Incomplete inhibition of HIV infection results in more HIV infected lymph node cells by reducing cell death

Laurelle Jackson; Jessica Hunter; Sandile Cele; Isabella Markham Ferreira; Andrew C. Young; Farina Karim; Rajhmun Madansein; Kaylesh J. Dullabh; Chih-Yuan Chen; Noel J. Buckels; Yashica Ganga; Khadija Khan; Mikael Boulle; Gila Lustig; Richard A. Neher; Alex Sigal

doi:10.7554/eLife.30134

Incomplete inhibition of HIV infection results in more HIV infected lymph node cells by reducing cell death

Laurelle Jackson, Jessica Hunter, Sandile Cele, Isabella Markham Ferreira, Andrew C. Young, Farina Karim, Rajhmun Madansein, Kaylesh J. Dullabh, Chih-Yuan Chen, Noel J. Buckels, Yashica Ganga, Khadija Khan, Mikael Boulle, Gila Lustig, Richard A. Neher, Alex Sigal

Research output: Contribution to journal › Article › peer-review

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Abstract

HIV has been reported to be cytotoxic in vitro and in lymph node infection models. Using a computational approach, we found that partial inhibition of transmissions of multiple virions per cell could lead to increased numbers of live infected cells. If the number of viral DNA copies remains above one after inhibition, then eliminating the surplus viral copies reduces cell death. Using a cell line, we observed increased numbers of live infected cells when infection was partially inhibited with the antiretroviral efavirenz or neutralizing antibody. We then used efavirenz at concentrations reported in lymph nodes to inhibit lymph node infection by partially resistant HIV mutants. We observed more live infected lymph node cells, but with fewer HIV DNA copies per cell, relative to no drug. Hence, counterintuitively, limited attenuation of HIV transmission per cell may increase live infected cell numbers in environments where the force of infection is high.

Original language	English
Article number	e30134
Number of pages	24
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.30134
Publication status	Published - 20 Mar 2018
Externally published	Yes

Keywords

cell-to-cell spread
computational and systems biology
HIV induced cell death
lymph node
multiple infections per cell
viral fitness

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.30134Licence: CC BY

Final published versionFinal published version, 1.62 MBLicence: CC BY

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Jackson, L., Hunter, J., Cele, S., Ferreira, I. M., Young, A. C., Karim, F., Madansein, R., Dullabh, K. J., Chen, C.-Y., Buckels, N. J., Ganga, Y., Khan, K., Boulle, M., Lustig, G., Neher, R. A., & Sigal, A. (2018). Incomplete inhibition of HIV infection results in more HIV infected lymph node cells by reducing cell death. eLife, 7, Article e30134. https://doi.org/10.7554/eLife.30134

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title = "Incomplete inhibition of HIV infection results in more HIV infected lymph node cells by reducing cell death",

abstract = "HIV has been reported to be cytotoxic in vitro and in lymph node infection models. Using a computational approach, we found that partial inhibition of transmissions of multiple virions per cell could lead to increased numbers of live infected cells. If the number of viral DNA copies remains above one after inhibition, then eliminating the surplus viral copies reduces cell death. Using a cell line, we observed increased numbers of live infected cells when infection was partially inhibited with the antiretroviral efavirenz or neutralizing antibody. We then used efavirenz at concentrations reported in lymph nodes to inhibit lymph node infection by partially resistant HIV mutants. We observed more live infected lymph node cells, but with fewer HIV DNA copies per cell, relative to no drug. Hence, counterintuitively, limited attenuation of HIV transmission per cell may increase live infected cell numbers in environments where the force of infection is high.",

keywords = "cell-to-cell spread, computational and systems biology, HIV induced cell death, lymph node, multiple infections per cell, viral fitness",

author = "Laurelle Jackson and Jessica Hunter and Sandile Cele and Ferreira, {Isabella Markham} and Young, {Andrew C.} and Farina Karim and Rajhmun Madansein and Dullabh, {Kaylesh J.} and Chih-Yuan Chen and Buckels, {Noel J.} and Yashica Ganga and Khadija Khan and Mikael Boulle and Gila Lustig and Neher, {Richard A.} and Alex Sigal",

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AU - Jackson, Laurelle

AU - Hunter, Jessica

AU - Cele, Sandile

AU - Ferreira, Isabella Markham

AU - Young, Andrew C.

AU - Karim, Farina

AU - Madansein, Rajhmun

AU - Dullabh, Kaylesh J.

AU - Chen, Chih-Yuan

AU - Buckels, Noel J.

AU - Ganga, Yashica

AU - Khan, Khadija

AU - Boulle, Mikael

AU - Lustig, Gila

AU - Neher, Richard A.

AU - Sigal, Alex

PY - 2018/3/20

Y1 - 2018/3/20

N2 - HIV has been reported to be cytotoxic in vitro and in lymph node infection models. Using a computational approach, we found that partial inhibition of transmissions of multiple virions per cell could lead to increased numbers of live infected cells. If the number of viral DNA copies remains above one after inhibition, then eliminating the surplus viral copies reduces cell death. Using a cell line, we observed increased numbers of live infected cells when infection was partially inhibited with the antiretroviral efavirenz or neutralizing antibody. We then used efavirenz at concentrations reported in lymph nodes to inhibit lymph node infection by partially resistant HIV mutants. We observed more live infected lymph node cells, but with fewer HIV DNA copies per cell, relative to no drug. Hence, counterintuitively, limited attenuation of HIV transmission per cell may increase live infected cell numbers in environments where the force of infection is high.

AB - HIV has been reported to be cytotoxic in vitro and in lymph node infection models. Using a computational approach, we found that partial inhibition of transmissions of multiple virions per cell could lead to increased numbers of live infected cells. If the number of viral DNA copies remains above one after inhibition, then eliminating the surplus viral copies reduces cell death. Using a cell line, we observed increased numbers of live infected cells when infection was partially inhibited with the antiretroviral efavirenz or neutralizing antibody. We then used efavirenz at concentrations reported in lymph nodes to inhibit lymph node infection by partially resistant HIV mutants. We observed more live infected lymph node cells, but with fewer HIV DNA copies per cell, relative to no drug. Hence, counterintuitively, limited attenuation of HIV transmission per cell may increase live infected cell numbers in environments where the force of infection is high.

KW - cell-to-cell spread

KW - computational and systems biology

KW - HIV induced cell death

KW - lymph node

KW - multiple infections per cell

KW - viral fitness

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VL - 7

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Incomplete inhibition of HIV infection results in more HIV infected lymph node cells by reducing cell death

Abstract

Keywords

UN SDGs

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