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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3181fe9450
Basic and Translational Science

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*§§†‡

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Abstract

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.

© 2011 Lippincott Williams & Wilkins, Inc.

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