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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy
Nature, Volume 477, No. 7362, Year 2011
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Description
Latency and ongoing replication have both been proposed to explain the drug-insensitive human immunodeficiency virus (HIV) reservoir maintained during antiretroviral therapy. Here we explore a novel mechanism for ongoing HIV replication in the face of antiretroviral drugs. We propose a model whereby multiple infections per cell lead to reduced sensitivity to drugs without requiring drug-resistant mutations, and experimentally validate the model using multiple infections per cell by cell-free HIV in the presence of the drug tenofovir. We then examine the drug sensitivity of cell-to-cell spread of HIV, a mode of HIV transmission that can lead to multiple infection events per target cell. Infections originating from cell-free virus decrease strongly in the presence of antiretrovirals tenofovir and efavirenz whereas infections involving cell-to-cell spread are markedly less sensitive to the drugs. The reduction in sensitivity is sufficient to keep multiple rounds of infection from terminating in the presence of drugs. We examine replication from cell-to-cell spread in the presence of clinical drug concentrations using a stochastic infection model and find that replication is intermittent, without substantial accumulation of mutations. If cell-to-cell spread has the same properties in vivo, it may have adverse consequences for the immune system, lead to therapy failure in individuals with risk factors, and potentially contribute to viral persistence and hence be a barrier to curing HIV infection. © 2011 Macmillan Publishers Limited. All rights reserved.
Authors & Co-Authors
Sigal, Alex
United States, Pasadena
California Institute of Technology
Kim, Jocelyn Tammy
United States, Pasadena
California Institute of Technology
United States, Los Angeles
University of California, Los Angeles
Balazs, Alejandro Benjamin
United States, Pasadena
California Institute of Technology
Milo, Ron
Israel, Rehovot
Weizmann Institute of Science Israel
Baltimore, David
United States, Pasadena
California Institute of Technology
Statistics
Citations: 411
Authors: 5
Affiliations: 3
Identifiers
Doi:
10.1038/nature10347
ISSN:
14764687
Research Areas
Infectious Diseases