HIV Cell-to-Cell Spread Results in Earlier Onset of Viral Gene Expression by Multiple Infections per Cell.
Cell-to-cell spread of HIV, a directed mode of viral transmission, has been observed to be more rapid than cell-free infection. However, a mechanism for earlier onset of viral gene expression in cell-to-cell spread was previously uncharacterized. Here we used time-lapse microscopy combined with automated image analysis to quantify the timing of the onset of HIV gene expression in a fluorescent reporter cell line, as well as single cell staining for infection over time in primary cells. We compared cell-to-cell spread of HIV to cell-free infection, and limited both types of transmission to a two-hour window to minimize differences due to virus transit time to the cell. The mean time to detectable onset of viral gene expression in cell-to-cell spread was accelerated by 19% in the reporter cell line and by 35% in peripheral blood mononuclear cells relative to cell-free HIV infection. Neither factors secreted by infected cells, nor contact with infected cells in the absence of transmission, detectably changed onset. We recapitulated the earlier onset by infecting with multiple cell-free viruses per cell. Surprisingly, the acceleration in onset of viral gene expression was not explained by cooperativity between infecting virions. Instead, more rapid onset was consistent with a model where the fastest expressing virus out of the infecting virus pool sets the time for infection independently of the other co-infecting viruses.
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.|University of KwaZulu-Natal, Durban, South Africa.|Charité Medical School, Berlin, Germany.
Mikaël
M
Boullé
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
Thorsten G
TG
Müller
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
Sabrina
S
Dähling
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
Yashica
http://orcid.org/0000-0001-8330-2853
Y
Ganga
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
Laurelle
L
Jackson
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
Deeqa
D
Mahamed
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.|University of KwaZulu-Natal, Durban, South Africa.
Lance
L
Oom
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.
Gila
G
Lustig
Max Planck Institute for Developmental Biology, Tübingen, Germany.
Richard A
http://orcid.org/0000-0003-2525-1407
RA
Neher
KwaZulu-Natal Research Institute for TB-HIV (K-RITH), Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.|University of KwaZulu-Natal, Durban, South Africa.
Alex
http://orcid.org/0000-0001-8571-2004
A
Sigal
D002478:Cells, Cultured; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics* / Q000635:transmission* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D059008:Time-Lapse Imaging