Chopera, Denis Rutendo.Cotton, Laura A.Zawaira, Alexander.Mann, Jaclyn Kelly.Ngandu, Nobubelo K.Ntale, Roman.Carlson, Jonathan M.Mlisana, Koleka Patience.Woodman, Zenda.de Assis Rosa, Debra.Martin, Eric.Miura, Toshiyuki.Pereyra, Florencia.Walker, Bruce D.Gray, Clive M.Martin, Darren Patrick.Ndung'u, Peter Thumbi.Brockman, Mark A.Abdool Karim, Salim Safurdeen.Brumme, Zabrina L.Williamson, Carolyn.2013-07-052013-07-0520122012Chopera, D., et al. 2012. Intersubtype differences in the effect of a rare p24 Gag mutation on HIV-1 replicative fitness. J. Virol. 86 (24) pp. 13423-13433.0022-538Xhttp://dx.doi.org/10.1128/JVI.02171-12http://hdl.handle.net/10413/9254Certain immune-driven mutations in HIV-1, such as those arising in p24Gag, decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P<0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24Gag codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness.enHIV infections--Virology.HIV (Viruses)AIDS (Disease)--Virology.Peer reviewed journal article