Shock and kill within the CNS: A promising HIV eradication approach?

Abstract

The most studied HIV eradication approach is the "shock and kill" strategy, which aims to reactivate the latent reservoir by latency reversing agents (LRAs) and allowing elimination of these cells by immune-mediated clearance or viral cytopathic effects. The CNS is an anatomic compartment in which (persistent) HIV plays an important role in HIV-associated neurocognitive disorder. Restriction of the CNS by the blood-brain barrier is important for maintenance of homeostasis of the CNS microenvironment, which includes CNS-specific cell types, expression of transcription factors, and altered immune surveillance. Within the CNS predominantly myeloid cells such as microglia and perivascular macrophages are thought to be a reservoir of persistent HIV infection. Nevertheless, infection of T cells and astrocytes might also impact HIV infection in the CNS. Genetic adaptation to this microenvironment results in genetically distinct, compartmentalized viral populations with differences in transcription profiles. Because of these differences in transcription profiles, LRAs might have different effects within the CNS as compared with the periphery. Moreover, reactivation of HIV in the brain and elimination of cells within the CNS might be complex and could have detrimental consequences. Finally, independent of activity on latent HIV, LRAs themselves can have adverse neurologic effects. We provide an extensive overview of the current knowledge on compartmentalized (persistent) HIV infection in the CNS and on the "shock and kill" strategy. Subsequently, we reflect on the impact and promise of the "shock and kill" strategy on the elimination of persistent HIV in the CNS.

Keywords: CNS; HAND; HIV; astrocytes; compartmentalization; eradication; inflammation; latency; latency reversal; microglia; perivascular macrophages; persistence; reservoir; shock and kill.

FIGURE 1

Overview of neuropathogenesis in virally unsuppressed and suppressed PWH. (A) Virally unsuppressed PWH: The exposure of viral proteins and inflammatory cytokines may cause increased permeability of the blood–brain barrier. This can contribute to the entrance of HIV within the CNS via free virus particles, infected CD4⁺ T cells, or infected monocytes. Subsequently, cells in the CNS can be infected. Ongoing rounds of viral infection occur, within the periphery and the CNS. Consequently, there can be a continuous influx of peripheral virus into the CNS. The presence of virus and viral proteins, release of cytokines and neurotoxic factors might cause neuronal damage and contribute to the development of HIV‐associated neurocognitive disorder (HAND). (B) Virally suppressed PWH: In suppressed PWH, CNS‐penetrating ART can pass the blood–brain barrier. These might cause oxidative stress, which might contributing to neuronal damage in these individuals. Cells in the periphery and CNS can be infected from before the start of therapy, but there are no rounds of ongoing infection. Nevertheless, these infected cells can still produce virus, cytokines, or can be intermittently activated, possibly also contributing to neuronal injury. Created with Biorender.com.

FIGURE 2

HIV latency regulation in periphery and its differences within the CNS. (A) Latency of HIV: The presence of transcription repression factors and inhibitory epigenetic around the HIV integration site and LTR prevent the transcription of HIV. Tat is not transcribed, which is needed for full‐length HIV transcription. (B) Differences in regulation of HIV transcription in the CNS: Within the CNS multiple factors within transcription regulation are differently regulated compared with the general situation in the periphery. Factors of which it is reported that they are altered in the CNS are outlined with a dashed orange line. Polymorphisms in the LTR and the Tat gene cause an altered binding of transcription factors and a different function of Tat. Moreover, within brain target cells, unique isoforms and levels of C/EBP, SP1, SP3, COUP, and TRBP alter their transcriptional activity. At last, within brain target cells, increased levels of transcription repression factors are observed, which repress transcription by blocking TF binding sites or establishing epigenetic modifications. Created with Biorender.com. HDAC, histone deacetylase; CTIP2, COUP‐TF interacting protein; HIC1, hypermethylated in Cancer 1; LSD1, lysine specific demethylase; HP1,  heterochromatin protein 1; HMAG1, high mobility group AT‐hook 1; AP1, activator protein 1; C/EBP, CCAAT enhancer binding protein; COUP, chicken ovalbumin upstream promotor; SP1, specificity protein 1; LTR, long terminal repeat; RNA Pol II, RNA Polymera se II; TF, transcription factor; Tat, transactivator of transcription; TAR, transactivation response element; TRPB, TAR binding proteins; NELF, Negative Elongation Factor; DSIF, DRB‐sensitivity inducing factor

FIGURE 3

The different classes of LRAs and compounds that are tested for their efficacy in culture models CNS cells or CNS quasispecies. Latency reversal agents (LRAs) can be divided within 5 classes, based on their working mechanisms. Within each of these classes, subclasses are defined. Within the figure, the LRAs that have been tested on CNS culture models or CNS viral quasispecies are indicated. Created with Biorender.com.