Research Report on the Association between Gene Variants and Neurocognitive Impairment in HIV Patients

Over the past few decades, antiretroviral therapy (ART) has greatly improved the health of people infected with human immunodeficiency virus (HIV). However, even with effective viral suppression and partial immune system recovery, up to 50% of People with HIV (PWH) still experience some degree of Neurocognitive Impairment (NCI) and other neurological diseases. Mild NCI is particularly persistent in this situation, even when viral RNA levels are reduced to below detectable levels.

Studies have shown that neuropsychiatric disorders such as depression and age-related diseases are more common in PWH. Additionally, factors such as low CD4+ T cell counts, metabolic syndrome, hepatitis C virus (HCV) co-infection, and depression are associated with increased risk of NCI. Although there is currently no more effective treatment than ART, research on mechanistic biomarkers of neurocognitive vulnerability may help in early diagnosis of NCI and development of new treatments.

Research background shows that HIV replication, aging, and chronic inflammation can trigger the Integrated Stress Response (ISR), a ubiquitous cellular pathway responding to stress signals such as interleukins. ISR regulates cellular homeostasis by activating specific sensor kinases like PERK (PKR-like endoplasmic reticulum kinase), which in turn activates downstream signaling molecules like eIF2α (eukaryotic initiation factor 2α). However, prolonged ISR activation can lead to cellular damage or death.

Recent studies suggest that specific Single-Nucleotide Variants (SNVs) of PERK, encoded by EIF2AK3, are associated with neurodegenerative diseases, and specific protein-coding haplotypes are associated with increased risk of Progressive Supranuclear Palsy (PSP). Therefore, this paper hypothesizes that specific minor alleles of EIF2AK3 may be risk factors for NCI in PWH.

Research Source

This research paper was collaboratively completed by Cagla Akay-Espinoza, Sarah E.B. Newton, Beth A. Dombroski, and Asha Kallianpur, among other researchers. The authors are from institutions including the University of Pennsylvania, Cleveland Clinic Lerner Research Institute, and the University of California, San Diego. The paper was published in the Journal of Neuroimmune Pharmacology in 2024.

Research Process

This study used a candidate gene approach, retrospectively analyzing data from 1047 Charter cohort participants to assess the association between SNVs of EIF2AK3 and neurocognitive performance in HIV-infected individuals. The main processes of this study include:

1. Study Subjects and Data Collection: Among 1047 participants, 992 had genomic DNA analysis data, drug treatment, and disease-related information.
2. Genotyping and Sequencing: Analysis of three non-coding SNVs such as rs6739095, rs1913671, rs11684404, and three coding SNVs including rs867529, rs1805165, and rs13045 through specific genomic data and targeted sequencing.
3. Neurocognitive Assessment: Using standardized neuropsychological assessment methods to test seven HIV-related cognitive domains, including learning, memory, executive function, and verbal fluency.
4. Statistical Analysis: Combining univariate and multivariate methods with linear and logistic regression to evaluate the association between SNVs and neurocognitive performance.

Main Results

The study found that all three non-coding EIF2AK3 SNVs were significantly associated with GDS and NCI. Specific data shows that the average GDS for rs11684404 cc gene risk allele groups were 0.43 (tt), 0.50 (ct), and 0.56 (cc), respectively. Among the three coding SNVs, over 30% of participants had at least one risk allele, including rs13045(a).

Through multivariate analysis, the rs13045(a) risk allele, current ART use, and depression scale score (BDI-II) >13 were independently associated with GDS and NCI. However, rs867529 and rs1805165 were not significant in models including rs13045(a). Nevertheless, coding SNVs were associated with performance in domains such as executive function, motor function, learning, and verbal fluency. Increased IL-6 levels in CSF were also significantly associated with coding EIF2AK3 SNVs.

Conclusion

This study demonstrates that both coding and non-coding SNVs of EIF2AK3 are significantly associated with global and domain-specific neurocognitive performance in HIV-infected individuals. Although these associations showed only small to medium effects in multivariate analysis, they suggest that specific gene variants may be potential genetic vulnerability factors for NCI in PWH. This study emphasizes the importance of detecting host factors in early disease processes, providing new perspectives for more effective prevention or treatment strategies.

Research Highlights

1. First demonstration of the association between multiple coding and non-coding SNVs of EIF2AK3 and cognitive performance in PWH.
2. Suggests the potential pathogenic mechanism of integrated stress response in HIV-infected individuals, highlighting the importance of the PERK pathway.
3. Elucidates the relationship between specific gene variants, IL-6 concentrations in CSF, and NCI symptoms, emphasizing the role of neuroinflammation in HIV-related NCI.
4. Provides potential new therapeutic targets, such as regulation of PERK and ISR pathways, with important scientific and clinical application value.

Other Valuable Information

The study indicates that the mechanisms of action of specific gene variants need further research, such as how specific cellular responses to pathological stress affect the NCI process. Additionally, future validation studies in larger cohorts exploring the relationship between these genes and molecular and imaging biomarkers are necessary. This will provide important basis for personalized medicine and adjunctive therapeutic measures.

This study provides detailed data and scientific arguments, further revealing the genetic basis and molecular mechanisms of neurocognitive impairment in HIV-infected individuals, with significant implications for scientific research and clinical applications.