Protease polymorphisms in HIV-1 subtype CRF01_AE represent selection by antiretroviral therapy and host immune pressure.
BACKGROUND
Most of our knowledge about how antiretrovirals and host immune responses influence the HIV-1 protease gene is derived from studies of subtype B virus. We investigated the effect of protease resistance-associated mutations (PRAMs) and population-based HLA haplotype frequencies on polymorphisms found in CRF01_AE pro.


METHODS
We used all CRF01_AE protease sequences retrieved from the LANL database and obtained regional HLA frequencies from the dbMHC database. Polymorphisms and major PRAMs in the sequences were identified using the Stanford Resistance Database, and we performed phylogenetic and selection analyses using HyPhy. HLA binding affinities were estimated using the Immune Epitope Database and Analysis.


RESULTS
Overall, 99% of CRF01_AE sequences had at least 1 polymorphism and 10% had at least 1 major PRAM. Three polymorphisms (L10 V, K20RMI and I62 V) were associated with the presence of a major PRAM (P < 0.05). Compared to the subtype B consensus, six additional polymorphisms (I13 V, E35D, M36I, R41K, H69K, L89M) were identified in the CRF01_AE consensus; all but L89M were located within epitopes recognized by HLA class I alleles. Of the predominant HLA haplotypes in the Asian regions of CRF01_AE origin, 80% were positively associated with the observed polymorphisms, and estimated HLA binding affinity was estimated to decrease 19-40 fold with the observed polymorphisms at positions 35, 36 and 41.


CONCLUSIONS
Polymorphisms in CRF01_AE protease gene were common, and polymorphisms at residues 10, 20 and 62 most likely represent selection by use of protease inhibitors, whereas R41K and H69K were more likely attributable to recognition of epitopes by the HLA haplotypes of the host population.
Manosuthi
Weerawat
W
University of California San Diego, La Jolla, California, USA. drweerawat@hotmail.com
Butler
David M
DM
Pérez-Santiago
Josué
J
Poon
Art Fy
AF
Pillai
Satish K
SK
Mehta
Sanjay R
SR
Pacold
Mary E
ME
Richman
Douglas D
DD
Pond
Sergei Kosakovsky
SK
Smith
Davey M
DM
D000595:Amino Acid Sequence / Q000235:genetics; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D044466:Asian People; D024882:Drug Resistance, Viral / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic
D044966:Anti-Retroviral Agents; D016333:HIV Protease