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Virology Jun 2024An important approach to stopping the AIDS epidemic is the development of a vaccine that elicits antibodies that block virus capture, the initial interactions of HIV-1...
An important approach to stopping the AIDS epidemic is the development of a vaccine that elicits antibodies that block virus capture, the initial interactions of HIV-1 with the target cells, and replication. We utilized a previously developed qRT-PCR-based assay to examine the effects of broadly neutralizing antibodies (bNAbs), plasma from vaccine trials, and monoclonal antibodies (mAbs) on virus capture and replication. A panel of bNAbs inhibited primary HIV-1 replication in PBMCs but not virus capture. Plasma from RV144 and RV305 trial vaccinees demonstrated inhibition of virus capture with the HIV-1 subtype prevalent in Thailand. Several RV305 derived V2-specific mAbs inhibited virus replication. One of these RV305 derived V2-specific mAbs inhibited both virus capture and replication, demonstrating that it is possible to elicit antibodies by vaccination that inhibit virus capture and replication. Induction of a combination of such antibodies may be the key to protection from HIV-1 acquisition.
PubMed: 38941746
DOI: 10.1016/j.virol.2024.110158 -
Vaccine Jun 2024COVID-19 has disproportionately burdened impoverished minority communities. This study recruited an age- and gender-diverse community sample of 541 Black adults in a...
COVID-19 has disproportionately burdened impoverished minority communities. This study recruited an age- and gender-diverse community sample of 541 Black adults in a United States Midwestern city with large racial health disparities, with the aim of examining factors associated with COVID-19 vaccination. All participants completed measures assessing their COVID-19 vaccination status (unvaccinated, received primary vaccination, or received primary plus booster vaccination) as well as demographic characteristics, socioeconomic factors, health and health system factors, and health behavior theory constructs related to vaccination. In this predominantly low-income sample, 55% of participants had received primary COVID-19 vaccination and 31% of the sample had received a booster dose. Multiple regression analyses established that having primary vaccination was significantly predicted by older age, political identification as Democrat, education beyond high school, barriers to accessing health care, as well as higher trust of vaccine benefits, less preference for natural immunity, stronger social norms favoring vaccination, and perceiving higher levels of collective responsibility. Surprisingly, higher global medical mistrust and difficulty with healthcare access were associated with vaccination. The model explained 76% of the variance in primary COVID-19 vaccination. Having received a COVID-19 booster was predicted by older age, previous COVID-19 infection, higher trust in vaccine benefits, and fewer worries about unforeseen future effects of vaccination. Study findings identified factors associated with COVID-19 vaccine uptake in racial minority communities, and support the benefits of interventions that harness social network supports for vaccination, address community vaccine concerns, and appeal to collective responsibility to promote vaccine uptake.
PubMed: 38937180
DOI: 10.1016/j.vaccine.2024.06.055 -
Current Opinion in HIV and AIDS Jun 2024To highlight recent data on HPV infection and cervical precancerous lesions in adolescents with HIV, and priorities for primary and secondary HPV prevention.
PURPOSE OF REVIEW
To highlight recent data on HPV infection and cervical precancerous lesions in adolescents with HIV, and priorities for primary and secondary HPV prevention.
RECENT FINDINGS
Incident and persistent high-risk HPV infections and cervical abnormalities are higher among young women with perinatally acquired HIV compared to their HIV-negative peers; data on HPV among males with perinatally acquired HIV are scarce. HPV vaccination is highly effective in preventing HPV-related disease, but antibody titers may decline in people with HIV. It remains unclear if emerging recommendations to reduce vaccine schedules from three doses to two or one dose are appropriate for children and adolescents with perinatally acquired HIV. Due to higher risks of HPV-related cancers, screening guidelines for cervical cancer differ in their frequency and age at initiation for women with HIV, but there are no recommendations for women with perinatally acquired HIV; nor for anal cancer screening for men with perinatally acquired HIV.
SUMMARY
Data on the effectiveness of reduced HPV vaccine schedules in children and adolescents with HIV are needed. Implementation research to guide strategies for vaccination, screening, and treatment should include children, adolescents, and young adults with perinatally acquired HIV to ensure they are not left behind.
PubMed: 38935056
DOI: 10.1097/COH.0000000000000868 -
Current Opinion in HIV and AIDS Jun 2024The primate microbiome consists of bacteria, eukaryotes, and viruses that dynamically shape and respond to host health and disease. Understanding how the symbiotic...
PURPOSE OF REVIEW
The primate microbiome consists of bacteria, eukaryotes, and viruses that dynamically shape and respond to host health and disease. Understanding how the symbiotic relationship between the host and microbiome responds to HIV has implications for therapeutic design.
RECENT FINDINGS
Advances in microbiome identification technologies have expanded our ability to identify constituents of the microbiome and to infer their functional capacity. The dual use of these technologies and animal models has allowed interrogation into the role of the microbiome in lentiviral acquisition, vaccine efficacy, and the response to antiretrovirals. Lessons learned from such studies are now being harnessed to design microbiome-based interventions.
SUMMARY
Previous studies considering the role of the microbiome in people living with HIV largely described viral acquisition as an intrusion on the host:microbiome interface. Re-framing this view to consider HIV as a novel, albeit unwelcome, component of the microbiome may better inform the research and development of pre and postexposure prophylaxes.
PubMed: 38935047
DOI: 10.1097/COH.0000000000000870 -
Vaccines May 2024The yellow fever (YF) vaccine is one of the safest and most effective vaccines currently available. Still, its administration in people living with HIV (PLWH) is limited...
The yellow fever (YF) vaccine is one of the safest and most effective vaccines currently available. Still, its administration in people living with HIV (PLWH) is limited due to safety concerns and a lack of consensus regarding decreased immunogenicity and long-lasting protection for this population. The mechanisms associated with impaired YF vaccine immunogenicity in PLWH are not fully understood, but the general immune deregulation during HIV infection may play an important role. To assess if HIV infection impacts YF vaccine immunogenicity and if markers of immune deregulation could predict lower immunogenicity, we evaluated the association of YF neutralization antibody (NAb) titers with the pre-vaccination frequency of activated and exhausted T cells, levels of pro-inflammatory cytokines, and frequency of T cells, B cells, and monocyte subsets in PLWH and HIV-negative controls. We observed impaired YF vaccine immunogenicity in PLWH with lower titers of YF-NAbs 30 days after vaccination, mainly in individuals with CD4 count <350 cells/mm. At the baseline, those individuals were characterized by having a higher frequency of activated and exhausted T cells and tissue-like memory B cells. Elevated levels of those markers were also observed in individuals with CD4 count between 500 and 350 cells/mm. We observed a negative correlation between the pre-vaccination level of CD8 T cell exhaustion and CD4 T cell activation with YF-NAb titers at D365 and the pre-vaccination level of IP-10 with YF-NAb titers at D30 and D365. Our results emphasize the impact of immune activation, exhaustion, and inflammation in YF vaccine immunogenicity in PLWH.
PubMed: 38932307
DOI: 10.3390/vaccines12060578 -
Viruses Jun 2024Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is... (Review)
Review
Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection.
Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus's direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.
Topics: Simian Immunodeficiency Virus; Animals; HIV Infections; Simian Acquired Immunodeficiency Syndrome; Humans; HIV; Disease Models, Animal; Haplorhini; Lymphocyte Depletion
PubMed: 38932264
DOI: 10.3390/v16060972 -
Pharmaceutics May 2024We describe the current Good Manufacturing Practice (cGMP) production and subsequent characterization of eOD-GT8 60mer, a glycosylated self-assembling nanoparticle HIV-1...
We describe the current Good Manufacturing Practice (cGMP) production and subsequent characterization of eOD-GT8 60mer, a glycosylated self-assembling nanoparticle HIV-1 vaccine candidate and germline targeting priming immunogen. Production was carried out via transient expression in the human embryonic kidney 293 (HEK293) cell line followed by a combination of purification techniques. A large-scale cGMP (200 L) production run yielded 354 mg of the purified eOD-GT8 60mer drug product material, which was formulated at 1 mg/mL in 10% sucrose in phosphate-buffered saline (PBS) at pH 7.2. The clinical trial material was comprehensively characterized for purity, antigenicity, glycan composition, amino acid sequence, and aggregation and by several safety-related tests during cGMP lot release. A comparison of the purified products produced at the 1 L scale and 200 L cGMP scale demonstrated the consistency and robustness of the transient transfection upstream process and the downstream purification strategies. The cGMP clinical trial material was tested in a Phase 1 clinical trial (NCT03547245), is currently being stored at -80 °C, and is on a stability testing program as per regulatory guidelines. The methods described here illustrate the utility of transient transfection for cGMP production of complex products such as glycosylated self-assembling nanoparticles.
PubMed: 38931864
DOI: 10.3390/pharmaceutics16060742 -
Children (Basel, Switzerland) Jun 2024Healthcare-associated infections (HAIs) pose a grave threat to patient safety, morbidity, and mortality, contributing to antimicrobial resistance. Thus, we estimated the...
BACKGROUND
Healthcare-associated infections (HAIs) pose a grave threat to patient safety, morbidity, and mortality, contributing to antimicrobial resistance. Thus, we estimated the point prevalence, risk factors, types, and pathogens of HAIs in hospitalized pediatric patients.
METHODS
A point prevalence survey (PPS) of HAIs in hospitalized pediatric patients < 18 years old was conducted from March to May 2021. Outcomes, risk factors, and types of HAIs associated with HAIs in 41 hospitals across Thailand were collected.
RESULTS
The prevalence of HAIs was 3.9% (95% CI 2.9-5.0%) (56/1443). By ages < 1 month, 1 month-2 years, 2-12 years, and 12-18 years, the prevalence of HAIs was 4.2%, 3.3%, 4.1%, and 3.0%, respectively ( = 0.80). Significant independent risk factors were extended hospital length of stay (LOS) and central venous catheter (CVC) use. Compared to an LOS of <4 days, LOSs of 4-7 days, 8-14 days, and >14 days had adjusted odds ratios (aORs) of 2.65 (95% CI 1.05, 6.68), 5.19 (95% CI 2.00, 13.4), and 9.03 (95% CI 3.97, 20.5), respectively. The use of a CVC had an aOR of 2.45 (95% CI 1.06-5.66). Lower respiratory tract infection (LRTI) was the most common HAI type (46.4%: 26/56). The highest prevalence of HAIs was predominantly observed in LRTI diagnoses, with the highest among these in the <1 month age category at 2.3% (17/738).
CONCLUSION
The prevalence of HAIs in hospitalized pediatric patients was 3.9%. Extended LOS and use of CVC were HAI risk factors. A strategy for reducing LOS and reviewing insertion indications or the early planned removal of a CVC was implemented. The surveillance of HAIs stands as a cornerstone and fundamental component of IPC, offering invaluable insights that enhance hospital IPC interventions aimed at preventing HAIs.
PubMed: 38929317
DOI: 10.3390/children11060738 -
International Journal of Molecular... Jun 2024Mutations have driven the evolution and development of new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with potential implications for...
Mutations have driven the evolution and development of new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with potential implications for increased transmissibility, disease severity and vaccine escape among others. Genome sequencing is a technique that allows scientists to read the genetic code of an organism and has become a powerful tool for studying emerging infectious diseases. Here, we conducted a cross-sectional study in selected districts of the Eastern Province of Zambia, from November 2021 to February 2022. We analyzed SARS-CoV-2 samples ( = 76) using high-throughput sequencing. A total of 4097 mutations were identified in 69 SARS-CoV-2 genomes with 47% (1925/4097) of the mutations occurring in the spike protein. We identified 83 unique amino acid mutations in the spike protein of the seven Omicron sublineages (BA.1, BA.1.1, BA.1.14, BA.1.18, BA.1.21, BA.2, BA.2.23 and XT). Of these, 43.4% (36/83) were present in the receptor binding domain, while 14.5% (12/83) were in the receptor binding motif. While we identified a potential recombinant XT strain, the highly transmissible BA.2 sublineage was more predominant (40.8%). We observed the substitution of other variants with the Omicron strain in the Eastern Province. This work shows the importance of pandemic preparedness and the need to monitor disease in the general population.
Topics: Zambia; Humans; SARS-CoV-2; COVID-19; Genome, Viral; Spike Glycoprotein, Coronavirus; Mutation; Cross-Sectional Studies; Retrospective Studies; Phylogeny; Genomics; High-Throughput Nucleotide Sequencing
PubMed: 38928045
DOI: 10.3390/ijms25126338 -
Antiviral Research Jun 2024Combinational antiretroviral therapy (cART) suppresses human immunodeficiency virus type 1 (HIV-1) viral replication and pathogenesis in acquired immunodeficiency...
Combinational antiretroviral therapy (cART) suppresses human immunodeficiency virus type 1 (HIV-1) viral replication and pathogenesis in acquired immunodeficiency syndrome (AIDS) patients. However, HIV-1 remains in the latent stage of infection by suppressing viral transcription, which hinders an HIV-1 cure. One approach for an HIV-1 cure is the "shock and kill" strategy. The strategy focuses on reactivating latent HIV-1, inducing the viral cytopathic effect and facilitating the immune clearance for the elimination of latent HIV-1 reservoirs. Here, we reported that the H3K4 trimethylation (H3K4me3)-specific demethylase KDM5A/B play a role in suppressing HIV-1 Tat/LTR-mediated viral transcription in HIV-1 latent cells. Furthermore, we evaluated the potential of KDM5-specific inhibitor JQKD82 as an HIV-1 "shock and kill" agent. Our results showed that JQKD82 increases the H3K4me3 level at HIV-1 5' LTR promoter regions, HIV-1 reactivation, and the cytopathic effects in an HIV-1-latent T cell model. In addition, we identified that the combination of JQKD82 and AZD5582, a non-canonical NF-κB activator, generates a synergistic impact on inducing HIV-1 lytic reactivation and cell death in the T cell. The latency-reversing potency of the JQKD82 and AZD5582 pair was also confirmed in peripheral blood mononuclear cells (PBMCs) isolated from HIV-1 aviremic patients and in an HIV-1 latent monocyte. In latently infected microglia (HC69) of the brain, either deletion or inhibition of KDM5A/B results in a reversal of the HIV-1 latency. Overall, we concluded that KDM5A/B function as a host repressor of the HIV-1 lytic reactivation and thus promote the latency and the survival of HIV-1 infected reservoirs.
PubMed: 38925368
DOI: 10.1016/j.antiviral.2024.105947