ABSTRACT
HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. In this study we analysed 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 years at enrolment. CD4% change over time was used to stratify participants into relative faster and slower progressor groups. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface. p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.
ABSTRACT
HIV-2 is thought to have entered the human population in the 1930s through cross-species transmission of SIV from sooty mangabeys in West Africa. Unlike HIV-1, HIV-2 has not led to a global pandemic, and recent data suggest that HIV-2 prevalence is declining in some West African states where it was formerly endemic. Although many early isolates of HIV-2 were derived from patients presenting with AIDS-defining illnesses, it was noted that a much larger proportion of HIV-2-infected subjects behaved as long-term non-progressors (LTNP) than their HIV-1-infected counterparts. Many HIV-2-infected adults are asymptomatic, maintaining an undetectable viral load for over a decade. However, despite lower viral loads, HIV-2 progresses to clinical AIDS without therapeutic intervention in most patients. In addition, successful treatment with anti-retroviral therapy (ART) is more challenging than for HIV-1. HIV-2 is significantly more sensitive to restriction by host restriction factor tripartite motif TRIM5α than HIV-1, and this difference in sensitivity is linked to differences in capsid structure. In this review we discuss the determinants of HIV-2 disease progression and focus on the important interactions between TRIM5α and HIV-2 capsid in long-term viral control.
Subject(s)
Capsid Proteins/metabolism , HIV Infections/epidemiology , HIV-1/physiology , HIV-2/physiology , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Adult , Africa, Western/epidemiology , Animals , Antiviral Restriction Factors , Asymptomatic Diseases , Capsid Proteins/genetics , Cercocebus atys , Disease Progression , Endemic Diseases , HIV Infections/mortality , Humans , Survival Analysis , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Virulence FactorsABSTRACT
KIR3DL1*0040102 allele differs from KIR3DL1*0040101 by a single-nucleotide change at position 12356 (intron 6).
Subject(s)
Black People/genetics , Receptors, KIR3DL1/chemistry , Receptors, KIR3DL1/genetics , Tissue Donors , Humans , Introns/genetics , Molecular Sequence Data , Protein Structure, Tertiary , Receptors, KIR3DL1/isolation & purification , Sequence AlignmentABSTRACT
KIR3DS1*0130109 is similar to KIR3DS1*0130101 except for a A > G change in intron 4.
Subject(s)
Histocompatibility Testing , Receptors, KIR3DS1/chemistry , Receptors, KIR3DS1/genetics , Sequence Analysis, DNA , Alleles , Base Sequence , Humans , Molecular Sequence Data , Protein Structure, Tertiary , Sequence AlignmentABSTRACT
KIR3DL1*0150210 has seven point mutations compared to the common Asian allele KIR3DL1*0150201.
Subject(s)
Alleles , Point Mutation , Receptors, KIR3DL1/genetics , Recombination, Genetic , Base Sequence , Exons , Genotype , Humans , Molecular Sequence Data , Molecular Typing , Receptors, KIR3DL1/immunology , Sequence Alignment , Sequence Analysis, DNAABSTRACT
KIR3DL1*0310102 differs from KIR3DL1*0150101 with 11 nucleotide substitutions.
Subject(s)
Alleles , Point Mutation , Receptors, KIR3DL1/genetics , Africa, Western , Base Sequence , Exons , Genotype , Humans , Introns , Molecular Sequence Data , Molecular Typing , Receptors, KIR3DL1/immunology , Sequence Alignment , Sequence Analysis, DNAABSTRACT
A novel KIR3DL1*0150103 found in West Africa with five single nucleotide polymorphisms compared to KIR3DL1*0150101.
Subject(s)
Alleles , Polymorphism, Single Nucleotide , Receptors, KIR3DL1/genetics , Tissue Donors , Africa, Western , Base Sequence , Bone Marrow Transplantation , Codon , Exons , Gene Expression , Humans , Introns , Molecular Sequence Data , Molecular Typing , Receptors, KIR3DL1/immunology , Sequence AlignmentABSTRACT
Full-length sequences of KIR3DL1*0150209 differ from those of KIR3DL1*0150201 with seven single-nucleotide polymorphisms.
Subject(s)
Alleles , Polymorphism, Single Nucleotide , Receptors, KIR3DL1/genetics , Asian People , Base Sequence , Genotype , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Introns , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Molecular Sequence Data , Polymerase Chain Reaction , Receptors, KIR3DL1/immunology , Sequence Analysis, DNA , Tissue DonorsABSTRACT
The full length sequence of KIR3DL1*0250103 differs from that of KIR3DL1*0150101 with nine single-nucleotide polymorphisms.
Subject(s)
Alleles , Polymorphism, Single Nucleotide , Receptors, KIR3DL1/genetics , Africa, Western , Base Sequence , Exons , Genotype , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Introns , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Molecular Sequence Data , Polymerase Chain Reaction , Receptors, KIR3DL1/immunology , Sequence Analysis, DNA , Tissue DonorsABSTRACT
KIR3DS1*0130111 differs from KIR3DS1*0130101 with two previously undescribed single nucleotide polymorphisms.
Subject(s)
Alleles , Exons , Polymorphism, Single Nucleotide , Receptors, KIR3DL1/genetics , Receptors, KIR3DS1/genetics , Amino Acid Substitution , Base Sequence , Genotype , Humans , Molecular Sequence Data , Molecular Typing , Polymerase Chain Reaction , Receptors, KIR3DL1/immunology , Receptors, KIR3DS1/immunology , Sequence Alignment , Sequence Analysis, DNAABSTRACT
KIR3DL1*0250102 differs from the common West African KIR3DL1*0150101 by 11 single nucleotide polymorphisms (SNPs).
Subject(s)
Receptors, KIR3DL1/genetics , Africa, Western , Alleles , Humans , Molecular Sequence Data , Protein Structure, Tertiary , Receptors, KIR3DL1/chemistryABSTRACT
KIR3DL1*087 is significantly different from KIR3DL1*0010101 with multiple non-synonymous changes and insertion/deletion sites.
Subject(s)
Alleles , Receptors, KIR3DL1/chemistry , Receptors, KIR3DL1/genetics , Sequence Analysis, DNA/methods , Base Sequence , Humans , Molecular Sequence Data , Protein Structure, Tertiary , Sequence AlignmentABSTRACT
Full-length sequence of KIR3DL1*0150102 differs from that of KIR3DL1*0150101 in intron 6.
Subject(s)
Introns , Receptors, KIR3DL1/genetics , Base Sequence , Humans , Molecular Sequence DataABSTRACT
KIR3DL1*0150211 differs from KIR3DL1*0150201 with six single nucleotide polymorphisms in introns 3, 4, 5, and 6.
Subject(s)
Alleles , Polymorphism, Single Nucleotide , Receptors, KIR3DL1/genetics , Base Sequence , Humans , Molecular Sequence Data , Sequence Analysis, DNAABSTRACT
The full-length genomic sequence of KIR3DL1*0040103 differs from KIR3DL1*0040101 at three nucleotide positions.
Subject(s)
Alleles , Receptors, KIR3DL1/genetics , Base Sequence , Black People , Humans , Molecular Sequence Data , Sequence Analysis, DNAABSTRACT
The complete length genomic sequence of KIR3DL1*03101 differs from KIR3DL1*0010101 at multiple intronic and exonic sites.
Subject(s)
Base Sequence , Exons , Introns , Receptors, KIR3DL1/genetics , Humans , Sequence Analysis, DNAABSTRACT
KIR3DL1*0010103 differs from KIR3DL1*0010101 with four single nucleotide polymorphisms.
Subject(s)
Base Sequence , Polymorphism, Single Nucleotide , Receptors, KIR3DL1/genetics , HumansABSTRACT
KIR3DL1*022 is significantly different from the most common West African allele - KIR3DL1*01501.
Subject(s)
Alleles , Living Donors , Receptors, KIR3DL1/genetics , Black People , HumansABSTRACT
KIR3DS1*0130110 differs from KIR3DS1*0130101 with two nucleotide substitutions at positions 7322 (G > T) and 12617 (C > A), respectively.
