-
Current Opinion in HIV and AIDS Jul 2023In recent years, clinical trials have explored broadly neutralizing antibodies (bNAbs) as treatment and cure of HIV. Here, we summarize the current knowledge, review the... (Review)
Review
PURPOSE OF REVIEW
In recent years, clinical trials have explored broadly neutralizing antibodies (bNAbs) as treatment and cure of HIV. Here, we summarize the current knowledge, review the latest clinical studies, and reflect on the potential role of bNAbs in future applications in HIV treatment and cure strategies.
RECENT FINDINGS
In most individuals who switch from standard antiretroviral therapy to bNAb treatment, combinations of at least two bNAbs effectively suppress viremia. However, sensitivity of archived proviruses to bNAb neutralization and maintaining adequate bNAb plasma levels are key determinants of the therapeutic effect. Combinations of bNAbs with injectable small-molecule antiretrovirals are being developed as long-acting treatment regimens that may require as little as two annual administrations to maintain virological suppression. Further, interventions that combine bNAbs with immune modulators or therapeutic vaccines are under investigation as HIV curative strategies. Interestingly, administration of bNAbs during the early or viremic stage of infection appears to enhance host immune responses against HIV.
SUMMARY
While accurately predicting archived resistant mutations has been a significant challenge for bNAb-based treatments, combinations of potent bNAbs against nonoverlapping epitopes may help overcome this issue. As a result, multiple long-acting HIV treatment and cure strategies involving bNAbs are now being investigated.
Topics: Humans; HIV Infections; Broadly Neutralizing Antibodies; HIV Antibodies; Antibodies, Neutralizing; HIV-1; Anti-Retroviral Agents; Viremia
PubMed: 37144579
DOI: 10.1097/COH.0000000000000802 -
Clinical Microbiology and Infection :... Aug 2023Pneumocystis jirovecii pneumonia (PCP) incidence is increasing in patients without HIV infection. In contrast to PCP in patients infected with HIV, diagnosis is often... (Review)
Review
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) incidence is increasing in patients without HIV infection. In contrast to PCP in patients infected with HIV, diagnosis is often delayed and illness is associated with increased mortality.
OBJECTIVES
To provide a comprehensive review of clinical presentation, risk factors, diagnostic strategies, and treatment options for PCP in patients without HIV infection.
SOURCES
Web-based literature review on PCP for trials, meta-analyses, and systematic reviews using PubMed. The restriction to the English language was applied.
CONTENT
Common underlying conditions in patients without HIV infection having PCP are haematological malignancies, autoimmune and inflammatory diseases, solid organ or haematopoietic stem cell transplant, and previous corticosteroid exposure. New risk groups include patients receiving monoclonal antibodies and immunomodulating therapies. Patients without HIV infection who have PCP present with rapid onset and progression of pneumonia, increased duration of hospitalization and a significantly higher mortality rate than patients infected with HIV. PCP is diagnosed by a combination of clinical symptoms and radiological as well as mycological features. Results of immunofluorescence microscopy from bronchoalveolar lavage, PCR testing, and computed tomography imaging as well as the evaluation of clinical presentation are required. The established treatment regime consists of trimethoprim and sulfamethoxazole.
IMPLICATIONS
Although the number of patients with immunosuppression due to causes different from HIV is increasing, a simultaneous rise in PCP incidence is observed. In the group of patients without HIV infection, rapid onset of symptoms, a more complex course, and a high mortality rate are recorded. Therefore, the time to diagnosis must be as short as possible to initiate effective therapy promptly. This review aims to raise awareness of PCP in an increasingly affected at-risk group and provides clinicians with a practical guide for efficient diagnosis and targeted therapy. Furthermore, it intends to display current inadequacies in research on the topic of PCP.
Topics: Humans; HIV Infections; Pneumonia, Pneumocystis; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Bronchoalveolar Lavage; Pneumocystis carinii
PubMed: 37086781
DOI: 10.1016/j.cmi.2023.04.015 -
Vaccines Jul 2023Antibody Dependent Enhancement (ADE) of an infection has been of interest in the investigation of many viruses. It is associated with the severity of the infection. ADE... (Review)
Review
Antibody Dependent Enhancement (ADE) of an infection has been of interest in the investigation of many viruses. It is associated with the severity of the infection. ADE is mediated by non-neutralizing antibodies, antibodies at sub-neutralizing concentrations, or cross-reactive non-neutralizing antibodies. Treatments like plasma therapy, B cell immunizations, and antibody therapies may trigger ADE. It is seen as an impediment to vaccine development as well. In viruses including the Dengue virus (DENV), severe acute respiratory syndrome (SARS) virus, Middle East respiratory syndrome (MERS) virus, human immunodeficiency virus (HIV), Ebola virus, Zika virus, and influenza virus, the likely mechanisms of ADE are postulated and described. ADE improves the likelihood of productively infecting cells that are expressing the complement receptor or the Fc receptor (FcR) rather than the viral receptors. ADE occurs when the FcR, particularly the Fc gamma receptor, and/or complement system, particularly Complement 1q (C1q), allow the entry of the virus-antibody complex into the cell. Moreover, ADE alters the innate immune pathways to escape from lysis, promoting viral replication inside the cell that produces viral particles. This review discusses the involvement of FcR and the downstream immunomodulatory pathways in ADE, the complement system, and innate antiviral signaling pathways modification in ADE and its impact on facilitating viral replication. Additionally, we have outlined the modes of ADE in the cases of different viruses reported until now.
PubMed: 37515055
DOI: 10.3390/vaccines11071240 -
Cell Jan 2024The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines...
The CD4-binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the occlusion of CD4bs by glycans, expansion of appropriate naive B cells with immunogens, and selection of functional antibody mutations. Here, we demonstrate that immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAb bound to HIV-1 Env demonstrated binding angles and heavy-chain interactions characteristic of all known human CD4-mimicking bnAbs. Macaque nAb were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAb. This vaccine study initiated in primates the B cells from which CD4bs bnAbs can derive, accomplishing the key first step in the development of an effective HIV-1 vaccine.
Topics: Animals; Humans; Broadly Neutralizing Antibodies; CD4 Antigens; Cell Adhesion Molecules; HIV-1; Macaca; AIDS Vaccines
PubMed: 38181743
DOI: 10.1016/j.cell.2023.12.002 -
PLoS Pathogens Oct 2023Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally... (Review)
Review
Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally elicited following viral infection and have been characterized in viral infections such as influenza, rotavirus, cytomegalovirus, HIV, and SARS-CoV-2. It has been widely assumed that these nonneutralizing antibodies do not function in a protective way in vivo and therefore are not desirable targets of antiviral interventions; however, increasing evidence now shows this not to be true. Several virus-specific nonneutralizing antibody responses have been correlated with protection in human studies and also shown to significantly reduce virus replication in animal models. The mechanisms by which many of these antibodies function is only now coming to light. While nonneutralizing antibodies cannot prevent viruses entering their host cell, nonneutralizing antibodies work in the extracellular space to recruit effector proteins or cells that can destroy the antibody-virus complex. Other nonneutralizing antibodies exert their effects inside cells, either by blocking the virus life cycle directly or by recruiting the intracellular Fc receptor TRIM21. In this review, we will discuss the multitude of ways in which nonneutralizing antibodies function against a range of viral infections.
Topics: Animals; Humans; Antibodies, Viral; Virus Diseases; Influenza, Human; Receptors, Fc; Antiviral Agents; Antibodies, Neutralizing; HIV Antibodies
PubMed: 37796829
DOI: 10.1371/journal.ppat.1011670 -
Proceedings of the National Academy of... Jul 2023Vaccines have played a fundamental role in the control of infectious diseases. We previously developed a messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like...
Vaccines have played a fundamental role in the control of infectious diseases. We previously developed a messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like particles (VLPs) through coexpression of the viral envelope with Gag. Here, we applied the same principle to the design of a VLP-forming mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To promote cognate interaction with simian immunodeficiency virus (SIV) Gag, we engineered different chimeric proteins encompassing the ectodomain and the transmembrane region of the SARS-CoV-2 Spike protein from the Wuhan-Hu-1 strain fused to the gp41 cytoplasmic tail of either HIV-1 (strain WITO) or SIV (strain mac239) with or without a partial truncation at amino acid 745 to enhance membrane expression. Upon cotransfection with SIV mRNA, the Spike-SIV (SSt) chimera yielded the highest level of cell-surface expression and extracellular VLP release. Immunization of BALB/c mice with mRNA at 0, 4, and 16 wk induced higher titers of Spike-binding and autologous neutralizing antibodies at all time points compared to mRNA alone. Furthermore, mice immunized with mRNA developed neutralizing antibodies effective against different variants of concern. These data demonstrate that the Gag/VLP mRNA platform can be successfully applied to vaccines against different agents for the prevention of infectious diseases of global relevance.
Topics: Humans; Animals; Mice; COVID-19 Vaccines; Antibodies, Viral; SARS-CoV-2; COVID-19; Antibodies, Neutralizing; Spike Glycoprotein, Coronavirus; Simian Immunodeficiency Virus
PubMed: 37428933
DOI: 10.1073/pnas.2305896120 -
Current Opinion in HIV and AIDS Jul 2023The discovery of broadly neutralizing HIV-1 antibodies (bNAbs) has provided a framework for vaccine design and created new hope toward an HIV-1 cure. These antibodies... (Review)
Review
PURPOSE OF REVIEW
The discovery of broadly neutralizing HIV-1 antibodies (bNAbs) has provided a framework for vaccine design and created new hope toward an HIV-1 cure. These antibodies recognize the HIV-1 Envelope and inhibit viral fusion with unprecedented breadth and potency. Beyond their unique neutralization capacity, bNAbs also activate immune cells and interfere with viral spread through nonneutralizing activities. Here, we review the landscape of bNAbs functions and their contribution to clinical efficacy.
RECENT FINDINGS
Parallel evaluation of bNAbs nonneutralizing activities using in vivo and in vitro models have revealed how their importance varies across antibodies and strains. Nonneutralizing bNAbs functions target both infected cells and viral particles, leading to their destruction through various mechanisms. Reservoir targeting and prevention in context of suboptimal neutralization highly depends on bNAbs polyfunctionality. We recently showed that bNAbs tether virions at the surface of infected cells, impairing release and forming immune complexes, with consequences that are still to be understood.
SUMMARY
Nonneutralizing activities of bNAbs target infected cells, virions, and immune complexes, promoting viral clearance and possibly improving immune responses. We review how these functions participate to the efficacy of bNAbs and how they can be manipulated to improve bNAbs therapies.
Topics: Humans; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; Antibodies, Neutralizing; HIV-1; Antigen-Antibody Complex
PubMed: 37249912
DOI: 10.1097/COH.0000000000000799 -
Clinical Immunology (Orlando, Fla.) Dec 2023Anti-HIV broadly neutralizing antibodies (bNAbs) offer a novel approach to treating, preventing, or curing HIV. Pre-clinical models and clinical trials involving the... (Review)
Review
Anti-HIV broadly neutralizing antibodies (bNAbs) offer a novel approach to treating, preventing, or curing HIV. Pre-clinical models and clinical trials involving the passive transfer of bNAbs have demonstrated that they can control viremia and potentially serve as alternatives or complement antiretroviral therapy (ART). However, antibody decay, persistent latent reservoirs, and resistance impede bNAb treatment. This review discusses recent advancements and obstacles in applying bNAbs and proposes strategies to enhance their therapeutic potential. These strategies include multi-epitope targeting, antibody half-life extension, combining with current and newer antiretrovirals, and sustained antibody secretion.
Topics: Humans; Broadly Neutralizing Antibodies; Antibodies, Neutralizing; HIV-1; HIV Infections; HIV Antibodies
PubMed: 37852345
DOI: 10.1016/j.clim.2023.109809 -
Current Opinion in HIV and AIDS Jul 2023To discuss progress and challenges in the development of antiretroviral regimens that combine broadly neutralizing antibodies (bNAbs) and long-acting (LA) small-molecule... (Review)
Review
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.
Topics: Humans; HIV Infections; Broadly Neutralizing Antibodies; Pharmaceutical Preparations; Pilot Projects; Antibodies, Neutralizing; HIV-1; Anti-Retroviral Agents; HIV Antibodies
PubMed: 37265259
DOI: 10.1097/COH.0000000000000801