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Neutralization of tier-2 viruses and epitope profiling of plasma antibodies from human immunodeficiency virus type 1 infected donors from India.

ABSTRACT: Broadly cross neutralizing antibodies (NAbs) are generated in a group of HIV-1 infected individuals during the natural infection, but little is known about their prevalence in patients infected with viral subtypes from different geographical regions. We tested here the neutralizing efficiency of plasma antibodies from 80 HIV-1 infected antiretroviral drug naive patients against a panel of subtype-B and C tier 2 viruses. We detected cross-neutralizing antibodies in approximately 19-27% of the plasma, however the subtype-C specific neutralization efficiency predominated (p = 0.004). The neutralizing activity was shown to be exclusively mediated by the immunoglobulin G (IgG) fraction in the representative plasma samples. Epitope mapping of three, the most cross-neutralizing plasma (CNP) AIIMS206, AIIMS239 and AIIMS249 with consensus-C overlapping envelope peptides revealed ten different binding specificities with only V3 and IDR being common. The V3 and IDR were highly antigenic regions but no correlation between their reciprocal Max50 binding titers and neutralization was observed. In addition, the neutralizing activity of CNP was not substantially reduced by V3 and gp41 peptides except a modest contribution of MPER peptide. The MPER was rarely recognized by plasma antibodies though antibody depletion and competition experiments demonstrated MPER dependent neutralization in two out of three CNP. Interestingly, the binding specificity of one of the CNP (AIIMS206) overlapped with broadly neutralizing mAb 2F5 epitope. Overall, the data suggest that, despite the low immunogenicity of HIV-1 MPER, the antibodies directed to this region may serve as crucial reagents for HIV-1 vaccine design.

SUBMITTER: Andrabi R

PROVIDER: S-EPMC3432049 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Neutralization of tier-2 viruses and epitope profiling of plasma antibodies from human immunodeficiency virus type 1 infected donors from India.

Andrabi Raiees R Bala Manju M Kumar Rajesh R Wig Naveet N Hazarika Anjali A Luthra Kalpana K

PloS one 20120831 8

Broadly cross neutralizing antibodies (NAbs) are generated in a group of HIV-1 infected individuals during the natural infection, but little is known about their prevalence in patients infected with viral subtypes from different geographical regions. We tested here the neutralizing efficiency of plasma antibodies from 80 HIV-1 infected antiretroviral drug naive patients against a panel of subtype-B and C tier 2 viruses. We detected cross-neutralizing antibodies in approximately 19-27% of the pla ...[more]

PMID: 22952740

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Project description:UNLABELLED:Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n = 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n = 1). We found that bNabs directed against the CD4 binding site (n = 10), peptidoglycans at the base of variable loop 3 (V3) (n = 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n = 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n = 3) as well as llama-derived (heavy chain only) antibodies (n = 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection. IMPORTANCE:SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes.

Project description:BackgroundHuman parvovirus B19 (B19V) is a common contaminant found in plasma pools and plasma derivatives. Previous studies were mainly focused on limited aspects, further assessment of prevalence of B19V DNA and antibodies in plasma donors, the contamination of B19V in pooled plasma and plasma derivatives should be performed in China.Study design and methodsIndividual plasma donors' samples from four provinces and pooled plasma from four Chinese blood product manufacturers were collected and screened using B19V DNA diagnostic kits between October 2018 and May 2020. The positive samples were investigated for the seroprevalence of B19V antibodies and subjected to sequence analysis and alignment for phylogenetic studies. Moreover, 11 plasma donors who were B19V DNA-positive at their first testing were also followed during the later donation period. Additionally, 400 plasma pools and 20 batches of plasma derivatives produced by pooled plasma with a viral load of B19V DNA exceeding 104IU/mL were also collected and tested for B19V DNA and antibodies.ObjectivesTo comprehensively and systematically determine the frequency and viral load of B19V DNA in plasma donors, pooled plasma, and plasma derivatives from four Chinese blood product manufacturers.ResultsA total of 17,187 plasma donors were analyzed and 44 (0.26%) specimens were found positive for B19V DNA. The quantitative DNA levels ranged from 1.01 × 101 to 5.09 × 1012 IU/mL. Forty-four DNA-positive specimens were also investigated for the seroprevalence of B19V antibodies, 75.0% and 2.3% of which were seropositive for B19V IgG and IgM antibodies, respectively. The phylogenic analyses showed that the prevalent genotypes in the four provinces' plasma donors belonged to B19V Genotype 1. Eleven individual plasma donors who were B19V DNA-positive at the first donation were then followed for a period, and in general, the DNA levels of B19V gradually decreased. Moreover, 64.8% (259/400) of the pooled plasma was contaminated by B19V, with concentrations of 1.05 × 100-3.36 × 109IU/mL. Approximately 72.6% of the DNA-positive plasma pools were only moderately contaminated (<104 IU/mL), while 27.4% contained >104 IU/mL. Twenty batches of plasma derivatives produced by pooled plasma with a viral load of B19V DNA exceeding 104IU/mL were also tested. B19V was detected in 5/5 PCC samples and 5/5 factor VIII samples but was not found in the intravenous immune globulin and albumin samples.ConclusionThe contamination of B19V in pooled plasma and plasma-derived clotting factor concentrates is serious. Whether B19V nucleic acid testing (NAT) screening of plasma and plasma derivatives is launched in China, blood product manufacturers should spontaneously perform B19V NAT screening in plasma donors and mini-pool plasma. These measures can ensure that samples with high titer B19V DNA are discarded in order to prevent and control this transfusion transmitted virus.

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

Neutralization of tier-2 viruses and epitope profiling of plasma antibodies from human immunodeficiency virus type 1 infected donors from India.

Publications

Neutralization of tier-2 viruses and epitope profiling of plasma antibodies from human immunodeficiency virus type 1 infected donors from India.

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