title: Multiploid inheritance of HIV-1 during cell-to-cell infection.
abstract: During cell-to-cell transmission of human immunodeficiency virus type 1 (HIV-1), many viral particles can be simultaneously transferred from infected to uninfected CD4 T cells through structures called virological synapses (VS). Here we directly examine how cell-free and cell-to-cell infections differ from infections initiated with cell-free virus in the number of genetic copies that are transmitted from one generation to the next, i.e., the genetic inheritance. Following exposure to HIV-1-expressing cells, we show that target cells with high viral uptake are much more likely to become infected. Using T cells that coexpress distinct fluorescent HIV-1 variants, we show that multiple copies of HIV-1 can be cotransmitted across a single VS. In contrast to cell-free HIV-1 infection, which titrates with Poisson statistics, the titration of cell-associated HIV-1 to low rates of overall infection generates a constant fraction of the newly infected cells that are cofluorescent. Triple infection was also readily detected when cells expressing three fluorescent viruses were used as donor cells. A computational model and a statistical model are presented to estimate the degree to which cofluorescence underestimates coinfection frequency. Lastly, direct detection of HIV-1 proviruses using fluorescence in situ hybridization confirmed that significantly more HIV-1 DNA copies are found in primary T cells infected with cell-associated virus than in those infected with cell-free virus. Together, the data suggest that multiploid inheritance is common during cell-to-cell HIV-1 infection. From this study, we suggest that cell-to-cell infection may explain the high copy numbers of proviruses found in infected cells in vivo and may provide a mechanism through which HIV preserves sequence heterogeneity in viral quasispecies through genetic complementation.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Immunology Institute, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1630, New York, NY 10029, USA.
authors.forename: Armando
authors.initials: A
authors.lastname: Del Portillo
authors.forename: Joseph
authors.initials: J
authors.lastname: Tripodi
authors.forename: Vesna
authors.initials: V
authors.lastname: Najfeld
authors.forename: Dominik
authors.initials: D
authors.lastname: Wodarz
authors.forename: David N
authors.initials: DN
authors.lastname: Levy
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Chen
mesh_terms: D002460:Cell Line; D005434:Flow Cytometry; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D011123:Polyploidy; D013601:T-Lymphocytes / Q000821:virology*