Reduced Replication Capacity of NL4-3 Recombinant Viruses Encoding Reverse Transcriptase Integrase Sequences From HIV-1 Elite Controllers
- Zabrina L. Brumme ,
- Chun Li ,
- Toshiyuki Miura ,
- Jennifer Sela ,
- Pamela C. Rosato ,
- Chanson J. Brumme ,
- Tristan J. Markle ,
- Eric Martin ,
- Brian L. Block ,
- Alicja Trocha ,
- Carl Kadie ,
- Todd M. Allen ,
- Florencia Pereyra ,
- David Heckerman ,
- Bruce D. Walker ,
- Mark A. Brockman
J Acquir Immune Defic Syndr. |
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 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 (RT)-Integrase sequences from 58 elite controllers and 50 untreated chronic progressors were constructed and replication capacity measured in vitro using a 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 to 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 RT-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 appeared 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.