Reduced replication capacity of NL4-3 recombinant viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers.
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.
Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
Zabrina L
ZL
Brumme
Chun
C
Li
Toshiyuki
T
Miura
Jennifer
J
Sela
Pamela C
PC
Rosato
Chanson J
CJ
Brumme
Tristan J
TJ
Markle
Eric
E
Martin
Brian L
BL
Block
Alicja
A
Trocha
Carl M
CM
Kadie
Todd M
TM
Allen
Florencia
F
Pereyra
David
D
Heckerman
Bruce D
BD
Walker
Mark A
MA
Brockman
D015658:HIV Infections / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D020276:HIV Long-Term Survivors; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D009154:Mutation; D011995:Recombination, Genetic; D014774:Virulence; D014779:Virus Replication
D019427:HIV Integrase; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C514801:p31 integrase protein, Human immunodeficiency virus 1