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Unique features of HLA-mediated HIV evolution in a Mexican cohort: a comparative study.

Avila-Rios S, Ormsby CE, Carlson JM, Valenzuela-Ponce H, Blanco-Heredia J, Garrido-Rodriguez D, Garcia-Morales C, Heckerman D, Brumme ZL, Mallal S, John M, Espinosa E, Reyes-Teran G - Retrovirology (2009)

Bottom Line: Mounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level.Our data were compared with data from the IHAC cohort, a large multi-center cohort of individuals from Canada, Australia and the USA.These results highlight the importance of comparative HIV evolutionary studies in immunologically different populations worldwide.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico. santiago.avila@cieni.org.mx

ABSTRACT

Background: Mounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level. However, it is not known whether characteristic HLA frequency distributions in different populations have resulted in additional unique footprints.

Methods: The phylogenetic dependency network model was applied to assess HLA-mediated evolution in datasets of HIV pol sequences from free plasma viruses and peripheral blood mononuclear cell (PBMC)-integrated proviruses in an immunogenetically unique cohort of Mexican individuals. Our data were compared with data from the IHAC cohort, a large multi-center cohort of individuals from Canada, Australia and the USA.

Results: Forty three different HLA-HIV codon associations representing 30 HLA-HIV codon pairs were observed in the Mexican cohort (q < 0.2). Strikingly, 23 (53%) of these associations differed from those observed in the well-powered IHAC cohort, strongly suggesting the existence of unique characteristics in HLA-mediated HIV evolution in the Mexican cohort. Furthermore, 17 of the 23 novel associations involved HLA alleles whose frequencies were not significantly different from those in IHAC, suggesting that their detection was not due to increased statistical power but to differences in patterns of epitope targeting. Interestingly, the consensus differed in four positions between the two cohorts and three of these positions could be explained by HLA-associated selection. Additionally, different HLA-HIV codon associations were seen when comparing HLA-mediated selection in plasma viruses and PBMC archived proviruses at the population level, with a significantly lower number of associations in the proviral dataset.

Conclusion: Our data support universal HLA-mediated HIV evolution at the population level, resulting in detectable HLA-associated footprints in the circulating virus. However, it also strongly suggests that unique genetic backgrounds in different HIV-infected populations may influence HIV evolution in a particular direction as particular HLA-HIV codon associations are determined by specific HLA frequency distributions. Our analysis also suggests a dynamic HLA-associated evolution in HIV with fewer HLA-HIV codon associations observed in the proviral compartment, which is likely enriched in early archived HIV sequences, compared to the plasma virus compartment. These results highlight the importance of comparative HIV evolutionary studies in immunologically different populations worldwide.

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Marked differences in HLA allele frequencies in three clade B-infected cohorts. Population frequencies for class I HLA genes A, B and C were compared between the Mexican cohort described in this study (n = 292) (dark grey). The combined IHAC cohort including individuals from British Columbia, Canada; Western Australia and the USA (n = 1845) (light grey) [37] (Brumme ZL, John M, et al, PLoS ONE 2009, in press), and the British Columbia HOMER cohort (n = 1045) (white) described in detail previously [34]. **Significant differences (q < 0.05) between the Mexican cohorts and both the IHAC and the HOMER cohorts, *significant differences (q < 0.05) between the Mexican cohort and the IHAC cohort only.
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Figure 4: Marked differences in HLA allele frequencies in three clade B-infected cohorts. Population frequencies for class I HLA genes A, B and C were compared between the Mexican cohort described in this study (n = 292) (dark grey). The combined IHAC cohort including individuals from British Columbia, Canada; Western Australia and the USA (n = 1845) (light grey) [37] (Brumme ZL, John M, et al, PLoS ONE 2009, in press), and the British Columbia HOMER cohort (n = 1045) (white) described in detail previously [34]. **Significant differences (q < 0.05) between the Mexican cohorts and both the IHAC and the HOMER cohorts, *significant differences (q < 0.05) between the Mexican cohort and the IHAC cohort only.

Mentions: In order to highlight the unique immunogenetic background of the Mexican population with respect to other populations in which HLA-associated HIV evolution has been studied, an HLA frequency comparison was carried out between our cohort of 292 HIV-positive individuals from Central/Southern Mexico, a previously described cohort of 1,045 HIV-positive individuals from British Columbia, Canada (HOMER cohort) [34] and the large International HIV Adaptation Combined (IHAC) cohort, including 1,845 individuals from British Columbia, Canada; Western Australia and the USA (Figure 4). Although both the HOMER cohort and the USA subset of the IHAC cohort include a minority of individuals self-identified as Hispanic, important differences were seen in HLA allele distribution in the three cohorts that account for the typical genetic admixture of the Mexican population [38,39]. As expected, there were significant differences between the allele frequencies of the cohort reported here and the HOMER and IHAC cohorts (chi2 = 597.41 and 782.13, p < 10-88 and 10-125, respectively). HLA-A*68, B*35, B*39, B*48, B*52, Cw*04 and Cw*08 alleles were observed at significantly higher frequencies in the Mexican cohort compared to HOMER and IHAC cohorts (p < 0.005, q < 0.01), consistent with typical Amerindian alleles [38,39,45]. Similarly, HLA-A*01, A*03, A*11, B*07, B*08, B*13, B*27, B*44, B*57, Cw*05, and Cw*06 alleles were observed at significantly lower frequencies in the Mexican cohort compared to HOMER and IHAC cohorts (p < 0.005, q < 0.01), consistent with the higher frequency of these alleles among Caucasians [38,39,45] (Figure 4). Additionally, HLA-A*02 and A*24 alleles had significantly higher frequencies, and HLA-A*25, B*15 and Cw*02 alleles had significantly lower frequencies in the Mexican cohort than in HOMER and IHAC cohorts, not specifically reported to be enriched in Amerindian, or Caucasian groups. Notably, the frequency of HLA-B*39 alleles was more than 7 times higher in the Mexican cohort than in HOMER and IHAC cohorts (Figure 4). Taken together, these results confirm the characteristic admixture of the mainly Amerindian and Caucasian genes of the Mexican mestizo population in a typical cohort of HIV-infected individuals from the Central/Southern region of the country, and reveal a previously uncharacterized, unique immunogenetic background for the study of HLA-associated HIV evolution at the population level.


Unique features of HLA-mediated HIV evolution in a Mexican cohort: a comparative study.

Avila-Rios S, Ormsby CE, Carlson JM, Valenzuela-Ponce H, Blanco-Heredia J, Garrido-Rodriguez D, Garcia-Morales C, Heckerman D, Brumme ZL, Mallal S, John M, Espinosa E, Reyes-Teran G - Retrovirology (2009)

Marked differences in HLA allele frequencies in three clade B-infected cohorts. Population frequencies for class I HLA genes A, B and C were compared between the Mexican cohort described in this study (n = 292) (dark grey). The combined IHAC cohort including individuals from British Columbia, Canada; Western Australia and the USA (n = 1845) (light grey) [37] (Brumme ZL, John M, et al, PLoS ONE 2009, in press), and the British Columbia HOMER cohort (n = 1045) (white) described in detail previously [34]. **Significant differences (q < 0.05) between the Mexican cohorts and both the IHAC and the HOMER cohorts, *significant differences (q < 0.05) between the Mexican cohort and the IHAC cohort only.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2734549&req=5

Figure 4: Marked differences in HLA allele frequencies in three clade B-infected cohorts. Population frequencies for class I HLA genes A, B and C were compared between the Mexican cohort described in this study (n = 292) (dark grey). The combined IHAC cohort including individuals from British Columbia, Canada; Western Australia and the USA (n = 1845) (light grey) [37] (Brumme ZL, John M, et al, PLoS ONE 2009, in press), and the British Columbia HOMER cohort (n = 1045) (white) described in detail previously [34]. **Significant differences (q < 0.05) between the Mexican cohorts and both the IHAC and the HOMER cohorts, *significant differences (q < 0.05) between the Mexican cohort and the IHAC cohort only.
Mentions: In order to highlight the unique immunogenetic background of the Mexican population with respect to other populations in which HLA-associated HIV evolution has been studied, an HLA frequency comparison was carried out between our cohort of 292 HIV-positive individuals from Central/Southern Mexico, a previously described cohort of 1,045 HIV-positive individuals from British Columbia, Canada (HOMER cohort) [34] and the large International HIV Adaptation Combined (IHAC) cohort, including 1,845 individuals from British Columbia, Canada; Western Australia and the USA (Figure 4). Although both the HOMER cohort and the USA subset of the IHAC cohort include a minority of individuals self-identified as Hispanic, important differences were seen in HLA allele distribution in the three cohorts that account for the typical genetic admixture of the Mexican population [38,39]. As expected, there were significant differences between the allele frequencies of the cohort reported here and the HOMER and IHAC cohorts (chi2 = 597.41 and 782.13, p < 10-88 and 10-125, respectively). HLA-A*68, B*35, B*39, B*48, B*52, Cw*04 and Cw*08 alleles were observed at significantly higher frequencies in the Mexican cohort compared to HOMER and IHAC cohorts (p < 0.005, q < 0.01), consistent with typical Amerindian alleles [38,39,45]. Similarly, HLA-A*01, A*03, A*11, B*07, B*08, B*13, B*27, B*44, B*57, Cw*05, and Cw*06 alleles were observed at significantly lower frequencies in the Mexican cohort compared to HOMER and IHAC cohorts (p < 0.005, q < 0.01), consistent with the higher frequency of these alleles among Caucasians [38,39,45] (Figure 4). Additionally, HLA-A*02 and A*24 alleles had significantly higher frequencies, and HLA-A*25, B*15 and Cw*02 alleles had significantly lower frequencies in the Mexican cohort than in HOMER and IHAC cohorts, not specifically reported to be enriched in Amerindian, or Caucasian groups. Notably, the frequency of HLA-B*39 alleles was more than 7 times higher in the Mexican cohort than in HOMER and IHAC cohorts (Figure 4). Taken together, these results confirm the characteristic admixture of the mainly Amerindian and Caucasian genes of the Mexican mestizo population in a typical cohort of HIV-infected individuals from the Central/Southern region of the country, and reveal a previously uncharacterized, unique immunogenetic background for the study of HLA-associated HIV evolution at the population level.

Bottom Line: Mounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level.Our data were compared with data from the IHAC cohort, a large multi-center cohort of individuals from Canada, Australia and the USA.These results highlight the importance of comparative HIV evolutionary studies in immunologically different populations worldwide.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico. santiago.avila@cieni.org.mx

ABSTRACT

Background: Mounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level. However, it is not known whether characteristic HLA frequency distributions in different populations have resulted in additional unique footprints.

Methods: The phylogenetic dependency network model was applied to assess HLA-mediated evolution in datasets of HIV pol sequences from free plasma viruses and peripheral blood mononuclear cell (PBMC)-integrated proviruses in an immunogenetically unique cohort of Mexican individuals. Our data were compared with data from the IHAC cohort, a large multi-center cohort of individuals from Canada, Australia and the USA.

Results: Forty three different HLA-HIV codon associations representing 30 HLA-HIV codon pairs were observed in the Mexican cohort (q < 0.2). Strikingly, 23 (53%) of these associations differed from those observed in the well-powered IHAC cohort, strongly suggesting the existence of unique characteristics in HLA-mediated HIV evolution in the Mexican cohort. Furthermore, 17 of the 23 novel associations involved HLA alleles whose frequencies were not significantly different from those in IHAC, suggesting that their detection was not due to increased statistical power but to differences in patterns of epitope targeting. Interestingly, the consensus differed in four positions between the two cohorts and three of these positions could be explained by HLA-associated selection. Additionally, different HLA-HIV codon associations were seen when comparing HLA-mediated selection in plasma viruses and PBMC archived proviruses at the population level, with a significantly lower number of associations in the proviral dataset.

Conclusion: Our data support universal HLA-mediated HIV evolution at the population level, resulting in detectable HLA-associated footprints in the circulating virus. However, it also strongly suggests that unique genetic backgrounds in different HIV-infected populations may influence HIV evolution in a particular direction as particular HLA-HIV codon associations are determined by specific HLA frequency distributions. Our analysis also suggests a dynamic HLA-associated evolution in HIV with fewer HLA-HIV codon associations observed in the proviral compartment, which is likely enriched in early archived HIV sequences, compared to the plasma virus compartment. These results highlight the importance of comparative HIV evolutionary studies in immunologically different populations worldwide.

Show MeSH
Related in: MedlinePlus