Background In patients infected with human immunodeficiencyvirus type 1 (HIV-1), combination antiretroviral therapy canresult in sustained suppression of plasma levels of the virus.However, replication-competent virus can still be recoveredfrom latently infected resting memory CD4 lymphocytes; thisfinding raises serious doubts about whether antiviral treatmentcan eradicate HIV-1.
Methods We looked for evidence of residual HIV-1 replicationin eight patients who began treatment soon after infection andin whom plasma levels of HIV-1 RNA were undetectable after twoto three years of antiretroviral therapy. We examined whetherthere had been changes over time in HIV-1 proviral sequencesin peripheral-blood mononuclear cells, which would indicateresidual viral replication. We also performed in situ hybridizationstudies on tissues from one patient to identify cells activelyexpressing HIV-1 RNA. We estimated the rate of decrease of latent,replication-competent HIV-1 in resting CD4 lymphocytes on thebasis of the decrease in the numbers of proviral sequences identifiedduring primary infection and direct sequential measurementsof the size of the latent reservoir.
Results Six of the eight patients had no significant variationsin proviral sequences during treatment. However, in two patientsthere was sequence evolution but no evidence of drug-resistantviral genotypes. In one patient, extensive in situ studies providedadditional evidence of persistent viral replication in lymphoidtissues. Using two independent approaches, we estimated thatthe half-life of the latent, replication-competent virus inresting CD4 lymphocytes was approximately six months.
Conclusions These findings suggest that combination antiretroviralregimens suppress HIV-1 replication in some but not all patients.Given the half-life of latently infected CD4 lymphocytes ofabout six months, it may require many years of effective antiretroviraltreatment to eliminate this reservoir of HIV-1.
Source Information
From the Aaron Diamond AIDS Research Center, Rockefeller University, New York (L.Z., B.R., Y.H., M.V., S.L., A.T., M.M., D.D.H.); Bernhard-Nocht-Institut fur Tropenmedizin, Hamburg, Germany (K.T.-R., P.R.); and the Theoretical Division, Los Alamos National Laboratory, Los Alamos, N.M. (A.S.P., B.T.K.). Other authors were Yong Guo, M.Sc., Margarita Duran, M.Sc., Arlene Hurley, R.N., John Tsay, B.Sc., Yu-Ching Huang, B.Sc., and Chia-Ching Wang, B.Sc. (Aaron Diamond AIDS Research Center, Rockefeller University, New York).
Address reprint requests to Dr. Ho at the Aaron Diamond AIDS Research Center, 455 First Ave., New York, NY 10016, or at dho{at}adarc.org.
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