RT Journal Article
SR Electronic
T1 The CNS in the face of ART contains T cell origin HIV which can lead to drug resistance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 588426
DO 10.1101/588426
A1 Gila Lustig
A1 Sandile Cele
A1 Farina Karim
A1 Yashica Ganga
A1 Khadija Khan
A1 Bernadett Gosnell
A1 Yunus Moosa
A1 Rohen Harrichandparsad
A1 Suzaan Marais
A1 Ravindra K. Gupta
A1 Anne Derache
A1 Jennifer Giandhari
A1 Tulio de Oliveira
A1 Katya Govender
A1 John Adamson
A1 Vinod Patel
A1 Alex Sigal
YR 2019
UL http://biorxiv.org/content/early/2019/03/25/588426.abstract
AB HIV persists despite antiretroviral therapy (ART) in cellular reservoirs thought to occur in distinct anatomical compartments. Therapy failure may occur because of incomplete ART adherence and possibly viral replication at some reservoir sites. The CNS may serve as a reservoir site due to lowered ART penetration and virus production from long-lived tissue resident macrophages. Compelling evidence for the CNS as a reservoir is the existence of individuals where HIV is suppressed below limit of detection in blood but detectable in the cerebrospinal fluid (CSF), termed CSF Escape. Here, we asked whether HIV in CSF Escape individuals is derived from macrophages or persists due to lowered ART. We used cell surface markers on the HIV envelope to determine the cellular source of HIV. We verified detection using in vitro derived virus from infected macrophages and T cells and tested CSF from CSF Escape individuals. We observed host surface markers consistent with T cell origin. We also measured ART concentrations in the CSF and plasma. We found a dramatic decrease in CSF ART concentrations described previously, but no significant difference between CSF Escape versus fully suppressed individuals. To examine the effect of the observed CSF ART concentrations on HIV replication, we used long-term infection with ART in cell culture. CSF Escape ART levels led to either HIV suppression or evolution of drug resistance, but not replication of drug sensitive HIV. These observations argue that persistent CNS viremia despite ART can be T cell generated and may result in drug resistance and therapy failure.