Current HIV Research最新文献

Reports of HIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) medi-ating a potential 'vaccinal effect' implicate passively transferred bNAbs in promoting endoge-nous anti-HIV-1 immune responses. To date, three clinical trials have reported either increased anti-HIV-1 neutralizing antibodies or T cell responses following bNAb administration to people living with HIV. Despite strong enthusiasm for this hypothesis, motivated in large part by its potential application to HIV-1 therapeutic strategies, the mechanism(s) underlying a vaccinal ef-fect remain unclear. Moreover, vaccinal effects on antibody and T cell responses are not consist-ently replicated. Partly, this inconsistency may be due to numerous difficulties in sensitively measuring a vaccinal effect in the context of human clinical trials. The magnitude of immune response increase following bNAb administration is generally modest, even when it is observed; a far greater enhancement of neutralization or T cell responses is likely required for a biologically meaningful impact. We review clinical and pre-clinical nonhuman primate studies that evaluated HIV-1/SIV monoclonal antibodies for vaccinal effects, with an emphasis on the strengths and limitations of these studies. Considerations for future studies investigating vaccinal effects are discussed, including appropriate comparators and specificity controls. Lastly, immune response characteristics of elite controller cohorts are outlined as potential vaccinal effect endpoints more likely to mediate HIV-1 suppression. As bNAb therapeutic interventions increasingly turn to combination approaches, including incorporation of immunomodulatory agents, attention to study design incorporating appropriate control groups, and relevant immunogenicity assays will enable more conclusive interpretation of vaccinal effects likely to mediate durable control of HIV. In any case, to date, the elicitation of vaccinal effects has been disappointing.

An optimal HIV vaccine should provide protective immunity before sexual debut to prevent infection in adolescents and young adults, including acute infections in women of childbearing age. Such a vaccine will likely require multiple sequential immunization doses and would therefore be ideally initiated in childhood. Many of the world's most successful vaccines are initiated in childhood for the induction of lifelong immunity and/or immunity that can be boosted later in life as part of the WHO Expanded Program on Immunization (EPI). Thus, the EPI vaccine framework provides an infrastructure that could be leveraged for the implementation of a multidose HIV immunization regimen. Early childhood also provides a window of time in which there is minimal HIV exposure risk, and the plasticity of the early life immune landscape may present advantages for the elicitation of broadly neutralizing Antibodies (bnAbs), a primary target for HIV vaccination. Sequential vaccination with adjuvanted immunogens targeting spe-cific bnAb lineages is a promising HIV vaccine strategy, and several vaccine candidates are cur-rently being tested in adult clinical trials. It will be critical also to evaluate the most promising immunogens and adjuvants in pediatric settings. Preclinical studies, including in vitro and in sil-ico modelling as well as studies in animal models, will be essential to guide the design of future pediatric vaccine trials. This review summarizes current advances in bnAb germline targeting immunization. It provides the rationale for a better integration of preclinical and clinical vaccine studies to facilitate the development of a vaccine that achieves protective immunity in preadoles-cence.

Introduction: People who inject drugs (PWID) are often part of sexual and drug use networks. Engaging in unprotected sex or sharing drug injection equipment, which could occur between connections (ties) in these networks, is known to increase HIV transmission risk. This study aimed to identify attributes associated with network connections between PWID and their contacts during an HIV outbreak in Athens, Greece (2013-2015).

Methods: Data from the Transmission Reduction Intervention Project (TRIP) were used. TRIP was a network-based intervention using information on recent HIV acquisition to reduce onward viral transmission among PWID. Descriptive network and individual-level statistics were calcu-lated. Exponential random graph models (ERGMs) were used to assess associations between in-dividual-level attributes and the likelihood of people having a risk tie (for instance, using drugs together) among PWID.

Results: The network consisted of 356 participants (i.e., known as nodes in network terminology) and 542 connections (i.e., known as edges). TRIP participants had a mean age of 36 (8) years, and most were males (79%). A substantial proportion of participants were homeless (23%). Each participant was connected on average with three others (i.e., known as degree). Degree assorta-tivity was positive, indicating that participants were more likely to connect with people of similar degree. ERGMs showed that TRIP participants were more likely to have a connection with others like them in possibly important ways (e.g., were of the same sex and nationality, and had similar living conditions, such as being homeless).

Discussion: This network analysis, including the use of ERGMs, indicated that individuals in networks of PWID tend to form ties with similar others, beyond what would be expected by chance alone. Limitations of the analysis include potentially reduced generalizability and repre-sentativeness due to the local context of the study, and diminished statistical power. Future re-search should prioritize longitudinal studies among PWID to examine how network connections evolve over time.

Conclusion: The analysis identified factors, such as housing instability, that are important in de-termining the observed network ties among PWID in Athens, Greece. Future development of interventions should consider these factors.

This review outlines the Gates Foundation's investments in support of global efforts dedicated to the research and development of a safe, highly effective, prophylactic HIV vaccine. Our current Collaboration for AIDS Vaccine Discovery (CAVD) portfolio encompasses a wide range of initiatives, including projects aimed at eliciting broadly neutralizing antibodies, enhanc-ing CD8 T cell responses, and, through central service facilities, developing innovative analytical tools and animal models to assess immune responses. One central service facility also offers prod-uct development services to translate preclinical findings into clinical trials. Additionally, we are investing in platforms designed for the controlled release of HIV immunogens, simplifying com-plex vaccine regimens. Our ultimate objective is to develop a highly efficacious, safe, and durable vaccine that ensures broad access, uptake, and affordability. Furthermore, we emphasize the crit-ical importance of fostering global partnerships, with a focus on supporting research capacity in low- and middle-income countries. By making intentional investments, we aim to stimulate sus-tainable research and development in the regions most affected by the HIV epidemic.

Achieving durable antibody-mediated protection remains critical in vaccine develop-ment, particularly for viral diseases like COVID-19 and HIV. We discuss factors influencing an-tibody durability, highlighting the role of long-lived plasma cells (LLPCs) in the bone marrow, which are essential for sustained antibody production over many years. The frequencies and prop-erties of bone marrow LLPC are critical determinants of the broad spectrum of antibody durability for different vaccines. Vaccines for diseases like measles and mumps elicit long-lasting antibod-ies; those for COVID-19 and HIV do not. High epitope densities in the vaccine are known to favor antibody durability, but we discuss three underappreciated variables that also play a role in long-lived antibody responses. First, in addition to high epitope densities, we discuss the im-portance of CD21 as a critical determinant of antibody durability. CD21 is a B cell antigen recep-tor (BCR) complex component. It significantly affects BCR signaling strength in a way essential for generating LLPC in the bone marrow. Second, all antibody-secreting cells (ASC) are not cre-ated equal. There is a four-log range of antibody secretion rates, and we propose epigenetic im-printing of different rates on ASC, including LLPC, as a factor in antibody durability. Third, antibody durability afforded by bone marrow LLPC is independent of continuous antigenic stim-ulation. By contrast, tissue-resident T-bet+CD21low ASC also persists in secondary lymphoid tissues and continuously produces antibodies depending on persisting antigen and the tissue mi-croenvironment. We discuss these variables in the context of making an HIV vaccine that elicits broadly neutralizing antibodies against HIV that persist at protective levels without continuous vaccination over many years.

Introduction: Toxoplasma gondii (T. gondii) can cause serious complications in both immunocompetent and immunosuppressed individuals. This study aims to assess the seroprevalence of T. gondii among HIV-positive individuals and to investigate its association with age, sex, CD4+ T cell count, HIV RNA levels, and hematological parameters.

Methods: This study included 247 HIV-positive individuals followed up at a tertiary care hospital between November 1, 2022, and November 30, 2024. We analyzed serum samples for T. gondii IgG antibodies using electrochemiluminescent microparticle immunoassay.

Results: The prevalence of T. gondii IgG seropositivity was found to be 32.8% (n=81; 95% CI: 26.9-39). The median age of seropositive individuals was 52 years (IQR: 42-61), which was significantly higher compared to seronegative individuals (p<0.001). The highest IgG seropositivity rate (66.7%) was observed in the 61-80 age group. Hemoglobin levels were significantly lower in IgG seropositive individuals (p=0.040). Logistic regression analysis indicated an increased risk of T. gondii infection with advancing age. The odds ratio for the 41-60 age group was 13.3 (95% CI: 1.6-106, p=0.02), while for the 61-80 age group, it was 28 (95% CI: 3.3-240, p=0.002).

Discussion: The seroprevalence of T. gondii in HIV-positive individuals was lower than both global and regional averages. Age was identified as an independent risk factor for T. gondii seropositivity. Additionally, hematological alterations associated with anemia were observed in seropositive individuals. Further large-scale, multi-center, and regionally representative studies are required to optimize T. gondii infection management and screening strategies in people living with HIV.

Conclusion: These findings suggest that T. gondii infection in HIV-positive individuals increases with age and may be associated with anemia, highlighting the need for age-focused screening and management strategies.

The application of single-cell analysis to investigate immune cell diversity has historically been considered a complex task. Recently, innovative techniques have emerged revolutionizing the way immune cells can be explored, offering unprecedented insights into the dynamics of this complex system. In particular, novel approaches have enabled a detailed characterization of B-cell responses, encompassing immune repertoire, gene expression, and phenotype analysis at an individual cell level. By analyzing single B-cells, researchers can unravel their heterogeneity, trace clonal evolution, and track immune responses during infections and vaccinations over time, gaining a deeper understanding of the mechanisms underlying antibody secretion and immune memory formation. This knowledge can inform the development of optimal immunogens, adjuvants, and vaccine platforms, which are crucial for inducing robust, long-lasting protective responses and overcoming existing challenges in vaccine research. This is particularly valuable for rational vaccine design against certain pathogens, such as human immunodeficiency virus [HIV-1], for which a successful vaccine remains to be developed due to the need to elicit rare broadly neutralizing antibodies that target conserved epitopes on the genetically diverse envelope glycoprotein trimer. This review will highlight the latest advancements in single-cell sequencing techniques and bioinformatic tools for the analysis of B-cell responses in the context of infectious diseases and vaccinations. Single-cell sequencing techniques, their applications, and their pivotal role in advancing the design of next-generation vaccines, especially in the context of HIV-1, will be discussed.

Developing an effective HIV-1 vaccine remains a critical global health challenge, hin-dered by the virus's high genetic diversity, immune evasion strategies, and structural complexity of its Envelope (Env) glycoprotein. Broadly neutralizing antibodies (bNAbs), capable of targeting conserved Env epitopes, offer a promising path for vaccine design. Germline-targeting (GT) strat-egies have emerged as a promising approach to engage naive B cell precursors that have the po-tential to mature into bNAb-producing cells. Advances in GT have enabled the design of immu-nogens capable of recruiting specific bNAb precursors in animal models and early clinical trials. Despite these successes, achieving neutralization breadth requires sequential immunizations with tailored boosting strategies to guide B cell maturation. Studies underscore the importance of using immunogens that mimic native Env structures while modulating glycosylation patterns to focus immune responses. Emerging approaches, such as membrane-bound presentation and mRNA de-livery, hold the potential for enhancing immunogen effectiveness and rapid pre-clinical and in human screening to identify combinations of immunogens that foster bNAb lineages. This review seeks to synthesize key developments in GT strategies for HIV-1 vaccines, highlighting the de-sign and implementation of immunogens that drive bNAb precursor maturation. It aims to under-score the importance of integrating structural insights, immunogen sequence design, and delivery methods to enhance the induction of bNAbs, offering direction for future research to address ex-isting gaps and optimize vaccine efficacy.

Despite recent advances in other prevention strategies, an effective vaccine is still needed to guarantee a sustained end to the HIV/AIDS pandemic. However, the traditional ap-proaches of vaccinology have thus far failed to produce an effective vaccine. More basic research may be needed to enhance our understanding of HIV immunity and the immunological principles behind vaccination and to leverage advanced technologies before applied research activities can be successfully used to develop a distributable HIV vaccine. US Government funding plays a crucial role in promoting, enabling, and advising independent scientists and experts to perform such research. This article was written to provide, to the broader scientific community, detail about the tools NIAID uses for research funding, how and why they were used for HIV vaccine development, and how they have been helpful; it is written from the perspective of a Program Officer's experiences while working for more than 25 years in the Division of AIDS (DAIDS) of NIAID at the NIH (the US National Institutes of Health). Several types of funding activities pro-mote HIV vaccine development efforts, but three types of such activities and their impact on HIV vaccine development will be discussed in more detail.

Introduction: The effectiveness of antiretroviral therapy (ART) in treating HIV is in-fluenced by the clinical response of patients, which, in turn, impacts the development of drug resistance. This study aimed to assess the correlation between clinical treatment response and resistance to first-line reverse transcriptase inhibitors in HIV patients receiving treatment for ≤12 and >12 months in South Sulawesi, a province in Indonesia.

Methods: In this cross-sectional study, 36 people living with HIV (PLHIV) experiencing viro-logical failure (VF) were sampled from HIV services in the province from August 2022 to January 2023. HIV-1 viral RNAs were extracted, sequenced, and analyzed for drug sensitivity and re-sistance classification using the Stanford University HIV Drug Resistance Database (HIVdb) ac-cording to World Health Organization (WHO) recommendations, determining resistance levels and HIV subtypes. Phylogenetic analysis of PR-RT sequences (~1200 base pairs) was performed using the Muscle program and MEGA11 software, utilizing the neighbor-joining method with the Kimura two-parameter model.

Results: Genotyping of plasma samples revealed that a significant proportion of patients exhib-ited mutations associated with resistance to both nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs (NNRTIs) (48.6% and 51.4%, respectively). Clinical response indica-tors, such as initial body mass index and occurrence of opportunistic infections, were found to correlate with specific drug resistance, highlighting the importance of monitoring treatment re-sponse. Moreover, virologic response showed strong associations with resistance to specific drugs, suggesting the need for tailored therapeutic approaches. Patient behaviors related to trans-mission risk factors were also found to be linked to resistance levels, underscoring the multifac-torial nature of resistance development.

Conclusion: Overall, this study underscores the importance of considering treatment response in managing HIV and suggests implications for optimizing therapy regimens to mitigate resistance emergence.