HIV Infection, Neurotoxicity, Inflammation, Premature Aging, and Therapeutic Challenges to PLWH: An Overview

Area of Science:

• Neuroscience
• Immunology
• Virology

Background:

• Human immunodeficiency virus (HIV) infection persists lifelong, establishing latent reservoirs in various tissues, including the central nervous system (CNS).
• These reservoirs evade immune clearance and antiretroviral therapy (ART), leading to viral rebound upon treatment interruption and necessitating lifelong therapy.
• In the CNS, HIV persistence is driven by limited ART penetration across the blood-brain barrier (BBB) and infection of resident immune cells like microglia.

Purpose of the Study:

• To review the mechanisms of HIV-associated inflammation, neurotoxic pathways, and accelerated brain aging in people living with HIV (PLWH) receiving modern ART.
• To understand the contribution of these factors to the development of HIV-associated neurocognitive disorders (HAND) despite viral suppression.

Main Methods:

• This is a review article, synthesizing existing research on HIV pathogenesis, CNS involvement, and the impact of ART.
• It examines data on ART penetration, neuroinflammation, cellular tropism in the CNS, and age-related changes in PLWH.

Main Results:

• Modern ART reduces viral burden but does not eliminate neurocognitive complications due to suboptimal CNS drug penetration and ART toxicities.
• Persistent low-level viral activity and chronic inflammation accelerate brain aging, immune activation, and metabolic dysregulation in aging PLWH.
• These pathological processes contribute significantly to the high prevalence of HAND among virally suppressed PLWH.

Conclusions:

• HIV infection in the CNS leads to persistent neuroinflammation and accelerated brain aging, even with effective systemic ART.
• Understanding these pathways is crucial for developing strategies to prevent and treat HAND in the growing population of aging PLWH.
• Further research is needed to improve ART CNS penetration and mitigate long-term neurotoxic effects.