Neural progenitor cells act as HIV reservoirs

The cells which give rise to neurons and other nervous system cells could provide a sanctuary for HIV, according to research published in the November edition of AIDS. These neural progenitor cells could contribute to the reservoir of HIV found in the brain.

HIV can reside in the brain for many years. Although HIV replication is most readily apparent in brain macrophages and microglial cells, which act as the brain’s immune system, HIV markers have also been identified in other cell types in the brain, particularly astrocytes (a support cell).

Astrocytes are known to tolerate long-term HIV infection but the potential of other neural cell types to harbour HIV is unclear. In this study, researchers form GSF (Germany’s National Research Centre for Environment and Health) asked whether neural progenitor cells could be sites of HIV persistence and reservoirs for replication-competent virus in the brain.

Neural progenitor cells develop from neural stem cells which are self-renewing cells capable of generating many neural cell types. Once formed, neural progenitor cells can commit to more restricted cell lineages – they can become astrocytes for example.

Cultures of neural progenitor cells were exposed to HIV to determine if the virus can establish a chronic infection and to examine the potential effects of chronic infection on these cells. Comparisons were made with astrocyte cultures, also exposed to HIV.

HIV replication was monitored by quantifying release of Gag antigen (this is a sensitive parameter frequently used to investigate HIV infection of brain cells). Nine days after exposure to HIV-1, both progenitor and astrocyte cultures released Gag, demonstrating HIV infection. At 13 and 17 days after infection, Gag release was detected only for progenitor cultures.

Quantitative real-time polymerase chain reaction (PCR) analysis found similar quantities of HIV proviral DNA in progenitor and astrocyte populations 28 days after HIV infection (982 and 1182 proviral copies/10⁴ cells, respectively).

Prolonged monitoring revealed that HIV-infected progenitor populations continued to release detectable amounts of Gag antigen for over 60 days. Furthermore, the presence of HIV proviral DNA was confirmed at 96 and 115 days after infection, indicating that HIV DNA can persist in these progenitor cells for long periods.

The study also provided evidence that persistence of HIV can influence biological properties of progenitor populations. After HIV infection, cultured neural progenitor cells showed an upregulated production of glial fibrillary acidic protein (GFAP) and phenotypical changes. Upregulated production of GFAP is a hallmark of reactive astrocytes in response to HIV infection, suggesting similarities in the responses of neural progenitor cells and more mature astrocytes to HIV.

The study authors suggest that the results indicate persistence and sustained production of functional HIV in progenitor cell populations but point out that the results were seen in cultured cells rather than cells within the brain.

“This cell culture study supports the hypothesis that HIV can persist in neural progenitor populations, which can release the virus in different amounts depending on the extracellular environment and can undergo changes in response to HIV persistence. Owing to the manifold inherent difficulties of investigating HIV persistence in primary human brain tissues, it is still unclear at this stage to what extent this hypothesis reflects the in-vivo situation,” the researchers concluded.