Efficient Reactivation of Latent Viral Reservoirs and Induction of Antigen-Specific Immune Responses Using a Bifunctional HSV-Vectored Therapeutic Vaccine in Chronically SIV-Infected Macaques

แนวคิดหลัก

A bifunctional HSV-vectored therapeutic vaccine can effectively reactivate latent viral reservoirs and elicit robust antigen-specific immune responses, providing a promising strategy for achieving a functional cure for chronic viral infections like HIV/SIV.

บทคัดย่อ

The study demonstrates that a modified HSV-ΔICP34.5-based construct can more efficiently reactivate latent HIV/SIV proviruses compared to wild-type HSV. The mechanism involves modulating the IKKα/β-NF-κB pathway and the PP1-HSF1 pathway, leading to enhanced binding of HSF1 to the HIV/SIV LTR and increased viral gene expression.
To develop a bifunctional therapeutic vaccine, the authors constructed recombinant HSV-ΔICP34.5ΔICP47 vectors expressing SIV antigens, including Gag, Env, and a fusion antigen sPD1-SIVgag. These constructs effectively elicited robust SIV-specific T cell immune responses, including polyfunctional CD8+ T cells, in both mice and chronically SIV-infected, ART-treated rhesus macaques.
In the macaque study, the HSV-sPD1-SIVgag/SIVenv vaccine delayed viral rebound and reduced the peak viral load after ART interruption, suggesting effective reactivation of latent SIV reservoirs and control of viral replication. The authors propose that this bifunctional HSV-vectored therapeutic vaccine strategy holds promise for achieving an HIV functional cure by simultaneously reactivating viral latency and inducing antigen-specific immune responses.

สถิติ

HSV-ΔICP34.5 infection led to a significantly higher increase in the mRNA levels of HIV genes (LTR, Tat, Gag, Vpr, Vif) compared to HSV-wt infection in J-Lat 10.6 cells.
HSV-ΔICP34.5 infection resulted in a higher level of p24 protein, a marker of HIV replication, in ACH-2 cells compared to HSV-wt.
The frequency of SIV Gag-specific IFN-γ-secreting spot-forming cells (SFCs) was significantly higher in the HSV-sPD1-SIVgag group (1350 SFCs per 106 splenocytes) compared to the HSV-SIVgag group (498 SFCs per 106 splenocytes) in mice.
In chronically SIV-infected, ART-treated macaques, the ART+HSV-sPD1-SIVgag/SIVenv group showed a lower peak viral load (average 12.20-fold decrease) compared to the pre-ART level, while the ART+HSV-empty group had a higher peak viral load (average 2.74-fold increase).

คำพูด

"HSV-ΔICP34.5 could reactivate HIV latency more efficiently than HSV-wt."
"The HSV-sPD1-SIVgag/SIVenv construct elicited robust SIV-specific T cell immune responses, including polyfunctional CD8+ T cells, in chronically SIV-infected, ART-treated rhesus macaques."
"The ART+HSV-sPD1-SIVgag/SIVenv group showed a lower peak viral load (average 12.20-fold decrease) compared to the pre-ART level, suggesting effective reactivation of latent SIV reservoirs and control of viral replication."

ข้อมูลเชิงลึกที่สำคัญจาก

Purging viral latency by a bifunctional HSV-vectored therapeutic vaccine in chronically SIV-infected macaques

by Wen,Z., Li,P... ที่ www.biorxiv.org 02-22-2024

https://www.biorxiv.org/content/10.1101/2024.02.20.581122v1

สอบถามเพิ่มเติม

What other potential mechanisms or host factors could be involved in the efficient reactivation of latent viral reservoirs by the modified HSV-ΔICP34.5 constructs?

The efficient reactivation of latent viral reservoirs by the modified HSV-ΔICP34.5 constructs could involve several potential mechanisms or host factors beyond the IKKα/β-NF-κB pathway and PP1-HSF1 pathway identified in the study. Some of these mechanisms could include:

Epigenetic Regulation: Epigenetic modifications, such as DNA methylation and histone acetylation, play a crucial role in regulating viral latency. The modified HSV-ΔICP34.5 constructs may influence these epigenetic marks to promote the reactivation of latent viral reservoirs.

Immune Checkpoint Molecules: Apart from PD1, other immune checkpoint molecules like CTLA-4, TIM-3, and LAG-3 could impact the immune response and viral latency. Modulating these pathways could potentially enhance the efficacy of the therapeutic vaccine.

Inflammatory Signaling Pathways: Activation of other inflammatory signaling pathways, such as the JAK-STAT pathway or the MAPK pathway, could contribute to the reactivation of latent viral reservoirs by the HSV constructs.

Cellular Stress Responses: Cellular stress responses, including the unfolded protein response (UPR) or oxidative stress pathways, might interact with the viral latency mechanisms and be influenced by the HSV constructs.

Microenvironment Factors: Factors in the microenvironment, such as cytokines, chemokines, and immune cell populations, could also impact the reactivation of latent viral reservoirs by modulating the immune response.

Exploring these additional mechanisms and host factors could provide a more comprehensive understanding of how the modified HSV-ΔICP34.5 constructs efficiently reactivate latent viral reservoirs.

How could the therapeutic efficacy of the HSV-sPD1-SIVgag/SIVenv vaccine be further improved to achieve a complete and durable functional cure in chronically SIV-infected, ART-treated macaques?

To enhance the therapeutic efficacy of the HSV-sPD1-SIVgag/SIVenv vaccine for achieving a complete and durable functional cure in chronically SIV-infected, ART-treated macaques, several strategies could be considered:

Optimizing Vaccine Dosage and Administration: Fine-tuning the vaccine dosage and administration schedule could improve the immune response and durability of protection.

Combination Therapy: Combining the HSV-based vaccine with other immunomodulatory agents, such as immune checkpoint inhibitors or adjuvants, could enhance the immune response and viral clearance.

Targeting Multiple Antigens: Including additional SIV antigens or epitopes in the vaccine formulation to broaden the immune response and target different viral reservoirs could improve efficacy.

Enhancing T Cell Function: Strategies to enhance the functionality of T cells, such as promoting effector memory T cell formation or reducing T cell exhaustion, could improve the ability to eliminate infected cells.

Incorporating Novel Adjuvants: Using novel adjuvants or delivery systems to enhance antigen presentation and immune activation could boost the vaccine's efficacy.

Personalized Vaccination Strategies: Tailoring the vaccine approach based on individual immune profiles or viral characteristics could improve the specificity and effectiveness of the vaccine.

By implementing these approaches, the therapeutic efficacy of the HSV-sPD1-SIVgag/SIVenv vaccine could be further enhanced to achieve a complete and durable functional cure in chronically SIV-infected, ART-treated macaques.

What are the potential challenges and considerations in translating this bifunctional HSV-vectored therapeutic vaccine strategy to clinical trials for HIV patients?

Translating the bifunctional HSV-vectored therapeutic vaccine strategy to clinical trials for HIV patients presents several challenges and considerations:

Safety and Regulatory Approval: Ensuring the safety of the vaccine in human trials and obtaining regulatory approval for a novel therapeutic approach are critical steps in the translation process.

Efficacy in Humans: Demonstrating the efficacy of the vaccine in human HIV patients, especially in terms of viral suppression, immune response durability, and long-term outcomes, is essential.

Optimal Vaccine Formulation: Identifying the optimal vaccine formulation, including antigen selection, dosage, and administration schedule, for maximum efficacy in human populations is crucial.

Patient Selection and Stratification: Determining the appropriate patient population for clinical trials, including consideration of viral load, immune status, and treatment history, is important for assessing vaccine efficacy.

Combination Therapy Considerations: Assessing the potential interactions and synergies of the vaccine with existing antiretroviral therapies or other HIV treatment modalities is necessary for comprehensive patient care.

Long-Term Follow-Up: Conducting long-term follow-up studies to monitor vaccine efficacy, immune response durability, and potential side effects over an extended period is essential for assessing the vaccine's long-term benefits.

Cost and Accessibility: Addressing the cost of vaccine production, distribution, and accessibility to ensure that the vaccine can reach and benefit a broad population of HIV patients.

Navigating these challenges and considerations will be crucial in successfully translating the bifunctional HSV-vectored therapeutic vaccine strategy to clinical trials for HIV patients and ultimately achieving an HIV functional cure.