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Review
. 2023 Dec;20(6):357-367.
doi: 10.1007/s11904-023-00675-9. Epub 2023 Nov 10.

Genomic Exploration of the Brain in People Infected with HIV-Recent Progress and the Road Ahead

Amara Plaza-Jennings  1   2 , Schahram Akbarian  3   4   5
Affiliations
Review

Genomic Exploration of the Brain in People Infected with HIV-Recent Progress and the Road Ahead

Amara Plaza-Jennings et al. Curr HIV/AIDS Rep. 2023 Dec.

Abstract

Purpose of review: The adult human brain harbors billions of microglia and other myeloid and lymphoid cells highly susceptible to HIV infection and retroviral insertion into the nuclear DNA. HIV infection of the brain is important because the brain is a potentially large reservoir site that may be a barrier to HIV cure strategies and because infection can lead to the development of HIV-associated neurocognitive disorder. To better understand both the central nervous system (CNS) reservoir and how it can cause neurologic dysfunction, novel genomic, epigenomic, transcriptomic, and proteomic approaches need to be employed. Several characteristics of the reservoir are important to learn, including where the virus integrates, whether integrated proviruses are intact or defective, whether integrated proviruses can be reactivated from a latent state to seed ongoing infection, and how this all impacts brain function.

Recent findings: Here, we discuss similarities and differences of viral integration sites between brain and blood and discuss evidence for and against the hypothesis that in the absence of susceptible T-lymphocytes in the periphery, the virus housing in the infected brain is not able to sustain a systemic infection. Moreover, microglia from HIV + brains across a wide range of disease severity appear to share one type of common alteration, which is defined by downregulated expression, and repressive chromosomal compartmentalization, for microglial genes regulating synaptic connectivity. Therefore, viral infection of the brain, including in immunocompetent cases with near-normal levels of CD4 blood lymphocytes, could be associated with an early disruption in microglia-dependent neuronal support functions, contributing to cognitive and neurological deficits in people living with HIV.

Keywords: HAND; HIV-associated Neurocognitive Disorders; Human Brain; Microglia-neuronal Interactions; Neurogenomics of HIV; Postmortem.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A Current understanding of the CNS as a reservoir site. Both microglia and T-cells, which migrated from the periphery are infected in the brain. CNS-resident T-cells have been shown to reactivate and produce virus upon treatment interruption. It is still unknown whether microglia harbor latent replication-competent virus which can reactivate. It is also unknown whether viral reactivation in the CNS can seed ongoing peripheral infection. B Current understanding of changes in gene expression contributing to HAND. Microglia are infected, and this can lead to downregulation of microglial genes with a role in neuronal support, including synaptic function. It is unclear how infection impacts astrocytes or oligodendrocytes and how all of these changes together cause HAND. C Schematic of microglia interacting with the neuronal synapse. Genes involved in neuronal support that are dysregulated in microglia in HIV infection [23] are indicated
Fig. 2
Fig. 2
HIV integration site mapping in the brain vs. T-cells. A Integration site selection in the brain and in T-cells. In T-cells, CPSF6 and LEDGF guide integration site selection, but this has not yet been shown in microglia. Integration sites are found predominately in intergenic regions, promoter (P) proximal regions, and introns. Very few are found in exons (E). Relative frequencies of integration events into different genomic features are demonstrated by the thickness of the arrows. B Clonal integration sites, from the replication of an infected cell, are found at similar frequencies in the brain and in T-cells. C Recurrent integration sites, or two independent integration events into the same gene, are more common in T-cells than in the brain
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