Current Opinion in HIV and AIDS最新文献

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: To review recent insights into the factors affecting HIV disease progression in children living with HIV, contrasting outcomes: following early ART initiation with those in natural, antiretroviral therapy (ART)-naive infection; in children versus adults; and in female individuals versus male individuals.

Recent findings: Early life immune polarization and several factors associated with mother-to-child transmission of HIV result in an ineffective HIV-specific CD8+ T-cell response and rapid disease progression in most children living with HIV. However, the same factors result in low immune activation and antiviral efficacy mediated mainly through natural killer cell responses in children and are central features of posttreatment control. By contrast, rapid activation of the immune system and generation of a broad HIV-specific CD8+ T-cell response in adults, especially in the context of 'protective' HLA class I molecules, are associated with superior disease outcomes in ART-naive infection but not with posttreatment control. The higher levels of immune activation in female individuals versus male individuals from intrauterine life onwards increase HIV infection susceptibility in females in utero and may favour ART-naive disease outcomes rather than posttreatment control.

Summary: Early-life immunity and factors associated with mother-to-child transmission typically result in rapid HIV disease progression in ART-naive infection but favour posttreatment control in children following early ART initiation.

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.

Purpose of review: Passive administration of broadly neutralizing antibodies (bNAbs) is being evaluated as a therapeutic approach to prevent or treat HIV infections. However, a number of challenges face the widespread implementation of passive transfer for HIV. To reduce the need of recurrent administrations of bNAbs, gene-based delivery approaches have been developed which overcome the limitations of passive transfer.

Recent findings: The use of DNA and mRNA for the delivery of bNAbs has made significant progress. DNA-encoded monoclonal antibodies (DMAbs) have shown great promise in animal models of disease and the underlying DNA-based technology is now being tested in vaccine trials for a variety of indications. The COVID-19 pandemic greatly accelerated the development of mRNA-based technology to induce protective immunity. These advances are now being successfully applied to the delivery of monoclonal antibodies using mRNA in animal models. Delivery of bNAbs using viral vectors, primarily adeno-associated virus (AAV), has shown great promise in preclinical animal models and more recently in human studies. Most recently, advances in genome editing techniques have led to engineering of monoclonal antibody expression from B cells. These efforts aim to turn B cells into a source of evolving antibodies that can improve through repeated exposure to the respective antigen.

Summary: The use of these different platforms for antibody delivery has been demonstrated across a wide range of animal models and disease indications, including HIV. Although each approach has unique strengths and weaknesses, additional advances in efficiency of gene delivery and reduced immunogenicity will be necessary to drive widespread implementation of these technologies. Considering the mounting clinical evidence of the potential of bNAbs for HIV treatment and prevention, overcoming the remaining technical challenges for gene-based bNAb delivery represents a relatively straightforward path towards practical interventions against HIV infection.

Purpose of review: Successful HIV-1 prevention and therapy will require broad and potent coverage of within-host and global viral diversity. Broadly neutralizing antibody (bNAb) combination and multispecific therapeutics provide an opportunity to meet this challenge due to the complementary activity of individual antibody components. Here, we review the principles and applications of this concept.

Recent findings: The Antibody Mediated Prevention (AMP) trials have demonstrated the high bar for neutralization potency and breadth that bNAb-mediated prevention modalities will need to achieve to have a meaningful impact on the HIV-1 epidemic. Additional clinical studies have recently shown that an even higher bar may be required for therapeutic inhibition of the diverse within-host quasispecies present in viremic and aviremic people with HIV-1 (PWH). We discuss how the complementarity of bNAbs in terms of neutralization profiles, resistance mutations and coverage of within-host quasispecies may overcome these stringent requirements and lead to effective bNAb combination or multispecific antibody based prophylactic and therapeutic strategies.

Summary: The design of next-generation bNAb-based combination or multispecific therapeutics for the prevention and/or treatment of HIV-1 infection will need to leverage the complementarity of component bNAbs to maximize the potency and breadth that will be required for clinical success.

Purpose of review: This review summarizes recent studies reporting the induction of vaccinal effects by human immunodeficiency virus (HIV-1) antibody therapy. It also puts into perspective preclinical studies that have identified mechanisms involved in the immunomodulatory properties of antiviral antibodies. Finally, it discusses potential therapeutic interventions to enhance host adaptive immune responses in people living with HIV (PLWH) treated with broadly neutralizing antibodies (bNAbs).

Recent findings: Recent studies in promising clinical trials have shown that, in addition to controlling viremia, anti-HIV-1 bNAbs are able to enhance the host's humoral and cellular immune response. Such vaccinal effects, in particular the induction of HIV-1-specific CD8 + T-cell responses, have been observed upon treatment with two potent bNAbs (3BNC117 and 10-1074) alone or in combination with latency-reversing agents (LRA). While these studies reinforce the idea that bNAbs can induce protective immunity, the induction of vaccinal effects is not systematic and might depend on both the virological status of the patient as well as the therapeutic strategy chosen.

Summary: HIV-1 bNAbs can enhance adaptive host immune responses in PLWH. The challenge now is to exploit these immunomodulatory properties to design optimized therapeutic interventions to promote and enhance the induction of protective immunity against HIV-1 infection during bNAbs therapy.

Purpose of review: To discuss progress and challenges in the development of antiretroviral regimens that combine broadly neutralizing antibodies (bNAbs) and long-acting (LA) small-molecule antiretroviral drugs (ARVs).

Recent findings: Data are extremely limited, with results from only a single phase 1a clinical trial reported to date. That study, a combination of lenacapavir plus the bNAbs teropavimab and zinlirvimab, maintained viral suppression over 26 weeks in 18 of 20 participants. A second pilot study, ACTG A5357, which tests the safety and virologic efficacy of the combination of LA injectable cabotegravir with the bNAb VRC07-523LS is fully enrolled; results are expected in the second half of 2023.

Summary: The development of regimens that combine bNAbs and LA ARVs has been challenging. Both agents need similar half-lives in order to harmonize dosing schedules. In addition, the need to perform bNAb susceptibility testing to assure activity of the bNAb in order to protect against the risk of developing resistance to the LA ARV has slowed enrollment into trials and poses substantial logistical challenges to widespread adoption of these combinations should they prove safe and effective. Improvements in manufacture that reduce the cost of goods and advances in delivery systems are needed to ensure equitable access to these regimens.

Purpose of review: Anti-human immunodeficiency virus (HIV) antibody-based therapeutics offer an alternative treatment option to current antiretroviral drugs. This review aims to provide an overview of the Fc- and Fab-engineering strategies that have been developed to optimize broadly neutralizing antibodies and discuss recent findings from preclinical and clinical studies.

Recent findings: Multispecific antibodies, including bispecific and trispecific antibodies, DART molecules, and BiTEs, as well as Fc-optimized antibodies, have emerged as promising therapeutic candidates for the treatment of HIV. These engineered antibodies engage multiple epitopes on the HIV envelope protein and human receptors, resulting in increased potency and breadth of activity. Additionally, Fc-enhanced antibodies have demonstrated extended half-life and improved effector function.

Summary: The development of Fc and Fab-engineered antibodies for the treatment of HIV continues to show promising progress. These novel therapies have the potential to overcome the limitations of current antiretroviral pharmacologic agents by more effectively suppressing viral load and targeting latent reservoirs in individuals living with HIV. Further studies are needed to fully understand the safety and efficacy of these therapies, but the growing body of evidence supports their potential as a new class of therapeutics for the treatment of HIV.