Cell-based transmission of HIV is far more efficient than the transfer of cell-free virus, and is likely to play a prominent role in HIV transmission when infected cells enter the bloodstream, as can occur during the intravenous injection of drugs by substance abusers. This may complicate vaccination efforts, because cell-based transmission allows HIV to evade neutralizing antibodies. An understanding of the molecular mechanisms underlying cell-to-cell transmission thus appears particularly relevant for the prevention of HIV transmission among drug abusers. We have identified the host proteins kindlin-3 and pacsin2 as novel binding partners HIV-1 Gag. Both proteins are dispensable for the completion of a full replication cycle after infection with cell-free virus. Nevertheless, both are essential for the spreading of HIV-1 among T cells, indicating that kindlin-3 and pacsin2 are critical for the cell-to-cell transmissionof HIV-1. Kindlin-3 is required for the function of integrins such as LFA-1, which has been implicated in HIV transmission. However, our data demonstrate a striking requirement for kindlin-3 for HIV-1 replication even in T lymphoid cells lacking LFA-1. Our working model is that HIV-1 Gag mimics the kindlin-recruiting activity of integrins to induce donor cell polarization towards the virological synapse and thereby promote virus transfer. Pacsin2 can generate membrane curvature and nucleate filopodia formation. HIV-1 frequently buds from filopodia, and viral filopodia capped by Gag have been implicated in HIV-1 cell-cell transmission. Thus, pacsin2 may be important for HIV-1 transmission because it is involved in viral filopodia formation. The goal of the project is to understand the roles of kindlin-3 and pacsin2, and of the cellular pathways in which these proteins are known to function, in the spreading of HIV-1. We also propose to investigate whether these pathways are altered among a cohort of elite controllers that includes drug abusers. The planned research may yield important translational insights into how to reduce HIV transmission among drug abusers.

Public Health Relevance

The transfer of HIV from cell to cell is thought to play a prominent role in HIV transmission when infected cells enter the bloodstream, as can occur during the intravenous injection of drugs by substance abusers. The goal of the project is to understand the roles of specific host proteins that are taken up into virions in the cell-based transmission of HIV-1. The planned research may yield important translational insights into how to reduce HIV transmission among drug abusers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
1DP1DA038034-01
Application #
8762797
Study Section
Special Emphasis Panel (ZDA1-SXC-E (04))
Program Officer
Satterlee, John S
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$836,875
Indirect Cost
$336,875
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655