Share this article on:

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: 1 February 2011 - Volume 56 - Issue 2 - pp 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.

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: mark_brockman@sfu.ca).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions this article on the journal's Web site (www.jaids.com).

© 2011 Lippincott Williams & Wilkins, Inc.