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Introduction: Encephalitis is a life-threatening neurological condition with multiple causes in the setting of Human Immunodeficiency Virus (HIV). CD8 Encephalitis (CD8E) is a newly recognised condition which can present in an acute manner, with pertinent features including classical radiological findings with an intense brain parenchymal infiltration of CD8+ T cells. This review attempted to clarify the symptomatology, distribution and determinants of this condition, as well as to examine its vast unknowns. Methods: A literature review was undertaken in July 2022, utilising the PubMed and Google Scholar databases. Papers published between 2006–2022 were reviewed. Eighteen papers, totalling 57 patients, were found and analysed. Statistical analysis was undertaken using Chi-squared and Wilcoxon rank-sum tests as appropriate, with p < 0.05 deemed significant. Results: In this review, 57 patients were identified, with a female (61%, 34/56) and Black African (70%, 40/57) preponderance. Females were more likely to present with headache (p = 0.006), and headache was more likely to be present in those who died (p = 0.02). There was no statistically significant association between baseline CD4 count (p = 0.079) and viral load (p = 0.72) with disease outcome. Overall, 77% (41/53) of patients had classical imaging findings, including bilateral gadolinium-enhancing punctate and perivascular white matter lesions. However, many patients (23/57) required a brain biopsy as part of their diagnostic workup. Corticosteroid treatment was commonly prescribed in patients (64%, 35/55) and had a mortality benefit, with an overall survival in this group of 71% (p = 0.0008). In those who died, median survival was 5.5 months. In rare instances, recurrence of the disease was noted, which responded poorly to treatment. Discussion: CD8E represents a new and complex condition with few risk factors identified for its occurrence. The presenting symptoms are broad, but headache appears to be more common in females and more significantly associated with death. Though rare, CD8E is likely under-diagnosed, possibly due to overlapping features with other illnesses and lack of physician experience in its recognition and management. Corticosteroids demonstrate a clear mortality benefit, but more studies are required to determine their optimal dosing and duration, as well as the use of steroid-sparing agents. Further reviews should help to better determine the risk factors for the condition, as well as non-invasive biomarkers, to aid in diagnosis and help to predict poor prognosis and disease recurrence. [ABSTRACT FROM AUTHOR]