Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure

Umotoy, Jeffrey C.; Taeye, Steven W. de

doi:10.3389/fimmu.2021.708806

Cited by 16 publications

(9 citation statements)

References 168 publications

(204 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antibody conjugates (ACs) comprising of an antibody carrier and small molecule CCR-5 antagonist were developed to enhance the CCR5-dependent therapies, specifically, to increase their clinical effects, reduce off-target effect and toxicity, and extend the pharmacokinetic profile of the attached molecule ( 202 ). To increase the potency of CCR5 targeted therapies, anti-CCR5 monoclonal antibodies were conjugated with a CCR5 small molecule antagonist, targeting nonoverlapping epitopes ( 203 ) and with a fusion inhibitor ( 204 ).…”

Section: Impact For Therapiesmentioning

confidence: 99%

“…Given the role of CCR5 in immune cell migration and inflammation, CCR5 blockade with leronlimab was applied in critical COVID-19 patients, and led to the reduction of the IL-6 levels, restoration of CD4/CD8 ratio, and resolution of SARS-CoV-2 burden, thus implicating CCR5 as a potential therapeutic target for COVID-19 (201). Antibody conjugates (ACs) comprising of an antibody carrier and small molecule CCR-5 antagonist were developed to enhance the CCR5-dependent therapies, specifically, to increase their clinical effects, reduce off-target effect and toxicity, and extend the pharmacokinetic profile of the attached molecule (202). To increase the potency of CCR5 targeted therapies, anti-CCR5 monoclonal antibodies were conjugated with a CCR5 small molecule antagonist, targeting nonoverlapping epitopes (203) and with a fusion inhibitor (204).…”

Section: Ccr5 Blockade -Targeting the Interaction Of Ccr5 With Hivmentioning

confidence: 99%

See 1 more Smart Citation

CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair

2022

View full text Add to dashboard Cite

CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4+ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS. Meanwhile, over 40 African nonhuman primate species are long-term hosts of simian immunodeficiency virus (SIV), an ancestral family of viruses that give rise to the pandemic CCR5 (R5)-tropic HIV-1. Many natural hosts typically do not progress to immunodeficiency upon the SIV infection. They have developed various strategies to minimize the SIV-related pathogenesis and disease progression, including an array of mechanisms employing modulation of the CCR5 receptor activity: (i) deletion mutations abrogating the CCR5 surface expression and conferring resistance to infection in null homozygotes; (ii) downregulation of CCR5 expression on CD4+ T cells, particularly memory cells and cells at the mucosal sites, preventing SIV from infecting and killing cells important for the maintenance of immune homeostasis, (iii) delayed onset of CCR5 expression on the CD4+ T cells during ontogenetic development that protects the offspring from vertical transmission of the virus. These host adaptations, aimed at lowering the availability of target CCR5+ CD4+ T cells through CCR5 downregulation, were countered by SIV, which evolved to alter the entry coreceptor usage toward infecting different CD4+ T-cell subpopulations that support viral replication yet without disruption of host immune homeostasis. These natural strategies against SIV/HIV-1 infection, involving control of CCR5 function, inspired therapeutic approaches against HIV-1 disease, employing CCR5 coreceptor blocking as well as gene editing and silencing of CCR5. Given the pleiotropic role of CCR5 in health beyond immune disease, the precision as well as costs and benefits of such interventions needs to be carefully considered.

show abstract

Section: Impact For Therapiesmentioning

confidence: 99%

Section: Ccr5 Blockade -Targeting the Interaction Of Ccr5 With Hivmentioning

confidence: 99%

CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair

2022

View full text Add to dashboard Cite

show abstract

“…Thus, Ibalizumab does not exert selective pressure toward CD4 resistance (46). Monoclonal antibody approaches could be further improved by the development of antibody conjugates with an increased anti-HIV-1 activity, as reviewed in (47).…”

Section: Antibodiesmentioning

confidence: 99%

How to break free: HIV-1 escapes from innovative therapeutic approaches

2022

View full text Add to dashboard Cite

With nearly 38 million of people worldwide living with HIV-1 and no definitive cure available after almost 40 years of research, AIDS is still a major global public health issue. Modern antiretroviral therapies can achieve viral replication suppression to undetectable levels, thus allowing an almost normal life to HIV-1–infected individuals. However, the virus cannot be fully eradicated. This may lead over time to the accumulation of mutations in the viral genome and, eventually, to the emergence of drug-resistant viruses, which may affect the efficacy of the therapy and the patient’s quality of life. To overcome some of the limitations of the standard antiretroviral therapy, innovative therapeutic approaches such as “shock and kill” and immunotherapies, as well as technologies based on RNA interference and CRISPR-Cas9 genome editing are under investigation. Nevertheless, the virus may find a way to break free even from these novel strategies. In this review, we focus on the mechanisms that enable HIV-1 escape from the most advanced therapies and discuss some of the challenges to prevent this issue.

show abstract

“…Additional technical breakthroughs, including but not limited to increasing chemical stability, improving pharmacokinetics and delivery efficiency, are still needed before it is widely used in clinical practice. However, for individuals who have been resistant to available antiviral drugs, siRNA-based agents might be optimal alternatives [140].…”

Section: "Block-and-lock" Strategymentioning

confidence: 99%

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

Wang

Wei

et al. 2022

Molecules

View full text Add to dashboard Cite

The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called ‘shock-and-kill’ regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection.

show abstract

Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure

Cited by 16 publications

References 168 publications

CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair

CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair

How to break free: HIV-1 escapes from innovative therapeutic approaches

Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation

Contact Info

Product

Resources

About