The CNS acts as a reservoir for inactive HIV

When people with HIV take antiviral therapy (ART), their viral load is so low that standard blood tests cannot detect the virus. However, once ART is stopped, detectable HIV reappears as new cells are infected. This is called “rebound” virus, and the cells that release the virus to reignite the infection come from a small population of HIV-infected CD4+ T cells that remain dormant in the blood and lymph tissue while people are on ART.

It’s a problem called latency, and overcoming it is a major goal for researchers trying to create curative treatments for HIV — a particular focus of the UNC HIV Treatment Center.

Now, virologist Ron Swanstrom, PhD, director of the UNC Center for AIDS Research and Charles P. Distinguished Professor of Biochemistry and Biophysics at the UNC School of Medicine. Scientists led by Postel describe another layer of the challenge of HIV latency. and published his work in Nature Microbiology.

Swanstrom and colleagues, along with collaborators from UCSF, Yale, the University of Gothenburg in Sweden, and others, provide indirect evidence for the existence of a distinct latent pool of CD4+ T cells in the central nervous system (CNS). They achieved this by analyzing rebound virus in cerebral spinal fluid (CSF) during periods when people had just stopped taking ART.

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“Our analysis of rebound virus suggests that infected T cells hidden in the CNS are separate from latent reservoirs in the blood,” said Swanstrom, senior author of the study. “Our analysis allows us to infer the presence of a distinct pool of latently infected cells in the CNS waiting to restart infection after ART is interrupted.”

The researchers compared the genetic sequences of rebound virus particles when ART was discontinued in 11 human participants. This approach allowed scientists to assess similarities between viral populations in blood and CSF to determine whether they are part of a common latent reservoir. In many cases, the viral populations were not the same, suggesting that they may represent different populations of latently infected cells.

The researchers also studied the details of viral replication to determine whether the rebound virus was selected for replication in CD4+ T cells, the primary home of the virus, or evolved to replicate in central nervous system myeloid cells such as macrophages and microglia. All rebound viruses tested were adapted to grow in T cells. For many participants, researchers compared viral populations in blood and CSF before ART initiation and after ART discontinuation.

These experiments provide further evidence that HIV-infected CD4+ T cells can migrate from the blood into the CNS, but also that some latently infected cells can reside in the CNS during therapy. Any curative therapy requires activation of this dormant reservoir, as well as latent reservoirs in the blood and lymph tissue.

Reference: Kinser L, Joseph SB, Gillies MM, Sizemore S, Zhou S, Houser BM et al. Rebound virus in cerebrospinal fluid reveals a potential HIV-1 reservoir. Nat Microbiol. 2023. doi: 10.1038/s41564-022-01309-3

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