Clinical Relevance of Total HIV DNA in Peripheral Blood Mononuclear Cell Compartments as a Biomarker of HIV-Associated Neurocognitive Disorders (HAND)

Abstract

The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. It is hypothesized that the critical events initiating this condition occur outside the brain, particularly in the peripheral blood. Diagnoses of HIV-induced neurocognitive disorders largely rely on neuropsychometric assessments, which are not precise. Total HIV DNA in the peripheral blood mononuclear cells (PBMCs), quantified by PCR, correlate with disease progression, which is a promising biomarker to predict HAND. Numerous PCR assays for HIV DNA in cell compartments are prone to variation due to the lack of standardization and, therefore, their utility in predicting HAND produced different outcomes. This review evaluates the clinical relevance of total HIV DNA in circulating mononuclear cells using different published quantitative PCR (qPCR) protocols. The rationale is to shed light on the most appropriate assays and sample types used to accurately quantify HIV DNA load, which predicts severity of neurocognitive impairment. The role of monocytes as a vehicle for trafficking HIV into the CNS makes it the most suitable sample for determining a HAND associated reservoir. Studies have also shown significant associations between monocyte HIV DNA levels with markers of neurodamage. However, qPCR assays using PBMCs are cheaper and available commercially, thus could be beneficial in clinical settings. There is need, however, to standardise DNA extraction, normalisation and limit of detection.

Keywords: HAND; HIV DNA; biomarker; qPCR.

Figure 1

Mechanism of neuropathogenesis. Two pathways involved shown by arrows: (1) Direct pathway caused by HIV and released HIV proteins. (2) Indirect pathway involving secretion cytokines. (a) Virus particles and viral proteins shed and cross Blood brain barrier (BBB). (b) Neural injury caused by direct viral infection and dysregulation by viral proteins. (c) Infected monocyte infiltrating BBB. (d) Release of cytokines from infected monocytes contributing to disruption of BBB. (e) BBB become more permeable to cytokines present in the periphery. (f) More cytokines released into the brain and (g) cytokines disrupt normal functioning ultimately leading to neuronal apoptosis resulting in different forms of HIV associated neurocognitive disorders (HAND).