Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 477:95–98

Latency and ongoing replication 1 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 2,3 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 4-7 , a mode of HIV transmission that can lead to multiple infection events per target cell Current antiretroviral therapy (ART) does not cure HIV infection because low-level viraemia persists from virus reservoirs that are insensitive to ART 1 . The reservoirs may be long-lived infected cells, cells with latent virus, ongoing cycles of infection termed ongoing replication, or a combination of sources 1 . How ongoing replication might take place in the face of ART has remained unclear. If ART succeeds in decreasing ongoing HIV replication to very low levels, why does it not eliminate replication completely? Here we explore a novel mechanism for ongoing HIV replication in the presence of ART. Multiple infections of one cell may propagate at drug concentrations where infection by single particles would die out: if more virions are transmitted per cell, the probability that at least one of the virions escapes the drug should increase T X has two important limiting regimes: m = 1, in which case T X < 1/f(d) and m/f(d) ? 1, in which case T X < 1. In the first case, where few viruses infect each cell, the infection is sensitive to the effect of the drug, whereas in the second, where many viruses infect each cell, the infection is insensitive. To test this, we infected the highly infection-permissive MT-4 T-cell line with cell-free HIV encoding yellow fluorescence protein (YFP) 15 at low (0.2) and high (100) m in the presence of tenofovir (TFV), a nucleotide reverse transcriptase inhibitor. We determined infected cell number by YFP fluorescence Multiple infections occur in vivo 2,16 and in cultur