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Reduced Replication Capacity of NL4-3 Recombinant Viruses Encoding Reverse Transcriptase–Integrase Sequences From HIV-1 Elite Controllers

Brumme, Zabrina L PhD*†‡; Li, Chun BSc‡§; Miura, Toshiyuki MD‡‖; Sela, Jennifer BSc; Rosato, Pamela C BSc; Brumme, Chanson J BSc†‡; Markle, Tristan J BSc*; Martin, Eric BSc*§§; Block, Brian L BSc; Trocha, Alicja DVM; Kadie, Carl M PhD; Allen, Todd M PhD; Pereyra, Florencia MD; Heckerman, David MD, PhD; Walker, Bruce D MD‡#; Brockman, Mark A PhD*§§†‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: February 1st, 2011 - Volume 56 - Issue 2 - p 100-108
doi: 10.1097/QAI.0b013e3181fe9450
Basic and Translational Science

Background: Identifying viral and host determinants of HIV-1 elite control may help inform novel therapeutic and/or vaccination strategies. Previously, we observed decreased replication capacity in controller-derived viruses suggesting that fitness consequences of human leukocyte antigen (HLA) class I-associated escape mutations in Gag may contribute to this phenotype. This study examines whether similar functional defects occur in Pol proteins of elite controllers.

Methods: Recombinant NL4-3 viruses encoding plasma RNA-derived reverse transcriptase-integrase sequences from 58 elite controllers and 50 untreated chronic progressors were constructed, and replication capacity measured in vitro using a green fluorescent protein (GFP) reporter T-cell assay. Sequences were analyzed for drug resistance and HLA-associated viral polymorphisms.

Results: Controller-derived viruses displayed significantly lower replication capacity compared with those from progressors (P < 0.0001). Among controllers, the most attenuated viruses were generated from individuals expressing HLA-B*57 or B*51. In viruses from B*57+ progressors (n = 8), a significant inverse correlation was observed between B*57-associated reverse transcriptase-integrase escape mutations and replication capacity (R = −0.89; P = 0.003); a similar trend was observed in B*57+ controller-derived viruses (n = 20, R = −0.36; P = 0.08).

Conclusions: HIV-1 Pol function seemed to be compromised in elite controllers. As observed previously for Gag, HLA-associated immune pressure in Pol may contribute to viral attenuation and subsequent control of viremia.

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From the *Faculty of Health Sciences and §§Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby BC, Canada; †British Columbia Centre for Excellence in HIV/AIDS, Vancouver BC, Canada; ‡Ragon Institute of MGH, MIT, and Harvard, Boston, MA; §Program of Biological Sciences in Dental Medicine, Harvard University, Cambridge, MA; ∥Division of Infectious Diseases Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; ¶Microsoft Research, Redmond WA; and #Howard Hughes Medical Institute, Chevy Chase, MD.

Received for publication January 5, 2010; accepted September 23, 2010.

Supported in part by grants AI028568 and AI030914 from the NIAID-NIH, the Howard Hughes Medical Institute, the Harvard University Center for AIDS Research, the Bill and Melinda Gates Foundation, and a gift from the Mark and Lisa Schwartz Foundation (to B.D.W.), and an Operating Grant from the Canadian Institutes of Health Research (CIHR) and a Jim Gray Seed Grant from Microsoft Research (to M.A.B. and Z.L.B.). Z.L.B. is supported by a CIHR New Investigator Award. C.J.B. is supported by a NSERC Julie Payette Scholarship.

Presented in part as: Li C, Brumme ZL, Miura T, Rosato P, Sela J, Brumme CJ, Heckerman D, Pereyra F, Walker BD, Brockman MA. Reduced replication capacity of NL4-3 chimeric viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers. AIDS Vaccine. 2009. Abstract P09-11.

The authors Z.L.B., C.L. contributed equally.

The authors declare no conflicts of interest related to this study.

Correspondence to: Mark A. Brockman, PhD, Associate Professor, Molecular Biology and Biochemistry, Simon Fraser University, South Sciences Building, Room 7153, 8888 University Drive, Burnaby, BC, Canada V5A 1S6 (e-mail:

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