Publication Date:
2011-08-19
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sigal, Alex -- Kim, Jocelyn T -- Balazs, Alejandro B -- Dekel, Erez -- Mayo, Avi -- Milo, Ron -- Baltimore, David -- HHSN266200500035C/PHS HHS/ -- T32 AI089398/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 17;477(7362):95-8. doi: 10.1038/nature10347.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21849975" target="_blank"〉PubMed〈/a〉
Keywords:
Adenine/analogs & derivatives/pharmacology
;
Anti-Retroviral Agents/*pharmacology
;
Cell Line
;
Drug Resistance, Viral/physiology
;
HEK293 Cells
;
HIV Infections/transmission/*virology
;
HIV-1/drug effects/*physiology
;
Humans
;
Models, Biological
;
Organophosphonates/pharmacology
;
Tenofovir
;
Virus Replication/drug effects/*physiology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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