Is the central nervous system a reservoir of HIV-1?

Abstract

Purpose of the review To summarize the evidence in the literature that supports the CNS as a viral reservoir for HIV-1 and to prioritise future research efforts. Recent findings HIV-1 DNA has been detected in brain tissue of patients with undetectable viral load or neurocognitive disorders, and is associated with long-lived cells such as astrocytes and microglia. In neurocognitively normal patients, HIV-1 can be found at high frequency in these cells (4% of astrocytes and 20% of macrophages). CNS cells have unique molecular mechanisms to suppress viral replication and induce latency, which include increased expression of dominant negative transcription factors and suppressive epigenetic factors. There is also evidence of continued inflammation in patients lacking a CNS viral load, suggesting the production and activity of viral neurotoxins (for example Tat). Summary Together, these findings provide evidence that the CNS can potentially act as a viral reservoir of HIV-1. However, the majority of these studies were performed in historical cohorts (absence of cART or presence of viral load) which do not reflect modern day patients (cART-treated and undetectable viral load). Future studies will need to examine patient samples with these characteristics to conclusively determine if the CNS represents a relevant and important viral reservoir.

Immuno-Pharmacological Targeting of Virus-Containing Compartments in HIV-1-Infected Macrophages

“…HIV-1 infects cells through the interaction of the gp120 envelope (Env) protein with the CD4 molecule (primary receptor) and a chemokine coreceptor (usually CCR5 in the initial phase of infection in humans, or CXCR4 in late-stage disease, although frequently in association with CCR5 and thus resulting in dualtropic R5X4 viruses). These entry receptors restrict the spectrum of target cells essentially to CD4 T lymphocytes (whose depletion in patients with HIV-1 infection is a hallmark of AIDS) and to mononuclear phagocytes (monocytes, macrophages, and microglia of the central nervous system, CNS, and myeloid dendritic cells, mDCs), with a few exceptions such as astrocytes in the CNS [1]. Once in the target cell, a preintegration complex (PIC) containing both viral and cellular proteins is formed to drive the viral genome to the cell nucleus.…”

HIV-specific CD8+ T cells and HIV eradication

“…While the lymphoid follicles provide a clear-cut example of HIV persistence facilitated by the lack of HIV-specific CD8 + T cell access, similar scenarios may also exist in immune-privileged sites such as the testicles and CNS (89)(90)(91)(92) (112). Effective enhancement of CD8 + T cell responses will also almost certainly require augmentation of HIV-specific CD4 + Th cell responses that are both critical for maintaining effective CD8 + T cell function and able to reverse some of the functional defects acquired during prolonged viral exposure (113).…”

Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

“…Hence, suboptimal dissemination of ARVs into the CNS might allow virus to replicate at low levels within brain-resident cells, resulting in HAND. Some studies have shown that viral nucleic acids can be recovered from the CNS of individuals who are treated with antiretrovirals and who have contempo-raneously undetected virus in plasma (59). While residual viral replication in brain-resident cells could contribute to neurological diseases observed in ARV-treated individuals, several studies have also implicated local inflammation (33,52,60,61).…”