HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain–blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV.

During the antiretroviral era, individuals living with HIV continue to experience milder forms of HIV-associated neurocognitive disorder (HAND). Viral proteins, including Tat, play a pivotal role in the observed alterations within the central nervous system (CNS), with mitochondrial dysfunction emerging as a prominent hallmark. As a result, our objective was to examine the expression of genes associated with mitophagy and mitochondrial biogenesis in the brain exposed to the HIV-1 Tat protein. We achieved this by performing bilateral stereotaxic injections of 100 ng of HIV-1 Tat into the hippocampus of Sprague–Dawley rats, followed by immunoneuromagnetic cell isolation. Subsequently, we assessed the gene expression of Ppargc1a, Pink1, and Sirt1-3 in neurons using RT-qPCR. Additionally, to understand the role of Tert in telomeric dysfunction, we quantified the activity and expression of Tert. Our results revealed that only Ppargc1a, Pink1, and mitochondrial Sirt3 were downregulated in response to the presence of HIV-1 Tat in hippocampal neurons. Interestingly, we observed a reduction in the activity of Tert in the experimental group, while mRNA levels remained relatively stable. These findings support the compelling evidence of dysregulation in both mitophagy and mitochondrial biogenesis in neurons exposed to HIV-1 Tat, which in turn induces telomeric dysfunction.

Oxidative stress and neuroinflammation are considered as the two main etiological reasons behind idiopathic Parkinson’s disease (PD). Nevertheless, the actual treatments are focused on improving motor symptoms by restoring dopamine (DA) presence, leaving said causes unattended. Probiotics could be a promising strategy for the improvement of these physiological features behind the disease and therefore constitute a complementary treatment for those having PD. This study evaluated the effect of the oral administration of a probiotic bacteria mixture from 3 strains of Limosilactobacillus fermentum LH01 , Limosilactobacillus reuteri LH03, and Lactiplantibacillus plantarum LH05 (LLH135), of human milk origin, for 4 weeks, on mice under the hemiparkinsonism model of intrastriatal administration of 6‐hidroxidopamine (6‐OHDA). We measured total antioxidant capacity (TAC), super oxide dismutase (SOD) activity, and 8‐deoxyguanosine (8‐OHdG) regarding oxidative stress. Concerning neuroinflammation, immunoreactivity for GFAP, IBA‐1, and CD68 was measured by immunohistochemistry and the latter markers corroborated in colocalization with immunofluorescence to assess activated microglia. The probiotic mixture diminished the oxidative stress features of SOD activity as well as 8‐OHdG generated by the model of hemiparkinsonism. These effects were accompanied as well by the dampening of the glial immunoreactivity and colocalization of IBA‐1 and CD68 that were present under the model. Our findings suggest that the administration of the probiotic LLH135 exerts neuroprotective effects by promoting an antioxidant response which could be explained by the modulation of the response from glial cells to dopaminergic neuronal damage induced with 6‐OHDA.

Although ART leads to viral suppression, people living with HIV (PLWH) still face an increased risk of comorbidities, such as cancer. The HIV-1 Tat protein may contribute to the promotion of chronic inflammation, oxidative stress, and genomic instability. While the presence of anti-Tat antibodies has been associated with slower disease progression, their potential role in modulating DNA damage remains unclear. Assess the effect of anti-Tat antibodies on cytotoxic and DNA damage in PLWH. A cross-sectional study was conducted in 178 PLWH. Serum anti-Tat IgG antibodies were measured using enzyme-linked immunosorbent assay (ELISA). Cytotoxicity and DNA damage were assessed via serum 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nuclear anomalies (Micronucleus cytome assay) in 2000 buccal cells. Statistical significance was considered at p < 0.05. Anti-Tat antibodies were found in 24.2% of participants. Positive individuals had lower CD4+ T cell counts (p = 0.045) and higher levels of pyknosis (p = 0.0001). No differences in 8-OHdG were found, but 8-OHdG correlated positively with CD4+ counts (rho = 0.334, p = 0.006). Pyknosis negatively correlated with CD4+ counts (rho = −0.272, p = 0.027). Anti-Tat antibodies may not prevent DNA damage but could be related to cytotoxic effects in PLWH.