Despite the profound success of antiretroviral therapy (ART) in prolonging survival and improving quality of life in HIV-infected individuals, ART does not completely eliminate HIV or fully restore health. While scientists agree that HIV can persist silently in long-lived “latently infected” cells, there is debate about whether the viral reservoir can be replenished through ongoing viral replication. The strongest case against ongoing replication is that virus found in the blood of ART-treated patients does not evolve over time or develop drug-resistance mutations, as would be expected with the rapid rate of mutation that occurs during HIV replication.
In FY 2011, NIAID-supported researchers provided evidence for a novel mechanism to explain how ongoing HIV replication may occur in the face of antiviral drugs without developing drug-resistance mutations. Working with laboratory-grown cells, the researchers compared the ability of antiretroviral drugs to prevent cell-free transmission, in which a single virus particle infects a target cell, with cell-to-cell transmission—a mode of HIV transmission that can lead to multiple infection events per target cell.
Although clinical levels of drug were able to inhibit cell-free viral transmission, cell-to-cell spread occurred at a rate sufficient to maintain multiple rounds of infection even in the presence of maximal levels of drug. The investigators concluded that the large dose of virus that can occur in cell-to-cell spread decreases the likelihood that every transmitted virus will be inhibited by drugs. Using computational modeling, they further argued that this low-level replication can replenish the viral reservoir in the absence of significant viral mutation because it occurs in an intermittent and localized manner.
If cell-to-cell spread has the same properties in the human body, these findings could have important implications for developing new treatment strategies for HIV-infected individuals, as well as for efforts to develop a cure.
Sigal A, Kim JT, Balazs AB, Dekel E, Mayo A, Milo R, Baltimore D. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature. 2011 Aug 17;477(7362):95-8.
Last Updated December 28, 2012