Alterations in cholesterol metabolism restrict HIV-1 trans infection in nonprogressors

Authors:
Rappocciolo G, Jais M, Piazza P, Reinhart TA, Berendam SJ, Garcia-Exposito L, Gupta P, Rinaldo CR
In:
Source: mBio
Publication Date: (2014)
Issue: 5(3): 1-11
Research Area:
Immunotherapy / Hematology
Gene Expression
Cells used in publication:
B cell, human
Species: human
Tissue Origin: blood
Culture Media:
Platform:
4D-Nucleofector™ X-Unit
Experiment
activated human B cells (activation with rhIL-4 and CD40Lfor 24h ), P3 4D nucleofector X solution kit, transfection according to manufacturers instructions: 1x10e6 cells/20µl , program EO-117, Transfection efficiency was measured by transfection of pmaxGFP: 57.1%
Abstract
HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of professional antigen-presenting cells (APC), i.e., dendritic cells (DC) and B lymphocytes, from NP lacked the ability to mediate HIV-1 trans infection of CD4(+) T cells. In contrast, APC from HIV-1-infected progressors (PR) and HIV-1-seronegative donors (SN) were highly effective in mediating HIV-1 trans infection. Direct cis infection of T cells with HIV-1 was comparably efficient among NP, PR, and SN. Lack of HIV-1 trans infection in NP was linked to lower cholesterol levels and an increase in the levels of the reverse cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in APC but not in T cells. Moreover, trans infection mediated by APC from NP could be restored by reconstitution of cholesterol and by inhibiting ABCA1 by mRNA interference. Importantly, this appears to be an inherited trait, as it was evident in APC obtained from NP prior to their primary HIV-1 infection. The present study demonstrates a new mechanism wherein enhanced lipid metabolism in APC results in remarkable control of HIV-1 trans infection that directly relates to lack of HIV-1 disease progression. IMPORTANCE HIV-1 can be captured by antigen-presenting cells (APC) such as dendritic cells and transferred to CD4 helper T cells, which results in greatly enhanced viral replication by a mechanism termed trans infection. A small percentage of HIV-1-infected persons are able to control disease progression for many years without antiretroviral therapy. In our study, we linked this lack of disease progression to a profound inability of APC from these individuals to trans infect T cells. This effect was due to altered lipid metabolism in their APC, which appears to be an inherited trait. These results provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism.