Study On Characteristics Of Heredity, Immune Responese And HIV Gene Mutations Between China HIV Infected Long-term Nonprogressors And Typical Progressors

[Objective]:The aim of this research is to compare the characteristics of heredity, immunity and HIV gene mutation between Chinese long-term nonprogressor(LTNP) and HIV typical progressor(TP) and to evaluate the factors associated with AIDS progression and viral control.[Methods]:39 volunteers were divided into 2 groups according to disease progression:21 LTNPs were from the same region of Henan province; 18 TPs had the similar biological backgrounds and most of the TPs were also from Henan province. All subjects were infected HIV through blood transmission at the same period. Host heredity characteristics (HLA types) were detected by PCR-SBT. Immune responses including peripheral blood T-lymphocyte subsets were detected by flow cytometry and neutralize antibody level were analyzed by single round PBMC neutralization using pseudoviruses. HIV genetic characteristics were mainly determined by RT-PCR targeting env V3-V4, gag and pol. Purified PCR products were also sequenced and the sequences were analyzed for the biological phenotype and the gene mutation under host selective pressures, including antigen epitope shifts, glycosylation site mutation and so on.[Results]:The results showed that:the average time since infection was 16±1.4 years in LTNP group which is significantly longer than that of TP 8±2.2 years (P<0.001). The viral load of LTNP was 2.76±0.93 (log copies/ml), and was significantly lower than 4.65±1.06 (log copies/ml) of TP (P<0.001). NK cell and CD4+T cell count of LTNP were 156±104/μl, 544±158/μl respectively, both of which were significantly higher than 78±43/μl,80±124/μl of TP(NK:P=0.004, CD4+T:P<0.001). The naive CD4+T cells and memory CD4+T cells in LTNP were 254±98/μl and 291±99/μl respectively, both of which were significantly higher than 31±74μl,42±53/μl of TP. The CD8+CD38+T cell frequency in LTNP was 52.4±12.8%, which was significantly lower than 83.1±14.7% of TP(P<0.001). The inverse correlation could be observed between the viral load(VL), CD8+CD38+T cell frequency and their CD4+T cell counts(VL:r=-0.55, P=0.033; CD8+CD38+:r=-0.667, P<0.001). The frequency of HLA-B*57 and HLA-A*30 in LTNP were 8.3%and 23.8%respectively, both of which were significantly higher than 0 and 4.3%of TP(A*30:P=0.01, B*57:P=0.033), while the frequency of HLA-DRB1*15 in LTNP was 10.5%which was significantly lower than 33.3%of TP(P=0.046). The frequency of NAbs IR to pseudovirus B8 and SF162 over 50%in LTNPs were 23.8%and 66.7%respectively, both of which were significantly higher than 0 and 16.7%of TP(B16:P=0.009, SF162:P=0.001), while B cell count was 174±48/μl in LTNP which was significantly higher than 92±68/μl of TP(P=0.001). The most prevalent strains were B1 and most strains were predicted to be CCR5-tropism. Analyzing the pairwise DNA distances in different gene compartment showed that env V3-V4 region were highly variable compared with gag and gag subdivided parts, and the mean DNA distances in LTNP was smaller than TP or similar to TP. Analysis of the immune selective pressure in V4 region showed that there were more immune pressure among TP than LTNP. There was also a trend that more glycosylation sites were missing in LTNP compared to TP. There were three major types of V3 loop central motif-GPGR, GPGQ and GQGR in all strains. GPGQ was the prevalent type in LTNP (53.3%) while GPGR was the prevalent type in TP(53.3%), and no significant difference was observed between the two groups. There were 19 kinds of CTL epitope mutations observed and the two groups had the similar mutant rates in each mutantion.[Conclusions]:The decrease of the NK cell, memory and naive CD4+T cell counts and the increased activation of CD8+T cells in patients with HIV might be associated with AIDS progression. The breadth level of NAbs might influence on disease progression and B cell count might be one reason of such differences between the two groups. HLA-DRB 1*15 might accelerate the disease progression and HLA-B*57 had the protection effect from disease progression among Chinese population; HLA-A*30 might also have the protection effect but needs a larger sample observation. The most prevalent strains were B' from blood transmission especially in Henan province and most strains were predicted to be CCR5-tropism. There were different selective pressures in V4 region between LTNP and TP, and further research on the function of V4 region may help understanding the role of V4 in disease progression.