Associations between HLA Frequencies and Pathogenic Features of Human Immunodeficiency Virus Type 1 Infection in Seroconverters from the Amsterdam Cohort of Homosexual Men

Abstract

HLA-disease associations may be important for understanding the pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection. Therefore, 106 homosexual men from the Amsterdam Cohort Study on AIDS with a known date of HIV-1 seroconversion were serologically typed for HLA. Several significant associations between HLA type and pathogenic features of HIV-1 infection were observed: Subjects with fever and skin rash during primary HIV-1 infection showed an increased frequency of HLA-B62 (relative risk [RR], 5.8; P = .005). The frequency of HLA-B35 was increased in subjects with a rapid decline in CD4+ T lymphocytes (RR, 3.2; P = .021). Kaplan-Meier survival analysis revealed a significant association between HLA-B35 and a decrease in CD4+ cells to < 200/microL (P = .01). The strongest association was found between HLA-DR1 and AIDS-related Kaposi's sarcoma (RR, 22.5; P < .001), also confirmed in survival analysis (P = .001). In AIDS patients with only opportunistic infections, increased frequencies of HLA-DR3 (P = .011) and -DQ2 (P = .007) were observed. Finally, the occurrence of syncytium-inducing HIV-1 variants was significantly associated with HLA-DQ2 (P = .01).

Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity

“…It has been speculated that the broader range of antigen presentation in individuals heterozygous at class I loci confers immunological advantage (9), which would be consistent with recent studies showing the importance of host cytotoxic T lymphocytes (CTL) in disease outcome (12)(13)(14). In particular, specific HLA-B antigens, including HLA-B27, -B51, -B57, -B8, and -B35, have been associated with different patterns of HIV-1-related disease progression (10,(15)(16)(17)(18).…”

Heterozygote advantage fails to explain the high degree of polymorphism of the MHC

“…For instance, a one-amino-acid difference in the peptide-binding region of the DRB1*1302 allele abrogates its protection to malaria (Davenport et al 1995). Protective HLA alleles have been described for a number of infectious diseases (Van Eden et al 1980;Hill et al 1991;Klein et al 1994), and the associated fitness differences are much larger than the small differences required for explaining the high degree of HLA polymorphism. The fact that the HLA alleles expressed in the South Amerindian population are different from those in the founder population, while North Amerindians still express the founder alleles (Parham and Ohta 1996), also suggests that different MHC alleles provide different degrees of protection against different pathogens.…”

“…It is now well established that different MHC alleles provide different levels of protection to specific pathogens (Van Eden et al 1980;Hill et al 1991;Klein et al 1994). One could nevertheless argue that by averaging over many different pathogens the lifetime fitness contributions of MHC alleles would become very similar, and hence that heterozygote advantage would be able to account for a high degree of MHC polymorphism.…”

Genetic Factors that Influence HIV Infection: The Role of the Major Histocompatibility Complex System

“…Focusing on particular aspects of the disease, researchers were able to study a cohort of 106 homosexual men from Amsterdam and correlate certain alleles with different aspects of HIV pathogenesis, including skin rash (HLA-B62), rapid decline of CD4+ T lymphocytes to < 200/microL (HLA-B35), AIDS-related Kaposi's sarcoma (HLA-DR1) and opportunistic infections (HLA-DR3 and DQ2) (Klein et al, 1994). HLA disease associations studies were performed in different populations, such as in India (Shankarkumar, 2004), south India (Selvaraj et al, 2006) and southern Africa (Lombard et al, 2006).…”

“…CTL responses associated with lack of HIV control. DC dysfunction Klein et al, 1994;Carrington et al, 1999;Kawana et al, 1999;Jin et al, 2002;FloresVillanueva et al, 2003;Liu et al, 2003;Arnaiz-Villena et al, 2009;Huang et al, 2009 ;Pereyra et al, 2010 Kaslow et al, 1996;den Uyl et al, 2004;Fellay et al, 2007;Pereyra et al, 2010 ;Salgado et al, 2011b …”