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Genetic and neutralization sensitivity of diverse HIV-1 env clones from chronically infected patients in China.

ABSTRACT: As HIV-1 continues to spread in China from traditional high risk populations to the general public, its genetic makeup has become increasingly complex. However, the impact of these genetic changes on the biological and neutralization sensitivity of the virus is unknown. The current study aims to characterize the genetic, biological, and neutralization sensitivity of HIV-1 identified in China between 2004 and 2007. Based on a total of 107 full-length envelope genes obtained directly from the infected patients, we found that those viruses fell into three major genetic groups: CRF01_AE, subtype B', and subtype C/CRF07_BC/CRF08_BC/B'C. Pseudotyped viruses built upon the viable env genes have demonstrated their substantial variability in mediating viral entry and in sensitivity to neutralization by subtype-specific plasma pools and broadly neutralizing monoclonal antibodies (bnmAb). Many viruses are resistant to one or more bnmAb, including those known to have high potency against diverse viruses from outside China. Sequence and structural analysis has revealed several mechanisms by which these resistant viruses escape recognition from bnmAb. We believe that these results will help us to better understand the impact of genetic diversity on the neutralizing sensitivity of the viruses and to facilitate the design of immunogens capable of eliciting antibodies with potency and breadth similar to those of bnmAb.

SUBMITTER: Shang H

PROVIDER: S-EPMC3077651 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Genetic and neutralization sensitivity of diverse HIV-1 env clones from chronically infected patients in China.

Shang Hong H Han Xiaoxu X Shi Xuanling X Zuo Teng T Goldin Mark M Chen Dan D Han Bing B Sun Wei W Wu Hao H Wang Xinquan X Zhang Linqi L

The Journal of biological chemistry 20110216 16

As HIV-1 continues to spread in China from traditional high risk populations to the general public, its genetic makeup has become increasingly complex. However, the impact of these genetic changes on the biological and neutralization sensitivity of the virus is unknown. The current study aims to characterize the genetic, biological, and neutralization sensitivity of HIV-1 identified in China between 2004 and 2007. Based on a total of 107 full-length envelope genes obtained directly from the infe ...[more]

PMID: 21325278

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Project description:IntroductionPolymorphisms in some host genes have a significant impact on susceptibility to HIV-1 infection and rate of disease progression (1, 2). The purpose of the current sub-study was to find out the relationship between polymorphisms in genes involved in the lipid metabolism and the CD4/CD8 T-cell counts.MethodsSub-study of a cross-sectional, observational study conducted in 468 patients with HIV infection attended at the outpatient clinic to investigate individual genetic predisposition to atherogenic dyslipidemia (AD). All patients were genetically characterized and all polymorphisms were in Hardy-Weinberg equilibrium. Thirteen polymorphisms were selected from nine genes: APOA5 (rs662799 and rs3135506); APOC3 (rs5128 and rs4520); LPL (rs328 and rs268); CETP (rs708272); HL (rs1800588); MTP (rs1800591); APOE (rs7412 and rs429358); LRP5 (rs7116604); and VLDLR (rs1454626). Lipid and lipoprotein parameters, CD4 and CD8 T-cell counts and plasma HIV-RNA were determinate. The statistical analysis was performed using SPSS statistical software version 19 (SPSS Inc., Chicago, IL, USA).ResultsWe studied 468 HIV-infected patients (men, 77%), with a mean (SD) age of 45.9 (19.7) years. The mean CD4 T-cell count and nadir CD4 was 547 (459) and 193 (159) cells/µL, respectively; 78.7% of participants were virologically suppressed. Patients carrying rs3135506 in the APOA5 gene presented a 9% increase in circulating TG levels (p=0.002) and 10% decrease in HDLc levels (p=0.005). Such association of APOA5 towards dyslipidemia was accompanied by a 21% decrease of the CD4 T-cell count (p=0.024) and a 19% increase in CD8 T-cell count (p=0.002) in carriers of the rare allele in the APOA5 rs662799 polymorphism adjusted by age and gender. Patients carrying the rare allele in rs5128 (APOC3) had a 16% decrease in circulating CD4 T cells (p=0.029); patients carrying rs1800591 (MTP) had a 29% decrease in CD4 T cells and 14% decrease in CD8 T cells (p=0.018 and p=0.008, respectively); patients carrying the rare allele rs1800588 in HL had a 11% increase in CD4 T cells (p=0.043); and carriers of the rs145626 in the VLDLR gene had 10% decrease in CD4 circulating T cells (p=0.013).ConclusionVariants in genes involved in the development of AD may also influence the immunological host-virus equilibrium in chronically HIV-infected subjects (2, 3).

Project description:BACKGROUND: HIV-1 subtype B' isolates have been predominantly circulating in China. Their intra- and inter-subtype neutralization sensitivity to autologous and heterologous plasmas has not been well studied. RESULTS: Twelve HIV-1 B' clinical isolates obtained from patients were tested for their intra- and inter-subtype neutralization sensitivity to the neutralization antibodies in the plasmas from patients infected by HIV-1 B' and CRF07_BC subtypes, respectively. We found that the plasmas from the HIV-1 B'-infected patients could potently neutralize heterologous viruses of subtype B' with mean ID50 titer (1/x) of about 67, but they were not effective in neutralizing autologous viruses of subtype B' with mean ID50 titer (1/x) of about 8. The plasmas from HIV-1 CRF07_BC-infected patients exhibited weak inter-subtype neutralization activity against subtype B' viruses with ID50 titer (1/x) is about 22. The neutralization sensitivity of HIV-1 B' isolates was inversely correlated with the neutralizing activity of plasmas from HIV-1 B'-infected patients (Spearman's r = -0.657, P = 0.020), and with the number of potential N-glycosylation site (PNGS) in V1-V5 region (Spearman's r = -0.493, P = 0.034), but positively correlated with the viral load (Spearman's r = 0.629, P = 0.028). It had no correlation with the length of V1-V5 regions or the CD4+ T cell count. Virus AH259V has low intra-subtype neutralization sensitivity, it can be neutralized by 17b (IC50: 10?g/ml) and 447-52D (IC50: 1.6?g/ml), and the neutralizing antibodies (nAbs) in plasma AH259P are effective in neutralizing infection by the primary HIV-1 isolates with different subtypes with ID50 titers (1/x) in the range of 32-396. CONCLUSIONS: These findings suggest that the HIV-1 subtype B' viruses may mutate under the immune pressure, thus becoming resistant to the autologous nAbs, possibly by changing the number of PNGS in the V1-V5 region of the viral gp120. Some of primary HIV-1 isolates are able to induce both intra- and inter-subtype cross-neutralizing antibody responses.

Dataset Information

Genetic and neutralization sensitivity of diverse HIV-1 env clones from chronically infected patients in China.

Publications

Genetic and neutralization sensitivity of diverse HIV-1 env clones from chronically infected patients in China.

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