HIV-1-specific CTL Responses In Subjects Infected With HIV-1 CRF07_BC And Its Relation With Host Genetic Background

Acquired immunodeficiency syndrome(AIDS) is an infectious disease caused by retrovirus HIV-1.Since its first report in June 1981,the pandemic of AIDS has been a great challenge to the global public health,especially in developing countries.Vaccine is one of the most effective and economical measures to control and prevent infectious diseases.In this scenario,a successful AIDS vaccine is urgently needed and intensively pursued by scientific community.Pathogen specific CD8+ cytotoxic T lymphocytes(CTL) are important in adaptive immune responses and play pivotal roles in controlling viral infection.Accumulative data suggested that HIV-1-specific CD8+ CTL responses play protective roles in containing viral replication and indicated that a successful AIDS vaccine should induce HIV-1-spocifc CD8+ CTL responses targeting immunodominant regions in addition to induction of neutralizing antibodies.After more than two decades of commitment to developing an effective AIDS vaccine,emerging consensus was that more efforts should be put into basic research focusing on HIV-1 pathogenesis and mechanism of protective immune responses in natural HIV-1 infection.HIV-1-specific CD8+ CTL responses were based on the recognition of HLA classⅠmolecules and the viral peptides presented,both of which are of high polymophism. The differences of circulating HIV-1 strains and genetic background of infected populations may impact on the recognition pattern of CTL responses and its association with disease progression.Based on such a postulate,the characterization of HIV-1-specific T cell responses in people infected with locally circulating HIV-1 strain was urgently needed to facilitate the development of more specific HIV-1 diagnostic reagents and vaccine.In this study,we assessed the profile of CTL responses in a Chinese IDU population infected with HIV-1 circulating recombinant form 07_BC(CRF07_BC),which has been spreading rapidly in western China from north to south.The breadth,magnitude,immunodominance,and cross-recognition of CTL responses in this CRF07_BC infected Chinese population were evaluated,the extent of HLA-I allele promiscuity among viral epitope was explored,and the correlation between CTL responses and the containment of viral replication was determined.The impact of broad antigen HLA-Bw4 on disease progression in HIV-1 infected subjects were also explored.Sixty HIV-1 positive subjects were recruited from Xinjiang,China to assess the HIV-1-specific T cell responses at single peptide level by employing ELISPOT using 2 sets of peptides covering the consensus clades B and C HIV-1 whole expressed genome.The median of the total magnitude and total number of overlapping synthetic peptides(OLPs) recognized were 10925 SFC/million PBMC and 25 OLPs, respectively,when tested by clade C peptides,which was significantly higher than when tested by clade B peptides.The immunodominant regions are widely distributed throughout the genome except in Tat,Vpu and Pol-PR,with Gag,Pol-RT,Pol-Int and Nef being most frequently targeted.HLA-I allele promiscuity among HIV-1 derived CTL epitopes were analyzed and extensive promiscuity was observed with above 36.72%(398/1084) of immunodominant responses higher than 500 SFC/10~6 PBMC targeting OLPs with reported CTL epitopes without matching HLA-I restriction. There have been no significant correlations identified between the accumulative CTL responses or overall breadth and CD4 cell count or plasma viral load.However, stronger and broader CTL responses in subjects with CD4 cell counts ranging from 200 to 400/μL were observed when compared to those with less than 200/μL or more than 400/μL.Three hundred and forty subjects chronically infected with HIV-1 and 69 HIV-1 negative subjects were recruited to investigate the impact of HLA classⅠmolecules carrying Bw4 epitopes on disease course of HIV-1 infection.When looking at HLA-B locus only,we found that subjects with Bw4(Bw4 homozygotes and Bw4Bw6 heterozygotes) had higher CD4+ T cell counts(P=0.004)and lower plasma viral load (P=0.003) than subjects without Bw4(Bw6 homozygotes).When compared with HIV-1 positive subjects with CD4+ T cell counts above 500/μL,those with CD4+ T cell counts below 500/μL were observed with decreased percentage of Bw4Bw6 heterozygote(P=0.0002) and increased percentage of Bw6 homozygotes(P＜0.0001). There is no significant difference in CD4+T eeU counts between Bw4 homozygotes and Bw4Bw6 heterozygote,but lower viral loads were observed in Bw4Bw6 heterozygotes(P=0.037).Then,both HLA-A and B loci carrying Bw4 epitope were analyzed,and we found that in HIV-1 infected subjects,CD4+ T cell counts in subjects with Bw4 epitopes in HLA-A alleles but no in HLA-B were comparable with those without Bw4 in HLA-A and HLA-B,but the trend with higher viral load was observed.In subjects with Bw4 epitopes in HLA-B alleles but no in HLA-A, significantly higher CD4+ T cel/counts and lower viral load were observed compared with those without Bw4 in HLA-A and HLA-B(P=0.013,0.007 respectively).These data indicate that HLA-B antigens carrying Bw4 epitope were protective in HIV-1 infection by maintaining higher CD4+ T cell counts and lower viral load,but such protective effect was not observed in HLA-A antigens carrying Bw4 epitope. This is the first study conducted to address T cell responses in Chinese subjects infected with HIV-1 CRF07_BC in which subtle differences in cross-reactivity were observed,though similar patterns of overall immune responses were demonstrated with clade B infected populations.The immunodominant regions identified in this population can facilitate future HIV-1 vaccine development in China.To our knowledge,this is also the first time to investigate the impact of alleles of HLA-1 locus A carrying Bw4 on disease progression in HIV-1 infection,and our data indicate that other than HLA-B,HLA-A antigens carrying Bw4 epitope may have no protective role in HIV-1 infection,which was well documented for HLA-B antigen.