIV incidence rate of 0.63/100 person-years), whereas 62% occurred among couples in which the index partner was not on ART (HIV incidence rate of 5.51/100 person-years; adjusted rate ratio, 6.9). HIV acquisition was higher in women than in men with non-ART using index partners (P < 0.001). CONCLUSIONS: Couples in a government clinic couples' HIV testing and follow-up program in Rwanda had an 89% reduction in HIV incidence when index partners were using ART, slightly lower than efficacy estimates from randomized trials. Antiretroviral therapy for prevention should be prioritized for key populations including discordant couples identified via couples' voluntary counseling and testing, with increased efforts to improve uptake, adherence, and viral load monitoring.

Clustered Mutations at the Murine and Human IgH Locus Exhibit Significant Linkage Consistent with Templated Mutagenesis.

Somatic hypermutation generates a myriad of Ab mutants in Ag-specific B cells, from which high-affinity mutants are selected. Chickens, sheep, and rabbits use nontemplated point mutations and templated mutations via gene conversion to diversify their expressed Ig loci, whereas mice and humans rely solely on untemplated somatic point mutations. In this study, we demonstrate that, in addition to untemplated point mutations, templated mutagenesis readily occurs at the murine and human Ig loci. We provide two distinct lines of evidence that are not explained by the Neuberger model of somatic hypermutation: 1) across multiple data sets there is significant linkage disequilibrium between individual mutations, especially among close mutations, and 2) among those mutations, those <8 bp apart are significantly more likely to match microhomologous regions in the IgHV repertoire than predicted by the mutation profiles of somatic hypermutation. Together, this supports the role of templated mutagenesis during somatic diversification of Ag-activated B cells.

Sports Related Concussion Impacts Speech Rate and Muscle Physiology.

OBJECTIVE: Establish objective and subjective speech rate and muscle function differences between athletes with and without sports related concussion (SRC) histories and provide potential motor speech evaluation in SRC. METHODS: Over 1,110 speech samples were obtained from 30, 19-22 year-old athletes who had sustained an SRC within the past 2 years and 30 pair-wise matched control athletes with no history of SRC. Speech rate was measured via average time per syllable, average unvoiced time per syllable, and expert perceptual judgment. Speech muscle function was measured via surface electromyography over the obicularis oris, masseter, and segmental triangle. Group differences were assessed using MANOVA, bootstrapping and predictive ROC analyses. RESULTS: Athletes with SRC had slower speech rates during DDK tasks than controls as evidenced by longer average time per syllable longer average unvoiced time per syllable and expert judgment of slowed rate. Rate measures were predictive of concussion history. Further, athletes with SRC required more speech muscle activation than controls to complete DDK tasks. CONCLUSION: Clear evidence of slowed speech and increased muscle activation during the completion of DDK tasks in athletes with SRC histories relative to controls. Future work should examine speech rate in acute concussion.