A group of commercial sex workers in the Pumwani Sex Worker Cohort, established in 1985 in Nairobi, Kenya, remain HIV-1 uninfected despite heavy exposure to HIV-1 through active sex work. Previous studies showed that this resistance is associated with a strong CD4+ T-cell response, which suggested that human leukocyte antigen class II antigens are important in resistance/susceptibility to HIV-1 infection. DRB1 is the most polymorphic locus among class II genes and forms haplotypes with DRB3, DRB4 and DRB5. The aim of this study is to investigate the role of DRB alleles/haplotypes on resistance/susceptibility to HIV-1 infection.
In total, 1090 women enrolled in the Pumwani cohort were genotyped for DRB1, DRB3, DRB4 and DRB5 using a high-resolution sequence-based method. Allele/haplotype frequencies were compared between HIV-positive women and women who have remained HIV negative for more than 3 years despite frequent exposure.
Human leukocyte antigen DRB genes were amplified, sequenced and genotyped using a two-step sequence-based method. Allele/haplotype frequencies were determined using PyPop32-0.6.0. Statistical analysis was conducted using SPSS 11.0 for Windows.
Three DRB1 alleles were associated with resistance: DRB1*010101 (P = 0.016; odd ratio (OR): 2.55; 95% confidence interval (CI): 1.16-5.61), DRB1*010201 (P = 0.019; OR: 1.86; 95% CI: 1.10-3.15), and DRB1*1102 (P = 0.025; OR: 1.72; 95% CI: 1.07-2.78). DRB1*030201 (P = 0.038; OR: 0.48; 95% CI: 0.23-0.98), DRB1*070101 (P = 0.035; OR: 0.54; 95% CI: 0.30-0.97), DRB1*1503 (P = 0.0004; OR: 0.34; 95% CI: 0.19-0.64), and DRB5*010101 (P = 0.001; OR: 0.37; 95% CI: 0.20-0.67) were associated with susceptibility. The haplotype DRB1*1102-DRB3*020201 was associated with HIV-1 resistance (P = 0.041; OR: 1.68; 95% CI: 1.02-2.78), whereas the haplotypes DRB1*070101-DRB4*01010101 (P = 0.041; OR: 0.52; 95% CI: 0.28-0.98) and DRB1*1503-DRB5*01010101 (P = 0.0002; OR: 0.30; 95% CI: 0.15-0.58) were associated with susceptibility. These associations with resistance/susceptibility to HIV-1 were independent of previously reported alleles HLA-DRB1*01 and HLA-A*2301.
Our findings indicate that human leukocyte antigen DRB-specific CD4+ T-cell responses are an important factor in resistance/susceptibility to HIV-1 infection.
"Moreover, each tested HLA-DR molecule bound on average to 19 out of the 27 peptides, which indicates that a vaccine encoding such peptides would have potential to induce T-cell responses against multiple targets in a wide proportion of the population. Notably, all peptides bound to at least one HLA class II molecule associated with AIDS protection, such as HLA-DRB1*0101, -DRB3*0202, -DRB1*13 and -DQB1*06 , , which suggests that those peptides may be involved in protective immunity against HIV-1. The 27 peptides were also shown to be highly conserved when compared to sequences from all HIV-1 circulating variants available at the Los Alamos HIV Database, indicating that the identified peptides, or sequences highly homologous to them, are broadly represented across several HIV-1 subtypes. "
[Show abstract][Hide abstract] ABSTRACT: T-cell based vaccine approaches have emerged to counteract HIV-1/AIDS. Broad, polyfunctional and cytotoxic CD4(+) T-cell responses have been associated with control of HIV-1 replication, which supports the inclusion of CD4(+) T-cell epitopes in vaccines. A successful HIV-1 vaccine should also be designed to overcome viral genetic diversity and be able to confer immunity in a high proportion of immunized individuals from a diverse HLA-bearing population. In this study, we rationally designed a multiepitopic DNA vaccine in order to elicit broad and cross-clade CD4(+) T-cell responses against highly conserved and promiscuous peptides from the HIV-1 M-group consensus sequence. We identified 27 conserved, multiple HLA-DR-binding peptides in the HIV-1 M-group consensus sequences of Gag, Pol, Nef, Vif, Vpr, Rev and Vpu using the TEPITOPE algorithm. The peptides bound in vitro to an average of 12 out of the 17 tested HLA-DR molecules and also to several molecules such as HLA-DP, -DQ and murine IA(b) and IA(d). Sixteen out of the 27 peptides were recognized by PBMC from patients infected with different HIV-1 variants and 72% of such patients recognized at least 1 peptide. Immunization with a DNA vaccine (HIVBr27) encoding the identified peptides elicited IFN-γ secretion against 11 out of the 27 peptides in BALB/c mice; CD4(+) and CD8(+) T-cell proliferation was observed against 8 and 6 peptides, respectively. HIVBr27 immunization elicited cross-clade T-cell responses against several HIV-1 peptide variants. Polyfunctional CD4(+) and CD8(+) T cells, able to simultaneously proliferate and produce IFN-γ and TNF-α, were also observed. This vaccine concept may cope with HIV-1 genetic diversity as well as provide increased population coverage, which are desirable features for an efficacious strategy against HIV-1/AIDS.
PLoS ONE 09/2012; 7(9):e45267. DOI:10.1371/journal.pone.0045267 · 3.23 Impact Factor
"Nevertheless, the human study indicated that the DRB-specific CD4 + T-cell responses are an important factor in resistance/susceptibility to HIV-1 infection (Lacap et al., 2008). For chimpanzees, it is known that they maintain CD4 + T-cell responses after HIV-1/SIV cpz infection. "
[Show abstract][Hide abstract] ABSTRACT: In humans, great apes, and different monkey species, the major histocompatibility complex (MHC) class II DRB region is known to display considerable copy number variation. The microsatellite D6S2878 has been shown to be a valuable marker for haplotyping the DR region in humans and macaque species. The present report illustrates that chimpanzee haplotypes also can be discriminated with this marker. The analyses resulted in the description of nine different region configurations, of which seven are present within the West African chimpanzee population studied. The region configurations vary in gene content from two up to five DRB genes. Subsequent cDNA sequencing increased the number of known full-length Patr-DRB sequences from 3 to 32, and shows that one to three Patr-DRB genes per haplotype apparently produce functional transcripts. This is more or less comparable to humans and rhesus macaques. Moreover, microsatellite analysis in concert with full-length DRB gene sequencing showed that the Patr-DRB*W9 and -DRB3*01/02 lineages most likely arose from a common ancestral lineage: hence, the Patr-DRB*W9 lineage was renamed to Patr-DRB3*07. Overall, the data demonstrate that the D6S2878 microsatellite marker allows fast and accurate haplotyping of the Patr-DRB region. In addition, the limited amount of allelic variation observed at the various Patr-DRB genes is in agreement with the fact that chimpanzees experienced a selective sweep that may have been caused by an ancient retroviral infection.
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