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Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions.

Li X, Price MA, He D, Kamali A, Karita E, Lakhi S, Sanders EJ, Anzala O, Amornkul PN, Allen S, Hunter E, Kaslow RA, Gilmour J, Tang J, IAVI Africa HIV Prevention Partnersh - Hum. Genet. (2014)

Bottom Line: This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50).In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001).Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL, 35294, USA.

ABSTRACT
Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of "missing heritability" in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.

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Related in: MedlinePlus

Longitudinal viral loads in HIV-1-infected men and women stratified by HLA-A*03:01. Viral load measurements at various intervals (2 to 36 months after infection) are plotted for HLA-A*03:01-positive and HLA-A*03:01-negative subjects. The thick and thin lines correspond to the expected mean value and 95 % confidence intervals for each stratum (see Table 2 for summary statistics based on mixed models). Arrows indicate plasma viral load measurements that are <400 RNA copies/ml (routinely transformed to 1.30 log10)
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Fig1: Longitudinal viral loads in HIV-1-infected men and women stratified by HLA-A*03:01. Viral load measurements at various intervals (2 to 36 months after infection) are plotted for HLA-A*03:01-positive and HLA-A*03:01-negative subjects. The thick and thin lines correspond to the expected mean value and 95 % confidence intervals for each stratum (see Table 2 for summary statistics based on mixed models). Arrows indicate plasma viral load measurements that are <400 RNA copies/ml (routinely transformed to 1.30 log10)

Mentions: When 35 common HLA variants (2- or 4-digit resolution levels, whenever possible) were screened in mixed models with adjustment for demographic factors (age and geography), only HLA-A*03:01 showed a clear interaction with sex (P = 0.003, FDR = 0.09). LOESS curves supported this finding, as women with (+) and without (−) HLA-A*03:01 persistently differed in VL over the study intervals (1,732 person-visits, P < 0.0001) (Fig. 1). In contrast, HLA-A*03:01+ and A*03:01− men (3,002 person-visits) had highly comparable VL trajectories (P = 0.66).Fig. 1


Host genetics and viral load in primary HIV-1 infection: clear evidence for gene by sex interactions.

Li X, Price MA, He D, Kamali A, Karita E, Lakhi S, Sanders EJ, Anzala O, Amornkul PN, Allen S, Hunter E, Kaslow RA, Gilmour J, Tang J, IAVI Africa HIV Prevention Partnersh - Hum. Genet. (2014)

Longitudinal viral loads in HIV-1-infected men and women stratified by HLA-A*03:01. Viral load measurements at various intervals (2 to 36 months after infection) are plotted for HLA-A*03:01-positive and HLA-A*03:01-negative subjects. The thick and thin lines correspond to the expected mean value and 95 % confidence intervals for each stratum (see Table 2 for summary statistics based on mixed models). Arrows indicate plasma viral load measurements that are <400 RNA copies/ml (routinely transformed to 1.30 log10)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4127002&req=5

Fig1: Longitudinal viral loads in HIV-1-infected men and women stratified by HLA-A*03:01. Viral load measurements at various intervals (2 to 36 months after infection) are plotted for HLA-A*03:01-positive and HLA-A*03:01-negative subjects. The thick and thin lines correspond to the expected mean value and 95 % confidence intervals for each stratum (see Table 2 for summary statistics based on mixed models). Arrows indicate plasma viral load measurements that are <400 RNA copies/ml (routinely transformed to 1.30 log10)
Mentions: When 35 common HLA variants (2- or 4-digit resolution levels, whenever possible) were screened in mixed models with adjustment for demographic factors (age and geography), only HLA-A*03:01 showed a clear interaction with sex (P = 0.003, FDR = 0.09). LOESS curves supported this finding, as women with (+) and without (−) HLA-A*03:01 persistently differed in VL over the study intervals (1,732 person-visits, P < 0.0001) (Fig. 1). In contrast, HLA-A*03:01+ and A*03:01− men (3,002 person-visits) had highly comparable VL trajectories (P = 0.66).Fig. 1

Bottom Line: This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50).In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001).Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alabama at Birmingham, 1665 University Boulevard, Birmingham, AL, 35294, USA.

ABSTRACT
Research in the past two decades has generated unequivocal evidence that host genetic variations substantially account for the heterogeneous outcomes following human immunodeficiency virus type 1 (HIV-1) infection. In particular, genes encoding human leukocyte antigens (HLA) have various alleles, haplotypes, or specific motifs that can dictate the set-point (a relatively steady state) of plasma viral load (VL), although rapid viral evolution driven by innate and acquired immune responses can obscure the long-term relationships between HLA genotypes and HIV-1-related outcomes. In our analyses of VL data from 521 recent HIV-1 seroconverters enrolled from eastern and southern Africa, HLA-A*03:01 was strongly and persistently associated with low VL in women (frequency = 11.3 %, P < 0.0001) but not in men (frequency = 7.7 %, P = 0.66). This novel sex by HLA interaction (P = 0.003, q = 0.090) did not extend to other frequent HLA class I alleles (n = 34), although HLA-C*18:01 also showed a weak association with low VL in women only (frequency = 9.3 %, P = 0.042, q > 0.50). In a reduced multivariable model, age, sex, geography (clinical sites), previously identified HLA factors (HLA-B*18, B*45, B*53, and B*57), and the interaction term for female sex and HLA-A*03:01 collectively explained 17.0 % of the overall variance in geometric mean VL over a 3-year follow-up period (P < 0.0001). Multiple sensitivity analyses of longitudinal and cross-sectional VL data yielded consistent results. These findings can serve as a proof of principle that the gap of "missing heritability" in quantitative genetics can be partially bridged by a systematic evaluation of sex-specific associations.

Show MeSH
Related in: MedlinePlus