Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2.

Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4-11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication-transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

Behçet's patients' response to COVID-19 vaccination.

Immune hyperstimulation by SARS-CoV2 results in multi-system involvement with consequent organ damage not dissimilar to Behçet's Disease (BD). Management of BD includes immunosuppressive medication, which led to concerns that; firstly, SARS-CoV-2 would stimulate BD activity, thrombin, clotting times, TPO antibodies, and the effectiveness and duration of the COVID-19 vaccines' response in this potentially vulnerable group. The main objectives of this study were: to assess BD patients' immune response to the COVID-19 vaccines based on age, gender, disease activity, BD phenotype, and immunomodulatory medication compared to healthy control participants by measuring anti-spike IgG levels. Further to evaluate the effect of the COVID-19 vaccines on T and B cells, immunoglobulins, thrombophilia, thyroid function and COVID-19 antibody production. Patients on immunosuppressive medication had a reduced immune response to COVID-19 vaccines. -Also, patients over 40 years and with the neurologic BD phenotype had lower responses. mRNA COVID-19 vaccines were more effective and had fewer side effects compared to conventional COVID-19 vaccines.

Determining Gentrification's Relationship to Birth Outcomes in Metropolitan California.

There is inconsistent evidence as to whether gentrification, the increase of affluent residents into low-income neighborhoods, is detrimental to health. To date, there is no systematic evidence on how gentrification may matter for a range of birth outcomes across cities with varying characteristics. We utilize California's Birth Cohort File (2009-2012), Decennial Census data, and the American Community Survey (2008-2012) to investigate the relationship of gentrification to: preterm birth, low birthweight, and small-for-gestational-age across California. We find that socioeconomic gentrification is uniformly associated with better birth outcomes. Notably, however, we find that only places specifically experiencing increases in non-White gentrification had this positive impact. These associations vary somewhat by maternal characteristics and by type of gentrification measure utilized; discrepancies between alternative measurement strategies are explored. This study provides evidence that socioeconomic gentrification is positively related to birth outcomes and the race-ethnic character of gentrification matters, emphasizing the continued need to examine how gentrification may impact a range of health and social outcomes.

Correlation Between Postvaccination Anti-Spike Antibody Titers and Protection Against Breakthrough Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Population-Based Longitudinal Study.

In this population-based cohort of 7538 adults, combined immunoglobulin (Ig) G, IgA, and IgM (IgG/A/M) anti-spike titers measured after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination were predictive of protection against breakthrough SARS-CoV-2 infection. Discrimination was significantly improved by adjustment for factors influencing risk of SARS-CoV-2 exposure, including household overcrowding, public transport use, and visits to indoor public places. Anti-spike IgG/A/M titers showed positive correlation with neutralizing antibody titers (rs = 0.80 [95% confidence interval, .72-.86]; P < .001) and S peptide-stimulated interferon-γ concentrations (rs = 0.31 [.13-.47]; P < .001).

Generation of Novel Severe Acute Respiratory Syndrome Coronavirus 2 Variants on the B.1.1.7 Lineage in 3 Patients With Advanced Human Immunodeficiency Virus-1 Disease.

The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is of public health concern in case of vaccine escape. Described are 3 patients with advanced human immunodeficiency virus (HIV)-1 and chronic SARS-CoV-2 infection in whom there is evidence of selection and persistence of novel mutations that are associated with increased transmissibility and immune escape.

HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19.

SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.

HIV-1 Accessory Protein Vpr Interacts with REAF/RPRD2 To Mitigate Its Antiviral Activity.

The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr enhances viral replication in both macrophages and, to a lesser extent, cycling T cells. Virion-packaged Vpr is released in target cells shortly after entry, suggesting it is required in the early phase of infection. Previously, we described REAF (RNA-associated early-stage antiviral factor; RPRD2), a constitutively expressed protein that potently restricts HIV replication at or during reverse transcription. Here, we show that a virus without an intact vpr gene is more highly restricted by REAF and, using delivery by virus-like particles (VLPs), that Vpr alone is sufficient for REAF degradation in primary macrophages. REAF is more highly expressed in macrophages than in cycling T cells, and we detected, by coimmunoprecipitation assay, an interaction between Vpr protein and endogenous REAF. Vpr acts quickly during the early phase of replication and induces the degradation of REAF within 30 min of viral entry. Using Vpr F34I and Q65R viral mutants, we show that nuclear localization and interaction with cullin 4A-DBB1 (DCAF1) E3 ubiquitin ligase are required for REAF degradation by Vpr. In response to infection, cells upregulate REAF levels. This response is curtailed in the presence of Vpr. These findings support the hypothesis that Vpr induces the degradation of a factor, REAF, that impedes HIV infection in macrophages.IMPORTANCE For at least 30 years, it has been known that HIV-1 Vpr, a protein carried in the virion, is important for efficient infection of primary macrophages. Vpr is also a determinant of the pathogenic effects of HIV-1 in vivo A number of cellular proteins that interact with Vpr have been identified. So far, it has not been possible to associate these proteins with altered viral replication in macrophages or to explain why Vpr is carried in the virus particle. Here, we show that Vpr mitigates the antiviral effects of REAF, a protein highly expressed in primary macrophages and one that inhibits virus replication during reverse transcription. REAF is degraded by Vpr within 30 min of virus entry in a manner dependent on the nuclear localization of Vpr and its interaction with the cell's protein degradation machinery.

Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors.

Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N3-methyladenine and N7-methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m2 daily × 5 may be safely administered with MX 150 mg/m2 intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.

The Impact of Residing in a Gang Territory on Adverse Birth Outcomes: Evidence from Los Angeles.

Gang violence remains an ongoing crisis in many communities in the United States. This paper assesses the potential association of gang-occupied neighborhoods with birth outcomes. Adverse birth outcomes serve as a "barometer" of population health, denoting both poor conditions for human development and portending future public health concerns. We draw upon (1) Los Angeles County Vital Statistics Birth Records (2008-2012), (2) GIS information on gang territory boundaries, (3) LA city geo-coded crime data, and (4) the 2010 U.S. Census and 2006-2010 American Community Survey. We find an association between gang-occupied neighborhoods and adverse birth outcomes; however, this association is largely explained by other neighborhood socio-demographic characteristics, crime notwithstanding. We also find that gangland neighborhoods tend to exacerbate the effects of crime for all birth outcomes, but only significantly so for small for gestational age births. Lastly, gang co-residence, crime, and other neighborhood demographics explain a substantial portion of socioeconomic and racial/ethnic disparities in adverse birth outcomes. Gangland neighborhoods appear to be a novel contributor to both population health and health disparities. Future studies should address these relationships in a broad range of metropolitan settings, paying careful attention to causal linkages and moderating effects of gangs and crime.

Effect of light scattering on upconversion photoluminescence quantum yield in microscale-to-nanoscale materials.

Scattering affects excitation power density, penetration depth and upconversion emission self-absorption, resulting in particle size -dependent modifications of the external photoluminescence quantum yield (ePLQY) and net emission. Micron-size NaYF4:Yb3+, Er3+ encapsulated phosphors (∼4.2 µm) showed ePLQY enhancements of >402%, with particle-media refractive index disparity (Δn): 0.4969, and net emission increases of >70%. In sub-micron phosphor encapsulants (∼406 nm), self-absorption limited ePLQY and emission as particle concentration increases, while appearing negligible in nanoparticle dispersions (∼31.8 nm). These dependencies are important for standardising PLQY measurements and optimising UC devices, since the encapsulant can drastically enhance UC emission.

Muslim-Non-Muslim Locational Attainment in Philadelphia: A New Fault Line in Residential Inequality?

This study examines Muslim-non-Muslim disparities in locational attainment. We pool data from the 2004, 2006, and 2008 waves of the Public Health Management Corporation's Southeastern Pennsylvania Household Survey. These data contain respondents' religious identities and are geocoded at the census-tract level, allowing us to merge American Community Survey data and examine neighborhood-level outcomes to gauge respondents' locational attainment. Net of controls, our multivariate analyses reveal that among blacks and nonblacks, Muslims live in neighborhoods that have significantly lower shares of whites and greater representations of blacks. Among blacks, Muslims are significantly less likely than non-Muslims to reside in suburbs. The Muslim disadvantages for blacks and nonblacks in neighborhood poverty and neighborhood median income, however, become insignificant. Our results provide support for the tenets of the spatial assimilation and place stratification models and suggest that Muslim-non-Muslim disparities in locational attainment define a new fault line in residential stratification.

Protamine sulfate for the reversal of enoxaparin associated hemorrhage beyond 12 h.

Clinical practice guidelines recommend protamine sulfate for reversal of enoxaparin associated bleeds dependent on the time from last administration and dose of enoxaparin. We present a case of a hemodynamically unstable patient with an enoxaparin induced abdominal wall hematoma/hemorrhage and the previous enoxaparin administration 21.5 h prior to presentation with a therapeutic anti-Xa assay (0.8 IU/mL) upon assessment in the emergency department. Along with resuscitative efforts, an interdisciplinary team collaborated to administer protamine sulfate 50 mg intravenous once (0.5 mg per 1 mg of enoxaparin) to reverse the therapeutic anticoagulation. Our case demonstrates the importance of monitoring renal function and the potential for accumulation of enoxaparin in patients with renal dysfunction leading to prolonged therapeutic anti-Xa assays. With the availability of anti-Xa assays, future reversal recommendations of enoxaparin associated bleeds using protamine sulfate should include the initial anti-Xa assay as a guide for the dosing regimen.

The Association of Minority Self-Rated Health with Black versus White Gentrification.

There exists controversy as to the impact gentrification of cities has on the well-being of minorities. Some accuse gentrification of causing health disparities for disadvantaged minority populations residing in neighborhoods that are changing as a result of these socioeconomic shifts. Past scholarship has suggested that fears of displacement and social isolation associated with gentrification lead to poorer minority health. However, there is a lack of research that directly links gentrification to minority health outcomes. We address this gap with individual data from the 2008 Philadelphia Health Management Corporation's Southeastern Pennsylvania Household Health Survey and census tract data from the 2000 Decennial Census and the 2006-2010 American Community Survey. We implement logistic multilevel models to determine whether and how a resident's self-rated health is affected by gentrification of their neighborhoods. We find that while gentrification does have a marginal effect improving self-rated health for neighborhood residents overall, it leads to worse health outcomes for Blacks. Accounting for racial change, while gentrification leading to increases in White population has no measurable effect on minority health, "Black gentrification" leads to marginally worse health outcomes for Black respondents. These results demonstrate the limitations that improvements of neighborhood socioeconomic character have in offsetting minority health disparities.

Determining the spatial heterogeneity underlying racial and ethnic differences in timely mammography screening.

BACKGROUND: The leading cause of cancer death for women worldwide continues to be breast cancer. Early detection through timely mammography has been recognized to increase the probability of survival. While mammography rates have risen for many women in recent years, disparities in screening along racial/ethnic lines persist across nations. In this paper, we argue that the role of local context, as identified through spatial heterogeneity, is an unexplored dynamic which explains some of the gaps in mammography utilization by race/ethnicity. METHODS: We apply geographically weighted regression methods to responses from the 2008 Public Health Corporations' Southeastern Household Health Survey, to examine the spatial heterogeneity in mammograms in the Philadelphia metropolitan area. RESULTS: We find first aspatially that minority identity, in fact, increases the odds of a timely mammogram: 74% for non-Hispanic Blacks and 80% for Hispanic/Latinas. However, the geographically weighted regression confirms the relation of race/ethnicity to mammograms varies by space. Notably, the coefficients for Hispanic/Latinas are only significant in portions of the region. In other words, the increased odds of a timely mammography we found are not constant spatially. Other key variables that are known to influence timely screening, such as the source of healthcare and social capital, measured as community connection, also vary by space. CONCLUSIONS: These results have ramifications globally, demonstrating that the influence of individual characteristics which motivate, or inhibit, cancer screening may not be constant across space. This inconsistency calls for healthcare practitioners and outreach services to be mindful of the local context in their planning and resource allocation efforts.

Synthesis of Naamidine A and Selective Access to N(2)-Acyl-2-aminoimidazole Analogues.

A short and scalable synthesis of naamidine A, a marine alkaloid with a selective ability to inhibit epidermal growth factor receptor (EGFR)-dependent cellular proliferation, has been achieved. A key achievement in this synthesis was the development of a regioselective hydroamination of a monoprotected propargylguanidine to deliver N(3)-protected cyclic ene-guanidines. This permits the extension of this methodology to prepare N(2)-acyl analogues in a fashion that obviates the troublesome acylation of the free 2-aminoimidazoles, which typically yields mixtures of N(2)- and N(2),N(2)-diacylated products.

Self-rated health and residential segregation: how does race/ethnicity matter?

Despite recent declines, racial segregation remains a detriment to minority neighborhoods. However, existing research is inconclusive as to the effects racial segregation has on health. Some argue that racial segregation is related to poor health outcomes, whereas others suspect that racial segregation may actually lead to improved health for some minority communities. Even less is known about whether minority access to white neighborhoods improves health. We address these gaps with individual data from the 2010 Public Health Management Corporation's Southeastern Pennsylvania Household Health Survey and census tract data from the 2010 Decennial Census and the 2006-2010 American Community Survey. We implement logistic multilevel models to determine whether and how a resident's self-rated health is affected by the racial/ethnic segregation of their neighborhoods. Our key finding suggests that the effects of segregation on self-rated health depend on an individual's race/ethnicity, with blacks and Latino residents most likely to experience adverse effects. Particularly, minorities living in predominantly white communities have a significantly higher likelihood to report poor/fair health than they would in segregated minority neighborhoods. These findings make clear that access to white neighborhoods is not sufficient to improve minority health; fuller neighborhood integration is necessary to ensure all have health equity.

Declining segregation through the lens of neighborhood quality: does middle-class and affluent status bring equality?

Middle- and upper-class status along with suburban residence are together considered symbolic of the American dream. However, the question of whether they mean access to better quality residential environments has gone largely unexplored. This study relies on data from the 2009 panel of the American Housing Survey and focuses on a range of neighborhood conditions, including indicators of physical and social disorder as well as housing value and a neighborhood rating. Contrary to the tenets of the spatial assimilation model, we find that middle-class and affluent status do not consistently lead to superior conditions for all households. Neighborhood circumstances vary considerably based on householder race and ethnicity, with blacks and Hispanics experiencing the greatest disparities from whites. In addition, suburban residence does not attenuate such differences, and in some cases, well-to-do minorities do even worse than whites in neighborhood quality in suburbs.

Influence of individuals' determinants including vaccine type on cellular and humoral responses to SARS-CoV-2 vaccination.

Vaccine development targeting SARS-CoV-2 in 2020 was of critical importance in reducing COVID-19 severity and mortality. In the U.K. during the initial roll-out most individuals either received two doses of Pfizer COVID-19 vaccine (BNT162b2) or the adenovirus-based vaccine from Oxford/AstraZeneca (ChAdOx1-nCoV-19). There are conflicting data as to the impact of age, sex and body habitus on cellular and humoral responses to vaccination, and most studies in this area have focused on determinants of mRNA vaccine immunogenicity. Here, we studied a cohort of participants in a population-based longitudinal study (COVIDENCE UK) to determine the influence of age, sex, body mass index (BMI) and pre-vaccination anti-Spike (anti-S) antibody status on vaccine-induced humoral and cellular immune responses to two doses of BNT162b2 or ChAdOx-n-CoV-19 vaccination. Younger age and pre-vaccination anti-S seropositivity were both associated with stronger antibody responses to vaccination. BNT162b2 generated higher neutralising and anti-S antibody titres to vaccination than ChAdOx1-nCoV-19, but cellular responses to the two vaccines were no different. Irrespective of vaccine type, increasing age was also associated with decreased frequency of cytokine double-positive CD4+T cells. Increasing BMI was associated with reduced frequency of SARS-CoV-2-specific TNF+CD8% T cells for both vaccines. Together, our findings demonstrate that increasing age and BMI are associated with attenuated cellular and humoral responses to SARS-CoV-2 vaccination. Whilst both vaccines induced T cell responses, BNT162b2 induced significantly elevated humoral immune response as compared to ChAdOx-n-CoV-19.

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial.

BACKGROUND: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHOD: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. FINDING: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. INTERPRETATION: 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. FUNDING: National Institute for Health and Care Research.

Preservation of memory B cell homeostasis in an individual producing broadly neutralising antibodies against HIV-1.

Immunological determinants favouring emergence of broadly neutralising antibodies are crucial to the development of HIV-1 vaccination strategies. Here, we combined RNAseq and B cell cloning approaches to isolate a broadly neutralising antibody (bnAb) ELC07 from an individual living with untreated HIV-1. Using single particle cryogenic electron microscopy (cryo-EM), we show that the antibody recognises a conformational epitope at the gp120-gp41 interface. ELC07 binds the closed state of the viral glycoprotein causing considerable perturbations to the gp41 trimer core structure. Phenotypic analysis of memory B cell subsets from the ELC07 bnAb donor revealed a lack of expected HIV-1-associated dysfunction, specifically no increase in CD21-/CD27- cells was observed whilst the resting memory (CD21+/CD27+) population appeared preserved despite uncontrolled HIV-1 viraemia. Moreover, single cell transcriptomes of memory B cells from this bnAb donor showed a resting memory phenotype irrespective of the epitope they targeted or their ability to neutralise diverse strains of HIV-1. Strikingly, single memory B cells from the ELC07 bnAb donor were transcriptionally similar to memory B cells from HIV-negative individuals. Our results demonstrate that potent bnAbs can arise without the HIV-1-induced dysregulation of the memory B cell compartment and suggest that sufficient levels of antigenic stimulation with a strategically designed immunogen could be effective in HIV-negative vaccine recipients.