HLA-Associated Alterations in Replication Capacity of Chimeric NL4-3 Viruses Carrying gag-protease from Elite Controllers of Human Immunodeficiency Virus Type 1

T Miura, MA Brockman, ZL Brumme… - Journal of …, 2009 - Am Soc Microbiol
T Miura, MA Brockman, ZL Brumme, CJ Brumme, F Pereyra, A Trocha, BL Block…
Journal of virology, 2009Am Soc Microbiol
Human immunodeficiency virus type 1 (HIV-1)-infected persons who maintain plasma viral
loads of< 50 copies RNA/ml without treatment have been termed elite controllers (EC).
Factors contributing to durable control of HIV in EC are unknown, but an HLA-dependent
mechanism is suggested by overrepresentation of “protective” class I alleles, such as B* 27,
B* 51, and B* 57. Here we investigated the relative replication capacity of viruses (VRC)
obtained from EC (n= 54) compared to those from chronic progressors (CP; n= 41) by …
Abstract
Human immunodeficiency virus type 1 (HIV-1)-infected persons who maintain plasma viral loads of <50 copies RNA/ml without treatment have been termed elite controllers (EC). Factors contributing to durable control of HIV in EC are unknown, but an HLA-dependent mechanism is suggested by overrepresentation of “protective” class I alleles, such as B*27, B*51, and B*57. Here we investigated the relative replication capacity of viruses (VRC) obtained from EC (n = 54) compared to those from chronic progressors (CP; n = 41) by constructing chimeric viruses using patient-derived gag-protease sequences amplified from plasma HIV RNA and inserted into an NL4-3 backbone. The chimeric viruses generated from EC displayed lower VRC than did viruses from CP (P < 0.0001). HLA-B*57 was associated with lower VRC (P = 0.0002) than were other alleles in both EC and CP groups. Chimeric viruses from B*57+ EC (n = 18) demonstrated lower VRC than did viruses from B*57+ CP (n = 8, P = 0.0245). Differences in VRC between EC and CP were also observed for viruses obtained from individuals expressing no described “protective” alleles (P = 0.0065). Intriguingly, two common HLA alleles, A*02 and B*07, were associated with higher VRC (P = 0.0140 and 0.0097, respectively), and there was no difference in VRC between EC and CP sharing these common HLA alleles. These findings indicate that cytotoxic T-lymphocyte (CTL) selection pressure on gag-protease alters VRC, and HIV-specific CTLs inducing escape mutations with fitness costs in this region may be important for strict viremia control in EC of HIV.
American Society for Microbiology