Current Opinion in HIV and AIDS最新文献

Purpose of the review: Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this model system are teaching the field of HIV vaccinology the basic immunology that is needed to induce broadly neutralizing antibodies (bnAbs) with vaccination and elicit protective T cell responses. These lessons are being translated into clinical trials to advance towards protective active vaccination against HIV-1 infection.

Recent findings: Preclinical vaccination studies in NHPs have shown that highly engineered HIV-1 immunogens can initiate bnAb precursors providing proof of concept for Phase I clinical trials. Additionally, NHP models of HIV-1 infection are elucidating the pathways for bnAb development while serving as systems to evaluate vaccine protection. Innovative immunization strategies have increased affinity maturation of HIV-1 antibodies in long-lived germinal centers. Preclinical studies in macaques have defined the protective level of neutralizing antibodies and have shown that T cell responses can synergize with antibody-mediated immunity to provide protection in the presence of lower neutralizing antibody titers.

Summary: The NHP model provides vaccine regimens and desired antibody and T cell responses that serve as benchmarks for clinical trials, accelerating HIV vaccine design.

Purpose of review: In the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.

Recent findings: With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.

Summary: The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.

Purpose of review: Explore whether immunization with germline-targeting Env immunogens during ART, followed by ATI, leads to the identification of viral envelope glycoproteins (Envs) that promote and guide the full maturation of broadly neutralizing antibody responses.

Recent findings: The HIV-1 envelope glycoprotein (Env) does not efficiently engage the germline precursors of broadly neutralizing antibodies (bnAbs). However, Env-derived proteins specifically designed to precisely do that, have been recently developed. These 'germline-targeting' Env immunogens activate naïve B cells that express the germline precursors of bnAbs but by themselves cannot guide their maturation towards their broadly neutralizing forms. This requires sequential immunizations with heterologous sets of Envs. These 'booster' Envs are currently unknown.

Summary: Combining germline-targeting Env immunization approaches during ART with ATI could lead to the identification of natural Envs that are responsible for the maturation of broadly neutralizing antibody responses during infection. Such Envs could then serve as booster immunogens to guide the maturation of glBCRs that have become activated by germline-targeting immunogens in uninfected subjects.

Purpose of review: The improved health of persons with HIV (PWH) resulting from antiretroviral therapy (ART) has led to recommendations for reduced laboratory monitoring. We studied, for all PWH in care over 20 years at the Southern Alberta Clinic (SAC), Canada, the changing use and results of HIV-specific laboratory testing [i.e., CD4+ testing, plasma HIV viral load (PVL), and genotypic antiretroviral resistance testing (GART)].In this descriptive retrospective longitudinal cohort observational study, we examined HIV-specific laboratory testing for all PWH from 2000 to 2020 within the context of HIV-related health outcomes, program costs, and mortality.

Recent findings: The number of PWH in care increased from 755 in 2000 to 2050 in 2020. Annual CD4+ testing per PWH increased from 2.7 per person in 2000 peaking to 3.5 in 2005 but decreasing to 1.4 by 2020. Annual PVL tests per PWH gradually decreased from 3.2 in 2000 to 2.0 in 2020. GART increased from 93 tests in 2000 to 315 in 2008 decreasing to 127 in 2020. Patients received GART at baseline, and after a viral breakthrough when indicated. Viral suppression rates for the population increased from 66 to 96%; median CD4+ cell count increased from 443 to 470 cells/μl, and overall morbidity decreased from 9.2 to 2.0% by 2020, respectively. Annual per patient laboratory costs decreased from a high of $302 in 2008 to $161 by 2020.

Summary: The reduced annual laboratory surveillance per PWH associated with modern ART resulted in modest cost savings and no apparent loss in quality of HIV care.

Purpose of review: HIV infection adds further complexity to the heterogenous process of aging. In this focused review, we examine and discuss recent advances to better elucidate mechanisms of biological aging perturbed and accelerated in the context of HIV, particularly among those with viral suppression through the benefits of antiretroviral therapy (ART). New hypotheses from these studies are poised to provide an improved understanding of multifaceted pathways that converge and likely form the basis for effective interventions toward successful aging.

Recent findings: Evidence to date suggests multiple mechanisms of biological aging impact people living with HIV (PLWH). Recent literature delves and expands on how epigenetic alterations, telomere attrition, mitochondrial perturbations, and intercellular communications may underpin accelerated or accentuated aging phenotypes and the disproportionate prevalence of age-related complications among PLWH. Although most hallmarks of aging are likely exacerbated in the setting of HIV, ongoing research efforts are providing new insight on the collective impact these conserved pathways may have in the aging disease processes.

Summary: New knowledge on underlying molecular disease mechanisms impacting people aging with HIV are reviewed. Also examined are studies that may facilitate the development and implementation of effective therapeutics and guidance on improving geriatric HIV clinical care.

Purpose of review: This review highlights advances in HIV transcription and epigenetic latency mechanisms and outlines current therapeutic approaches to eliminate or block the HIV-1 latent reservoir.

Recent findings: Novel host factors have been reported to modulate HIV-1 transcription and latency. Chromatin affinity purification strategies followed by mass spectrometry (ChAP-MS) identified the chaperone protein p32 to play an important role in HIV-1 transcriptional regulation via interactions with the viral transcriptional activator Tat. Similarly, an shRNA screen identified the methyltransferase SMYD5 contributing to HIV-1 transcriptional activation also by modulating Tat activity. These new factors, among others, represent potential druggable targets that could be explored in the 'block-and-lock' or 'shock-and-kill' approaches.

Summary: The HIV-1 latent reservoir is established early after infection, persists during antiretroviral therapy, and is the source of viral rebound after treatment interruption. An HIV cure requires either eliminating this reservoir or blocking latent proviral reactivation in the absence of antiretroviral therapy (ART). Understanding the mechanisms and key-players modulating HIV transcriptional and reactivation may facilitate therapeutic advancements. Here we summarize, the latest findings on host factors' roles in HIV transcriptional regulation.

Purpose of review: CD8+ T cell responses are a key component of the host immune response to human immunodeficiency virus (HIV) but vary significantly across individuals with distinct clinical outcomes. These differences help inform the qualitative features of HIV-specific CD8+ T cells that we should aim to induce by vaccination.

Recent findings: We review previous and more recent findings on the features of dysfunctional and functional CD8+ T cell responses that develop in individuals with uncontrolled and controlled HIV infection, with particular emphasis on proliferation, cytotoxic effector function, epitope specificity, and responses in lymph nodes. We also discuss the implications of these findings for both prophylactic and therapeutic T cell vaccine development within the context of T cell vaccine trials.

Summary: The induction of HIV specific CD8+ T cell responses is an important goal of ongoing vaccine efforts. Emerging data on the key features of CD8+ T cell responses that distinguish individuals who spontaneously control from those with progressive disease continues to provide key guidance.

Purpose of review: The success of HIV-1 eradication strategies relies on in-depth understanding of HIV-1-infected cells. However, HIV-1-infected cells are extremely heterogeneous and rare. Single-cell multiomic approaches resolve the heterogeneity and rarity of HIV-1-infected cells.

Recent findings: Advancement in single-cell multiomic approaches enabled HIV-1 reservoir profiling across the epigenetic (ATAC-seq), transcriptional (RNA-seq), and protein levels (CITE-seq). Using HIV-1 RNA as a surrogate, ECCITE-seq identified enrichment of HIV-1-infected cells in clonally expanded cytotoxic CD4+ T cells. Using HIV-1 DNA PCR-activated microfluidic sorting, FIND-seq captured the bulk transcriptome of HIV-1 DNA+ cells. Using targeted HIV-1 DNA amplification, PheP-seq identified surface protein expression of intact versus defective HIV-1-infected cells. Using ATAC-seq to identify HIV-1 DNA, ASAP-seq captured transcription factor activity and surface protein expression of HIV-1 DNA+ cells. Combining HIV-1 mapping by ATAC-seq and HIV-1 RNA mapping by RNA-seq, DOGMA-seq captured the epigenetic, transcriptional, and surface protein expression of latent and transcriptionally active HIV-1-infected cells. To identify reproducible biological insights and authentic HIV-1-infected cells and avoid false-positive discovery of artifacts, we reviewed current practices of single-cell multiomic experimental design and bioinformatic analysis.

Summary: Single-cell multiomic approaches may identify innovative mechanisms of HIV-1 persistence, nominate therapeutic strategies, and accelerate discoveries.