HIV-1 CNS in vitro infectivity models based on clinical CSF samples

Area of Science:

• Neuroscience
• Pharmacology
• Infectious Diseases

Background:

• Cerebrospinal fluid (CSF) antiretroviral concentrations are a surrogate for central nervous system (CNS) drug exposure.
• Current methods do not account for pharmacodynamic or combinative antiretroviral therapy (ART) effects.
• A novel endpoint measurement was developed to assess ART activity in CSF.

Purpose of the Study:

• To develop and validate a novel method for assessing antiretroviral activity in CSF.
• To compare the in vitro antiretroviral activity of CSF from patients on different ART regimens.
• To correlate CSF antiretroviral activity with drug concentrations.

Main Methods:

• CSF samples were collected from patients on tenofovir/emtricitabine with either rilpivirine or lopinavir/ritonavir/maraviroc, and HIV-uninfected controls.
• Antiviral activity was assessed in cell cultures using peripheral blood mononuclear cells (PBMCs) and neuro-derived glial (U87) and astrocyte (373) cell lines.
• Infectivity model half-maximal inhibitory concentration (IMIC50) values were calculated and correlated with CSF antiretroviral concentrations.

Main Results:

• CSF from both ART groups demonstrated in vitro antiretroviral activity.
• CSF antiretroviral activity was significantly greater in patients on the four-drug regimen (lopinavir/ritonavir/maraviroc) compared to the three-drug regimen (rilpivirine).
• CSF antiretroviral activity correlated positively with CSF concentrations of rilpivirine and lopinavir, but not maraviroc.

Conclusions:

• A novel method successfully quantified CSF antiretroviral activity.
• A four-drug ART regimen exhibited greater CSF antiviral activity than a three-drug regimen.
• Neuro-derived cell lines alongside PBMCs offer a valuable tool for future clinical research on ART in CSF.