Critical amino acids within the human immunodeficiency virus type 1 envelope glycoprotein V4 N- and C-terminals contribute to virus entry.
The importance of the fourth variable (V4) region of the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein (Env) in virus infection has not been well clarified, though the polymorphism of this region has been found to be associated with disease progression to acquired immunodeficiency syndrome (AIDS). In the present work, we focused on the correlation between HIV-1 gp120 V4 region polymorphism and the function of the region on virus entry, and the possible mechanisms for how the V4 region contributes to virus infectivity. Therefore, we analyzed the differences in V4 sequences along with coreceptor usage preference from CCR5 to CXCR4 and examined the importance of the amino acids within the V4 region for CCR5- and CXCR4-tropic virus entry. In addition, we determined the influence of the V4 amino acids on Env expression and gp160 processing intracellularly, as well as the amount of Env on the pseudovirus surface. The results indicated that V4 tended to have a shorter length, fewer potential N-linked glycosylation sites (PNGS), greater evolutionary distance, and a lower negative net charge when HIV-1 isolates switched from a coreceptor usage preference for CCR5 to CXCR4. The N- and C-terminals of the HIV-1 V4 region are highly conserved and critical to maintain virus entry ability, but only the mutation at position 417 in the context of ADA (a R5-tropic HIV-1 strain) resulted in the ability to utilize CXCR4. In addition, 390L, 391F, 414I, and 416L are critical to maintain gp160 processing and maturation. It is likely that the hydrophobic properties and the electrostatic surface potential of gp120, rather than the conformational structure, greatly contribute to this V4 functionality. The findings provide information to aid in the understanding of the functions of V4 in HIV-1 entry and offer a potential target to aid in the development of entry inhibitors.
Department of Microbiology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
Yan
Y
Li
Department of Forensic Medicine, Harbin Medical University, Harbin, China.
Dan
D
Yang
Department of Microbiology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
Jia-Ye
JY
Wang
Academy of Fundamental and Interdisciplinary Science, Harbin Institute of Technology, Harbin, China.
Yuan
Y
Yao
Department of Parasitology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
Wei-Zhe
WZ
Zhang
Department of Biochemistry, Harbin Medical University, Harbin, China.
Lu-Jing
LJ
Wang
Department of Parasitology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
De-Chun
DC
Cheng
Department of Parasitology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
Feng-Kun
FK
Yang
Department of Microbiology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
Feng-Min
FM
Zhang
Department of Microbiology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
Min
M
Zhuang
Department of Microbiology, Harbin Medical University, Harbin, China ; Department of Parasitology, Harbin Medical University, Harbin, China ; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Key Laboratory of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
Hong
H
Ling
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000378:metabolism*; D019295:Computational Biology; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006031:Glycosylation; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship; D056189:Viral Tropism; D053586:Virus Internalization
D000596:Amino Acids; D015699:HIV Envelope Protein gp120; D050505:Mutant Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4