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IAS 2015: Altered Cholesterol Metabolism May Protect Immune Cells of Non-Progressors

Enhanced cholesterol metabolism in certain immune cells may help explain why some people with HIV can naturally control the virus with little or no disease progression, according to research presented at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention and at the preceding IAS Towards an HIV Cure Symposium last month in Vancouver. The findings suggest that regulating cellular cholesterol metabolism may offer a new approach to controlling HIV and potentially achieving a functional cure, or long-term remission.

Giovanna Rappocciolo from the University of Pittsburgh and colleagues performed a laboratory analysis comparing antigen-presenting cells -- dendritic cells and B-cells that capture invading virus and display it for recognition by T-cells -- from HIV-positive people with typical disease progression and from non-progressors, or people whose disease does not progress for years even without antiretroviral therapy.

The researchers previously reported that professional antigen-presenting cells from non-progressors are inefficient at trans infection, or transferring intact virus to T-cells. Antigen-presenting cells from non-progressors showed impaired trans infection both before and after primary HIV infection, while cells from progressors showed normal trans infection. They hypothesized that the difference likely had a genetic basis.

In a poster presented atIAS, Rappocciolo and colleagues reported that a genetic analysis showed that this impaired trans infection appears to be due to enhanced cholesterol metabolism within non-progressors’ antigen-presenting cells, which leaves them with lower cholesterol levels.

Specifically, they performed a whole genome transcription analysis on dendritic cells, B-cells, and CD4 T-cells from 8 non-progressorsand 8 typical progressors in the Multicenter AIDS Cohort Study(MACS) -- a long-term study of the natural history of untreated and treated HIV/AIDS in men who have sex with men -- looking for differences inexpression of genes related to cholesterol metabolism.

They found that antigen-presenting cells from non-progressorsover-expressed several genes related to cholesterol metabolism pathways compared to typical progressors.

"We have shown that antigen-presenting cells from non-progressorscompletely lack the ability to trans infect T-cells," the researchers concluded. "This was associated with profoundly enhanced cholesterol metabolism that appears to be an inherited trait, and we have identified genes involved in the uptake, trafficking, and metabolism of cholesterol that are associated with the phenotype of defective trans infection."

These results, they added, "provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism."

8/12/15

Reference

G Rappocciolo, J Martinson, P Piazza, et al. Profound alterations in cholesterol metabolism restrict HIV-1 trans infection of CD4 T cells in nonprogressors. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract MOPEA013.

Other Source

National Institute of Allergy and Infectious Diseases. Cholesterol Metabolism in Immune Cells Linked to HIV Progression. Press release. July 17, 2015.