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Transmitted Multidrug-Resistant HIV Persists in PBMC DNA for Years
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Mark Mascolini
XVIII International Drug Resistance Workshop, June 9-13, 2009, Fort Myers, Florida
When acquired during primary infection, HIV resistant to the first 3 antiretroviral classes may persist for years in peripheral blood mononuclear cell (PBMC) DNA, according to results of a 5-person substudy [1] in the French PRIMO cohort [2]. Viral coreceptor use also remained unchanged after primary infection in these people.
Jade Ghosn (Universite Paris Descartes) and colleagues genotyped HIV and determined coreceptor use in plasma HIV RNA and in HIV DNA extracted from PBMCs of 5 people infected with triple-class-resistant virus and monitored for at least 18 months. After testing primary infection samples, the investigators repeated the analyses at 6 or 12 months, then every 12 months. They defined triple-class resistance as mutations conferring resistance to at least one drug in the first three antiretroviral classes. Ghosn and colleagues determined viral coreceptor use in cellular DNA by a combination of five genotype-based algorithms.
Five people infected between 1996 and 2006 had virus with the following coreceptor preferences and primary resistance mutations in reverse transcriptase (RT) and protease (PRO):
· Patient A: CXCR4; RT 41L, 103N, 118I, 210W, 215Y; PRO 63P, 90M
· Patient B: CCR5; RT 67N, 69N, 70R, 103N, 108I, 116Y, 151M, 184V, 215V, 219Q; PRO 10F, 36I, 46I, 82A
· Patient C: CXCR4; RT 41L, 67N, 69D, 74V, 115F, 118I, 179V, 184V, I88L, 210W, 215F; PRO 10V, 20R, 32I, 33F, 36L, 46I, 47A, 62I, 63P, 71V, 82A, 90M
· Patient D: CXCR4; RT 67N, 69N, 70R, 118I, 181C, 215F, 219Q; PRO 10I, 20R, 36I, 54V, 82A, 90M
· Patient E: CCR5; RT 67N, 69D, 70R, 103N, 184V, 219Q, 225H; PRO 10I, 36I, 46L, 53L, 54V, 63P, 71V, 82A
Patient A began successful therapy 30 months after infection, yet all resistance mutations persisted in PBMC DNA for 78 months (6.5 years), except for K103N, which reverted to wild-type at month 60. Use of the CXCR4 coreceptor remained unchanged in viral DNA to month 78.
Patient B began successful therapy and at month 6 genotyping could not be performed in plasma. This patient's mutation pattern remained unchanged in PBMC DNA through 2 years of follow-up, and the virus continued using CCR5.
Patient C began successful therapy but had an essentially unchanged mutation pattern in PBMC DNA for 12 months.
Patient D began treatment soon after diagnosis, and HIV RNA fell to undetectable levels within 6 months. Resistance mutations persisted in HIV DNA and virus remained X4 through 84 months of follow-up.
Patient E kept the same mutation pattern in HIV RNA and DNA for 36 months after infection, except for the M184V mutation, which reverted to wild-type in HIV RNA at month 12. But M184V persisted in HIV DNA throughout 36 months of follow-up. Coreceptor use did not change from CCR5 in HIV RNA or DNA through month 36.
Overall, multidrug-resistant virus persisted in these 5 people for a median of 78 months. Ghosn and colleagues proposed that persistence of coreceptor preference in RNA and DNA indicate early expansion of a monoclonal viral population.
References
1. Ghosn J, Galimand J, Meyer L, et al. Long-term persistence of resistance mutational pattern and evolution of HIV-tropism in blood plasma and in infected cells of patients who acquired a multidrug-resistant HIV-1 strain at the time of primary infection. XVIII International Drug Resistance Workshop. June 9-13, 2009. Fort Myers, Florida. Abstract 86.
2. Chaix ML, Descamps D, Wirden M, et al. Stable frequency of HIV-1 transmitted drug resistance in patients at the time of primary infection over 1996-2006 in France. AIDS. 2009;23:717-724.
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