HIV-1 endocytosis in astrocytes: a kiss of death or survival of the fittest?

Abstract

The brain is a target of HIV-1 and serves as an important viral reservoir. Astrocytes, the most abundant glial cell in the human brain, are involved in brain plasticity and neuroprotection. Several studies have reported HIV-1 infection of astrocytes in cell cultures and infected brain tissues. The prevailing concept is that HIV-1 infection of astrocytes leads to latent infection. Here, we provide our perspective on endocytosis-mediated HIV-1 entry and its fate in astrocytes. Natural entry of HIV-1 into astrocytes occurs via endocytosis. However, endocytosis of HIV-1 in astrocytes is a natural death trap where the majority of virus particles are degraded in endosomes and a few which escape intact lead to successful infection. Thus, regardless of artificial fine-tuning (treatment with cytokines or proinflammatory products) done to astrocytes, HIV-1 does not infect them efficiently unless the viral entry route or the endosomal enzymatic machinery has been manipulated.

Keywords: Chloroquine; DDX3; HIV-1 brain; HIV-1 latency; HIV-1 reservoir; Rab.

Figure 1. Natural HIV-1 infection in primary human fetal astrocytes

(Upper panel): Diagrammatic view of recombinant HIV-1 infectious molecular clone, NLENY1 showing yellow fluorescent protein (YFP) gene insertion. (Lower panel): Human fetal astrocytes after culture for a month were infected with NLENY1 (1.0 µg/mL p24 concentration). Infection was detected by green fluorescence in HIV-1 infected astrocytes on day 16 post-infection.

Figure 2. Viral entry bypass produces robust HIV-1 infection in astrocytes

Primary human fetal astrocytes were infected with VSV-pseudotyped NLENY1 virus (200 ng/mL p24 concentration) and infection was monitored for green fluorescence under fluorescent microscope. Green fluorescent astrocytes were showing HIV-1 infection (live) on day 26 post-infection.

Figure 3. Persistent long term HIV-1 infection in astrocytes

Primary human fetal astrocytes were infected with VSV-pseudotyped NLENY1 virus (200 ng/mL p24 concentration) and monitored for green fluorescence using fluorescent microscope. VSV-NLENY1 infected astrocytes were showing green fluorescence at day 110 post-infection.