While cART has successfully reduced viremia and mortality, a subset of individuals, up to 30%, faces challenges in reconstituting CD4+ T cell counts, irrespective of suppressed viral load. These individuals, termed immunological non-responders (INRs), are at a heightened risk of developing acquired immune deficiency syndromes (AIDS) and other associated diseases.
Recent research has highlighted the potential role of Vitamin D and Vitamin B3 (niacin), particularly as a nicotinamide adenine dinucleotide (NAD) booster, in influencing immune activation and CD4+ T cell reconstitution in INRs. This article delves into the emerging therapeutic strategy of promoting CD4+ T cell recovery through the use of NAD boosters, with a specific focus on nicotinamide mononucleotide (NMN).
Nicotinamide Adenine Dinucleotide (NAD) and its Role in Host Cells:
NAD, an essential co-enzyme for energy metabolism, plays a crucial role in maintaining cellular function. Depletion of NAD with aging has been linked to various disease conditions affecting the nervous system, liver, kidneys, intestines, muscles, hematopoiesis, and cardiovascular systems.
Consequently, replenishing NAD levels in patients using NAD precursors or inhibitors of NAD-consuming enzymes has emerged as a promising therapeutic approach. NAD boosters, including nicotinamide ribose (NR), nicotinamide (NAM), and nicotinamide mononucleotide (NMN), have been the focus of clinical trials. Recent investigations have expanded their scope to explore the role of NAD in modulating the immune system’s response to infections or cancer, primarily through the activation of NAD-consuming factors such as sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38.
Anti-inflammatory Role of NAD in Immune Responses:
NAD’s anti-inflammatory role during immune responses has been documented, with enhanced sirtuin 1 activity through boosted NAD leading to the deacetylation of nuclear factor-kappa B (NF-κB). This, in turn, downregulates NF-κB-regulated pro-inflammatory cytokines and modulates CD4+ T cell differentiation.
Exogenous NAD, boosted by NMN supplementation, has demonstrated the ability to restore inflammation induced by PARP activation. Despite controversies surrounding the role of the NAD-consumer CD38 in pro-inflammatory cytokine release, it is evident that critical factors modulated by NAD or its precursors warrant further investigation in the context of host immunoregulation against pathogens.
NAD Biosynthesis and NMN as a Potential Clinical Candidate:
The biosynthesis of NAD involves various precursors, with NMN being the direct precursor in the salvage pathway. NAM and NR, on the other hand, are indirect precursors requiring enzymes such as nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferases (NMNATs).
Notably, niacin (Vitamin B3) can be catalyzed by nicotinate phosphoribosyltransferase (NAPRT) in the Preiss-Handler pathway before entering the salvage pathway. While preclinical and clinical trials have reported undesirable adverse effects with high-dose niacin, NR, and NAM, similar adverse effects have not been associated with high-dose NMN. This suggests that NMN could be a superior candidate for clinical use, although its impact on HIV/AIDS remains unexplored.
Testing the Hypothesis: NMN Modulating Immune Activation in HIV/AIDS:
To address the hypothesis that NMN may modulate immune activation, research endeavors have sought to determine the effects of NMN on human CD4+ T cells in the context of in vitro and in vivo HIV-1 infection. This investigation aims to provide insights into the potential of NMN as a therapeutic intervention for enhancing CD4+ T cell recovery, suppressing immune activation, and mitigating clinical risks associated with immunological non-response in individuals living with HIV.
Discussion: Unraveling the Therapeutic Potential of Nicotinamide Mononucleotide (NMN) in HIV/AIDS
In this study, our investigation into the effects of nicotinamide mononucleotide (NMN) on HIV-1 infection has uncovered intriguing findings with significant implications for the treatment and management of individuals living with HIV. Our results demonstrate that a concentration of 10 mM NMN exerts a suppressive effect on HIV-1 production in primary CD4+ T cells at the post-translational level in vitro. Notably, this suppression is most pronounced in CD25+CD4+ T cells, emphasizing a selective impact on specific cellular subsets. Moreover, the application of NMN extends beyond in vitro settings, as it demonstrates the ability to suppress HIV-1 reactivation in primary CD4+ T cells derived from cART-treated individuals living with HIV.
Selective Impact on CD25+CD4+ T Cells:
Our findings underscore the specificity of NMN’s effects on CD25+CD4+ T cells, a subset crucial in the context of HIV-1 infection. CyTOF analysis revealed a consistent decrease in CD25 expression on both CXCR3+ effector and CCR4+ central memory CD4+ T cells following NMN treatment. This reduction in CD25, an interleukin-2 receptor, may play a pivotal role in modulating immune activation, as evidenced by the downregulation of CD25-related gene ontology pathways associated with cell proliferation, activation, and apoptosis.
Improved Therapeutic Effect of cART:
The synergy between NMN and combination antiretroviral therapy (cART) emerges as a significant aspect of our findings. In HIV-1-infected humanized mice, the addition of NMN to cART substantially improved CD4+ T cell reconstitution. This improvement was evident through a reduction in the frequencies of p24+CD4+ and ki67+CD4+ T cells. The observed impact on CD4+ T cell reconstitution suggests a potential avenue for NMN as a supplemental treatment to enhance the efficacy of cART, particularly in individuals with persistently low CD4+ T cell counts.
In Vitro and In Vivo Mechanisms of Action:
Our study delineates the dual inhibitory effects of NMN on HIV-1 replication in primary CD4 T cells. In vitro, NMN exhibited a suppressive effect on the translation of HIV-1 p24 and the proliferation of primary CD4 T cells. Importantly, this action occurred at a post-transcriptional stage, as evidenced by experiments utilizing single-cycle HIV-1 infection and latent ACH-2 cell models. Mechanistically, NMN’s influence on transcriptional factor Foxp3, as indicated by RNA-seq results, suggests a complex interplay in the modulation of CD4+ T cell activation and proliferation during HIV-1 infection.
Potential for the “Block and Lock” Strategy:
NMN’s consistent inhibitory effects on HIV-1 replication raise intriguing possibilities for its application in the “block and lock” strategy. Future studies will be essential to determine whether NMN could serve as a latency-locking agent, modulating HIV-1 expression through factors such as sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38. This avenue holds promise for innovative approaches in HIV/AIDS management.
Addressing Persistent Immune Activation:
Persistent immune activation in HIV-1 infection contributes to incomplete CD4+ T cell recovery despite cART. Our study suggests that NMN may act as a suppressive agent against immune hyperactivation in vivo. Although NMN alone did not significantly suppress HIV-1 replication in humanized mice, its combination with cART demonstrated improved CD4+ T cell reconstitution and alleviated immune hyperactivation. These findings highlight the potential of NMN as an intervention against persistent immune activation in individuals living with HIV.
Clinical Implications and Future Directions:
The promising outcomes of NMN in modulating CD4+ T cell activation and improving therapeutic outcomes in humanized mice pave the way for future clinical investigations. The potential of daily high-dose NMN treatment, especially in combination with cART, presents a novel avenue for improving CD4+ T cell reconstitution, particularly in immunological non-responders with persistently low CD4 counts. Further clinical testing and mechanistic studies are warranted to fully elucidate the therapeutic potential of NMN in the context of HIV/AIDS. The complex interplay between NMN and immune responses opens doors for innovative approaches that may reshape the landscape of HIV/AIDS management and treatment.
reference link : https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00443-7/fulltext#secsectitle0060