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TAP1 and TAP2 epitopes in HIV-1 disease progression
25
Abstracts
5.2
TAPI AND TAP2 EPITOPES IN HIV-I DISEASE PROGRESSION. Leslie G Louie*, Tristan Gittens*, William Klitz**, *School of Public Health, University of California, Berkeley, CA, USA. **Department of Integrative Biology, University of California, Berkeley, CA, USA. This study was undertaken to examine the effect of genetic variation in the antigen transporters (TAPI, TAP2) on risk of progression to AIDS and the possible epistasis with HLA class lalleles previously observed in association with AIDS. Subjects are 195 HIV -I seropositive men with at least 5 years of follow-up who participate in the San Francisco Men's Health Study (SFMHS). Since 1984, subjects have been seen at 6-12 month intervals. Disease progression is defined by slope of CD4+ T cells counts, calculated by least squares methods. Slopes are ranked, with the lowest slopes indicating fastest disease progression. Individuals are grouped by quantiles and by the mean ± s.d. Analyses are stratified by presence (n= 17) or absence (n= 178) of the DRB 1*0702 allele, which was previously shown to be associated with slower rate of disease progression in the SFMHS. This allele has an identical RFLP pattern to DRB 1*090 I, but is distinct from DRB 1*070 I. The DRB 1*0702 exon 2 sequence is distinct from DRB 1*090 I. TAPI and TAP2 epitopes were typed using ARMS-PCR methods (Powis et al. 1993). Preliminary analyses of the antigen transporters, TAPI and TAP2, have focused on the association of epitopes defined by amino acid residues 333 and 637 for TAPI and residues 379, 565, and 665 for TAP2. This is a reasonable approach, since different alleles sharing an epitope might have a similar effect on the ability to transport a particular peptide across the ER for association with a class I HLA molecule. Analyses of subjects stratified by DRB I *0702 show an effect for those without this protective DRB I allele. Among the 178 individuals without DRB 1*0702, having aspartic acid at TAPI position 637 (TAPl*OIOI and *0301) or alanine at TAP2 position 665 (TAP2*0201) was protective against disease progression, as defined by CD4 cell decline (Wilcoxon p = 0.05 and 0.03, respectively). Threonine at TAP2 position 665 (the alternative to alanine) was associated with increased risk of disease progression (Wilcoxon p = 0.008), though this result is not completely independent of the alanine effect. Particular haplotypes in the telomeric portion of the HLA class II region may slow the progression of HI V-I.
5.3
DISEASE PROGRESSION RATES CORRELATE WITH FREQUENCY OF HLA CLASS I PEPTIDE BINDING MOTIFS IN HIV-I PROTEIN. D. Mann, G. Nelson, Immunogenetics Section, Laboratory of Viral Carcinogenesis, NCI-FCRDC, Frederick, MD 21702-1201 One hundred thirty-nine HIV -I seropositive gay men with closely approximated dates of seroconversion that have been followed for> nine years were typed for class n alleles by serologic methods and for class n and TAP alleles by molecular techniques. A Cox proportional hazards model was used to define the relative hazards (RH) for individual alleles and combinations of alleles that were associated with relative rates of disease progression. Once identified, we sought to determine a potential mechanism that might account for the association of different class I alleles with variable rates of disease progression in HIV -I infection. Frequency of combination of amino acids known to anchor CTL-directed peptides presented by different HLA class I alleles were enumerated in 12 clade B viral protein sequences and examined for correlations (CC) with the alleles relative hazard for association with disease progression. High degrees of correlation were found with the major HIV-I structural proteins (gag CC 0.74 p=0.006; gp 120, c.c. 0.71 p=0.009) and total virus (C.c. 0.63, p=0.03). Thus, the frequency of available HLA class I binding peptide motifs in HIV -1 proteins may influence disease rates in this infection.
Abstracts
5.2
TAPI AND TAP2 EPITOPES IN HIV-I DISEASE PROGRESSION. Leslie G Louie*, Tristan Gittens*, William Klitz**, *School of Public Health, University of California, Berkeley, CA, USA. **Department of Integrative Biology, University of California, Berkeley, CA, USA. This study was undertaken to examine the effect of genetic variation in the antigen transporters (TAPI, TAP2) on risk of progression to AIDS and the possible epistasis with HLA class lalleles previously observed in association with AIDS. Subjects are 195 HIV -I seropositive men with at least 5 years of follow-up who participate in the San Francisco Men's Health Study (SFMHS). Since 1984, subjects have been seen at 6-12 month intervals. Disease progression is defined by slope of CD4+ T cells counts, calculated by least squares methods. Slopes are ranked, with the lowest slopes indicating fastest disease progression. Individuals are grouped by quantiles and by the mean ± s.d. Analyses are stratified by presence (n= 17) or absence (n= 178) of the DRB 1*0702 allele, which was previously shown to be associated with slower rate of disease progression in the SFMHS. This allele has an identical RFLP pattern to DRB 1*090 I, but is distinct from DRB 1*070 I. The DRB 1*0702 exon 2 sequence is distinct from DRB 1*090 I. TAPI and TAP2 epitopes were typed using ARMS-PCR methods (Powis et al. 1993). Preliminary analyses of the antigen transporters, TAPI and TAP2, have focused on the association of epitopes defined by amino acid residues 333 and 637 for TAPI and residues 379, 565, and 665 for TAP2. This is a reasonable approach, since different alleles sharing an epitope might have a similar effect on the ability to transport a particular peptide across the ER for association with a class I HLA molecule. Analyses of subjects stratified by DRB I *0702 show an effect for those without this protective DRB I allele. Among the 178 individuals without DRB 1*0702, having aspartic acid at TAPI position 637 (TAPl*OIOI and *0301) or alanine at TAP2 position 665 (TAP2*0201) was protective against disease progression, as defined by CD4 cell decline (Wilcoxon p = 0.05 and 0.03, respectively). Threonine at TAP2 position 665 (the alternative to alanine) was associated with increased risk of disease progression (Wilcoxon p = 0.008), though this result is not completely independent of the alanine effect. Particular haplotypes in the telomeric portion of the HLA class II region may slow the progression of HI V-I.
5.3
DISEASE PROGRESSION RATES CORRELATE WITH FREQUENCY OF HLA CLASS I PEPTIDE BINDING MOTIFS IN HIV-I PROTEIN. D. Mann, G. Nelson, Immunogenetics Section, Laboratory of Viral Carcinogenesis, NCI-FCRDC, Frederick, MD 21702-1201 One hundred thirty-nine HIV -I seropositive gay men with closely approximated dates of seroconversion that have been followed for> nine years were typed for class n alleles by serologic methods and for class n and TAP alleles by molecular techniques. A Cox proportional hazards model was used to define the relative hazards (RH) for individual alleles and combinations of alleles that were associated with relative rates of disease progression. Once identified, we sought to determine a potential mechanism that might account for the association of different class I alleles with variable rates of disease progression in HIV -I infection. Frequency of combination of amino acids known to anchor CTL-directed peptides presented by different HLA class I alleles were enumerated in 12 clade B viral protein sequences and examined for correlations (CC) with the alleles relative hazard for association with disease progression. High degrees of correlation were found with the major HIV-I structural proteins (gag CC 0.74 p=0.006; gp 120, c.c. 0.71 p=0.009) and total virus (C.c. 0.63, p=0.03). Thus, the frequency of available HLA class I binding peptide motifs in HIV -1 proteins may influence disease rates in this infection.