The HIV-1 late domain-2 S40A polymorphism in antiretroviral (or ART)-exposed individuals influences protease inhibitor susceptibility.
The p6 region of the HIV-1 structural precursor polyprotein, Gag, contains two motifs, P7TAP11 and L35YPLXSL41, designated as late (L) domain-1 and -2, respectively. These motifs bind the ESCRT-I factor Tsg101 and the ESCRT adaptor Alix, respectively, and are critical for efficient budding of virus particles from the plasma membrane. L domain-2 is thought to be functionally redundant to PTAP. To identify possible other functions of L domain-2, we examined this motif in dominant viruses that emerged in a group of 14 women who had detectable levels of HIV-1 in both plasma and genital tract despite a history of current or previous antiretroviral therapy.



Remarkably, variants possessing mutations or rare polymorphisms in the highly conserved L domain-2 were identified in seven of these women. A mutation in a conserved residue (S40A) that does not reduce Gag interaction with Alix and therefore did not reduce budding efficiency was further investigated. This mutation causes a simultaneous change in the Pol reading frame but exhibits little deficiency in Gag processing and virion maturation. Whether introduced into the HIV-1 NL4-3 strain genome or a model protease (PR) precursor, S40A reduced production of mature PR. This same mutation also led to high level detection of two extended forms of PR that were fairly stable compared to the WT in the presence of IDV at various concentrations; one of the extended forms was effective in trans processing even at micromolar IDV.



Our results indicate that L domain-2, considered redundant in vitro, can undergo mutations in vivo that significantly alter PR function. These may contribute fitness benefits in both the absence and presence of PR inhibitor.
Department of Molecular Genetics and Microbiology, Stony Brook University, Life Sciences Bldg., Stony Brook, NY, 11794-5222, USA.
Susan M
SM
Watanabe
Department of Microbiology, Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Viviana
V
Simon
Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Natasha D
ND
Durham
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523-1870, USA.
Brittney R
BR
Kemp
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523-1870, USA.
Satoshi
S
Machihara
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Kimdar Sherefa
KS
Kemal
Department of Health Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA.
Binshan
B
Shi
Los Alamos National Laboratory, Los Alamos, NM, USA.
Brian
B
Foley
Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Hongru
H
Li
Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Benjamin K
BK
Chen
Department of Medicine, University of California Davis, Davis, CA, USA.|Department of Medicine, Sacramento VA Medical Center, Cordova, CA, USA.
Barbara
B
Weiser
Department of Medicine, University of California Davis, Davis, CA, USA.|Department of Medicine, Sacramento VA Medical Center, Cordova, CA, USA.
Harold
H
Burger
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Kathryn
K
Anastos
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523-1870, USA. chaoping.chen@colostate.edu.
Chaoping
C
Chen
Department of Molecular Genetics and Microbiology, Stony Brook University, Life Sciences Bldg., Stony Brook, NY, 11794-5222, USA. carol.carter@stonybrook.edu.
Carol A
CA
Carter
D023241:Antiretroviral Therapy, Highly Active; D005260:Female; D057809:HEK293 Cells; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D060737:Reproductive Tract Infections / Q000821:virology; D014157:Transcription Factors; D057074:Virus Release; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
D017320:HIV Protease Inhibitors; D014157:Transcription Factors; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease
Anti-retroviral drugs; ESCRT; HIV Gag; HIV protease; Late domain; Protease inhibitors