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Resistance Mutations Persist in HIV DNA
After 12 Years With Undetectable Viral Load
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20th International AIDS Conference, July 20-25, 2014, Melbourne
Mark Mascolini
An array of resistance mutations acquired early in an 18-year course of antiretroviral therapy (ART) persisted in proviral DNA for the 12 years in which this patient has maintained an undetectable viral load in plasma [1]. The finding underscores the tenacity of resistant virus and the risk inherent in suspending ART.
Because of reports that antiretroviral resistance mutations linger in proviral DNA ensconced in peripheral blood mononuclear cells (PBMCs) of people with an undetectable viral load, virologists in Osaka's public health department analyzed PBMC samples from a man treated since 1996 to determine how long those mutations persist and whether the mutation mix changes over time. After HIV enters a cell, its RNA gets reverse transcribed to DNA, and that DNA survives in cells that enter a resting state to make up one of the so-called reservoirs that remain impervious to ART.
The Osaka investigators extracted proviral DNA from PBMCs stored over the course of this man's infection and measured it with the TaqMan real-time PCR assay. To identify resistance mutations in DNA, they used single-genome sequencing of HIV's pol region on at least 15 clones of proviral DNA at each assessment.
The patient began treatment in 1996 with zidovudine/lamivudine and inevitably acquired related resistance mutations. Later that year his clinicians switched nucleosides to stavudine/zalcitabine and added the protease inhibitor (PI) indinavir. PI-related mutations arose. In 1997 physicians swapped indinavir for nelfinavir and traded zalcitabine for didanosine. More mutations piled up. Not until 2002 did they construct a suppressive regimen, and the man's viral load remained undetectable over the ensuing 12 years.
Levels of detectable proviral DNA slowly dwindled from 156 copies per million PBMCs in 1995, before the man began treatment, to 13 copies in 2014, after a dozen years of sustained viral suppression. In 2001, a year before the patient switched to a suppressive regimen, resistant viral variants made up about 90% of virus in proviral DNA clones. Within 7 years of viral suppression, the proportion of resistant variants in proviral DNA clones dropped to 16%. But resistant clones remained detectable at about that level through the latest sample in 2014. In this period of full viral suppression in plasma, shifting resistance patterns could be detected in proviral DNA. The lamivudine-associated M184V mutation, for example, mingled with other mutations 18 years after the patient stopped taking lamivudine.
The researchers also reported that the "vast majority" of nonmutant clones examined during the period of complete viral suppression were genetically similar and clustered in one phylogenetic group "with almost no diversity."
The Osaka team suggested that persistence of resistance mutations in proviral DNA through 12 years of suppressive ART suggests that low-level replication of resistant virus continues despite viral control in plasma. But the genetic similarity of nonmutant virus over this time, they surmised, suggests that wild-type virus does not replicate during full suppression. The investigators proposed that "more potent and/or novel therapeutic strategies targeting the drug-resistant provirus may be necessary to achieve viral eradication."
Reference
1. Mori H, Kojima Y, Kawahata T. Drug resistance mutations persist in HIV-1 proviral DNA despite 12-years of successful viral suppression. 20th International AIDS Conference. July 20-25, 2014. Melbourne. Abstract MOPE046.
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