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BackgroundThe current opioid epidemic across the United States has fueled a surge in the rate of new hepatitis C virus (HCV) infections among young persons who inject drugs (PWIDs). Paramount to interrupting transmission is targeting these high-risk populations and understanding the underlying network structures facilitating transmission within these communities.MethodsDeep sequencing data were obtained for 52 participants from 32 injecting partnerships enrolled in the U-Find-Out (UFO) Partner Study, which is a prospective study of self-described injecting dyad partnerships from a large community-based study of HCV infection in young adult PWIDs from San Francisco. Phylogenetically linked transmission events were identified using traditional genetic-distance measures and viral deep sequence phylogenies reconstructed to determine the statistical support of inferences and the direction of transmission within partnerships.ResultsUsing deep sequencing data, we found that 12 of 32 partnerships were genetically similar and clustered. Three additional phylogenetic clusters were found describing novel putative transmission links outside of the injecting relationship. Transmission direction was inferred correctly for 5 partnerships with the incorrect transmission direction inferred in more than 50% of cases. Notably, we observed that phylogenetic linkage was most often associated with a lower number of network partners and involvement in a sexual relationship.ConclusionsDeep sequencing of HCV among self-described injecting partnerships demonstrates that the majority of transmission events originate from outside of the injecting partnership. Furthermore, these findings caution that phylogenetic methods may be unable to routinely infer the direction of transmission among PWIDs especially when transmission events occur in rapid succession within high-risk networks.

BackgroundHepatitis C virus (HCV), a major cause of morbidity and mortality, is common and rising among young persons who inject drugs (PWID). Reducing the level of viremia may be an intervention, yet the impact of viremia on HCV transmission is unknown.MethodsWe conducted a prospective study of injecting partnerships (Partner Study) of young adult (age < 30 years) PWID within the UFO Study, which enrolled those at risk for HCV or with seronegative viremic infection and up to 3 HCV RNA-positive regular injecting partners. We examined the level of HCV viremia and stage of infection in the HCV-positive partner in regression analyses of HCV transmission events that were corroborated via HCV phylogenetic linkage analyses.ResultsWe enrolled 69 at-risk/acutely infected PWID. There were 25 new HCV infections (incidence rate, 35.9 per 100 person-years; 95% confidence interval [CI], 24.3-53.2 per 100 person-years); 12/25 (48%) were phylogenetically linked to at least 1 partner. We found no association between the infected partner's quantitative level of HCV viremia and likely transmission in multivariate analyses (adjusted odds ratio [AOR], 0.90; 95% confidence interval [CI], 0.55-1.46); however, seronegative viremic infection in the infected partner was associated with increased transmission (AOR, 28.02; 95% CI, 5.61-139.95).ConclusionsThe HCV viremia level was not associated with increased odds of transmission, yet acute HCV infection (seronegative viremic) was. Explanations include high-risk behavior during acute infection or missed fluctuations in viremia during acute infection. Both point to the need for frequent testing to detect new infection and attempt to prevent onward transmission.

Hepatitis C virus (HCV) infections have sharply increased in the United States, where an estimated 2.4 million persons are living with chronic infection (1). In 2013, [approximately equal to]19,368 persons [...]

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

The increasing frequency of pathogenic coronaviruses in the human population has raised public health concerns about possible future pandemics. It is critical to understand whether immune responses to the current circulating coronaviruses provide protection against related viruses or those that may emerge in the future. In this issue of the JCI, Dangi, Palacio, and co-authors detail the extent of coronavirus cross-protection following both vaccination and natural infection and ultimately used murine models to highlight the mechanism behind this heterotypic immunity. This study provides insight into the possibility of a pan-coronavirus vaccine that could protect humans against future coronavirus outbreaks., Diverse coronaviruses The repeated emergence of different pathogenic human coronaviruses over the past 20 years has highlighted the impact of these viruses on public health and the need for a [...]

Background The factors associated with severe acute respiratory coronavirus 2 (SARS-CoV-2) reinfection remain poorly defined. Methods We identified patients with SARS-CoV-2 infection and at least 1 repeat reverse transcription polymerase chain reaction result a minimum of 90 days after the initial positive test and before 21 January 2021. Those with a repeat positive test were deemed to have reinfection (n = 75), and those with only negative tests were classified as convalescents (n = 1594). Demographics, coronavirus disease 2019 (COVID-19) severity, and treatment histories were obtained from the Boston Medical Center electronic medical record. Humoral responses were analyzed using SARS-CoV-2–specific enzyme-linked immunosorbent assays and pseudovirus neutralizations in a subset of reinfection (n = 16) and convalescent samples (n = 32). Univariate, multivariate, and time to event analyses were used to identify associations. Results Individuals with reinfection had more frequent testing at shorter intervals compared with the convalescents. Unstable housing was associated with more than 2-fold greater chance of reinfection. Preexisting comorbidities and COVID-19 severity after the initial infection were not associated with reinfection. SARS-CoV-2 immunoglobulin G levels and pseudovirus neutralization were not different within the early weeks after primary infection and at a timepoint at least 90 days later in the 2 groups. In the convalescents, but not in those with reinfection, the late as compared with early humoral responses were significantly higher. Conclusions Reinfection associates with unstable housing, which is likely a marker for virus exposure, and reinfection occurs in the presence of SARS-CoV-2 antibodies. [ABSTRACT FROM AUTHOR]

Judges made choices and rated strengths of preference between gambles composed of 50-50 chances to receive either of 2 monetary outcomes (x, y). Others judged how much they would pay to play their chosen gamble rather than the other gamble. Judged strengths of preference violated interval independence, because they depended on the value of a common outcome. For example, judges offered to pay an average of $44 to play ($74, $100) instead of ($8, $100) but offered to pay only $24 to play ($6, $74) instead of ($6, $8). Results violated the theory that utility of gambles is a nonconfigural average of the values of the outcomes and that strengths of preference are monotonically related to utility differences. Results can be explained by a configural weight model in which the lowest outcome receives greater weight.

Ending the hepatitis C virus (HCV) epidemic requires stopping transmission among networks of persons who inject drugs. Identifying transmission networks by using genomic epidemiology may inform community responses that can quickly interrupt transmission. We retrospectively identified HCV RNA-positive specimens corresponding to 459 persons in settings that use the state laboratory, including correctional facilities and syringe services programs, in Wisconsin, USA, during 2016-2017. We conducted next-generation sequencing of HCV and analyzed it for phylogenetic linkage by using the Centers for Disease Control and Prevention Global Hepatitis Outbreak Surveillance Technology platform. Analysis showed that 126 persons were linked across 42 clusters. Phylogenetic clustering was higher in rural communities and associated with female sex and younger age among rural residents. These data highlight that HCV transmission could be reduced by expanding molecular-based surveillance strategies to rural communities affected by the opioid crisis. [ABSTRACT FROM AUTHOR]

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic “signatures” within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.

Certain major histocompatibility complex class I (MHC-I) alleles are associated with spontaneous control of viral replication in human immunodeficiency virus (HIV)-infected people and simian immunodeficiency virus (SIV)- infected rhesus macaques (RMs). These cases of "elite" control of HIV/SIV replication are often immune-mediated, thereby providing a framework for studying anti-lentiviral immunity. In this study, we examined how vaccination impacts SIV replication in RMs expressing the MHC-I allele Mamu-B*17. Approximately 21% of Mamu-B*17+ and 50% of Mamu-B*08+ RMs control chronic-phase viremia after SIVmac239 infection. Because CD8+ T cells targeting Mamu-B*08-restricted SIV epitopes have been implicated in virologic suppression in Mamu-B*08+ RMs, we investigated whether this might also be true for Mamu-B*17+ RMs. Two groups of Mamu-B*17+ RMs were vaccinated with genes encoding Mamu-B*17-restricted epitopes in Vif and Nef. These genes were delivered by themselves (group 1) or together with env (group 2). Group 3 included MHC-I-matched RMs and served as the control group. Surprisingly, the group 1 vaccine regimen had little effect on viral replication compared to group 3, suggesting that unlike Mamu-B*08+ RMs, preexisting SIV-specific CD8+ T cells alone do not facilitate long-term virologic suppression in Mamu-B*17+ RMs. Remarkably, however, 5/8 group 2 vaccinees controlled viremia to <15 viral RNA copies/ml soon after infection. No serological neutralizing activity against SIVmac239 was detected in group 2, although vaccine-elicited gp140-binding antibodies correlated inversely with nadir viral loads. Collectively, these data shed new light on the unique mechanism of elite control in Mamu-B*17+ RMs and implicate vaccine-induced, nonneutralizing anti- Env antibodies in the containment of immunodeficiency virus infection. [ABSTRACT FROM AUTHOR]

Certain major histocompatibility complex class I (MHC-I) alleles (e.g., HLA-B*27) are enriched among human immunodeficiency virus type 1 (HIV-1)-infected individuals who suppress viremia without treatment (termed "elite controllers" [ECs]). Likewise, Mamu-B*08 expression also predisposes rhesus macaques to control simian immunodeficiency virus (SIV) replication. Given the similarities between Mamu-B*08 and HLA-B*27, SIV-infected Mamu-B*08+ animals provide a model to investigate HLA-B*27-mediated elite control. We have recently shown that vaccination with three immunodominant Mamu-B*08-restricted epitopes (Vif RL8, Vif RL9, and Nef RL10) increased the incidence of elite control in Mamu-B*08+ macaques after challenge with the pathogenic SIVmac239 clone. Furthermore, a correlate analysis revealed that CD8+ T cells targeting Nef RL10 was correlated with improved outcome. Interestingly, this epitope is conserved between SIV and HIV-1 and exhibits a delayed and atypical escape pattern. These features led us to postulate that a monotypic vaccine-induced Nef RL10-specific CD8+ T-cell response would facilitate the development of elite control in Mamu-B*08+ animals following repeated intrarectal challenges with SIVmac239. To test this, we vaccinated Mamu-B*08+ animals with nef inserts in which Nef RL10 was either left intact (group 1) or disrupted by mutations (group 2). Although monkeys in both groups mounted Nef-specific cellular responses, only those in group 1 developed Nef RL10-specific CD8+ T cells. These vaccine-induced effector memory CD8+ T cells did not prevent infection. Escape variants emerged rapidly in the group 1 vaccinees, and ultimately, the numbers of ECs were similar in groups 1 and 2. High-frequency vaccine-induced CD8+ T cells focused on a single conserved epitope and therefore did not prevent infection or increase the incidence of elite control in Mamu-B*08+ macaques. [ABSTRACT FROM AUTHOR]

Recent documented infection with an endemic coronavirus (eCoV) associates with less severe coronavirus disease 2019 (COVID-19), yet the immune mechanism behind this protection has not been fully explored. We measured both antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in SARS-CoV-2 naïve individuals classified into two groups, either with or without presumed recent eCoV infections. There was no difference in neutralizing antibodies and T cell responses against SARS-CoV-2 antigens between the two groups. SARS-CoV-2 naïve individuals with recent presumed eCoV infection, however, had higher levels of Fc receptor (FcR) binding antibodies against eCoV spikes (S) and SARS-CoV-2 S2. There was also a significant correlation between eCoV and SARS-CoV-2 FcR binding antibodies. Recent eCoV infection boosts cross-reactive antibodies that can mediate Fc effector functions, and this may play a role in the observed heterotypic immune protection against severe COVID-19., Competing Interests: The authors have declared that no conflict of interest exists.

Immune responses from prior SARS-CoV-2 infection and COVID-19 vaccination do not prevent re-infections and may not protect against future novel coronaviruses (CoVs). We examined the incidence of and immune differences against human endemic CoVs (eCoV) as a proxy for response against future emerging CoVs. Assessment was among those with known SARS-CoV-2 infection, COVID-19 vaccination but no documented SARS-CoV-2 infection, or neither exposure. Retrospective cohort analyses suggest that prior SARS-CoV-2 infection, but not COVID-19 vaccination alone, protects against subsequent symptomatic eCoV infection. CD8 + T cell responses to the non-structural eCoV proteins, nsp12 and nsp13, were significantly higher in individuals with previous SARS-CoV-2 infection as compared to the other groups. The three groups had similar cellular responses against the eCoV spike and nucleocapsid, and those with prior spike exposure had lower eCoV-directed neutralizing antibodies. Incorporation of non-structural viral antigens in a future pan-CoV vaccine may improve protection against future heterologous CoV infections., Competing Interests: Declaration of Interests The authors have declared that no conflict of interest exists.