Interestingly, four of the autologous Envs (HIV-1 NLR-2007
Interestingly, four of the autologous Envs (HIV-1 NLR-2007.J10, HIV-1 NLR-2007.J12, HIV-1 NLR-2007.J24, HIV-1 NLR-2007.J32) obtained from this donor were found to possess longer V1 loop length with identical amino acid sequence (Fig.2b) consisting of 41 amino acids compared to HIV-1 NLR-2007.J48 that was found to contain 27 amino acids in the V1 region. of protective N-glycans. In summary, we show evidence of escape of circulating HIV-1 clade C in an individual from autologous BCN antibodies by three distinct mechanisms. Keywords:HIV-1, Neutralizing antibody, Envelope, Plasma The HIV-1 envelope (Env) protein that mediates entry of viral RNA into the cellular cytoplasm is the target of neutralizing antibodies. During the course of the infection, HIV-1 evolves within an individual to escape the humoral immune pressure by selection of mutations, alterations of the glycosylation pattern and varying loop lengths. Variation in lengths and glycosylation patterns in the hypervariable loops of viral Env, particularly in the V1V2 loop has been shown to be associated with alterations in virus entry and neutralization [114]. Neutralizing antibodies to autologous circulating HIV-1 develop in most infected individuals within 6 months [5,15,16], however only in some individuals, neutralizing antibodies with considerable breadth and potency develops over time Clidinium Bromide [17,18]. Broadly neutralizing monoclonal antibodies (bnAbs) isolated from individuals infected with HIV-1 have identified major targets in the CD4 binding site (CD4bs), the membrane proximal external region (MPER), the trimer apex (V1/V2), the V3-glycan supersite and the gp120/gp41 interface on the HIV-1 Env [19]. Variable loop length (particularly the V1V2 loop) and glycosylation signatures within these loops have been demonstrated to be selectively associated with resistance and enhanced sensitivity to some bnAbs [6,7,9,10,2024]. Glycan supersites in the V3 region of HIV-1 envelope form vulnerable targets that are exploited by potent and broadly neutralizing monoclonal antibodies (bnAbs) such as PGT121 and PGT128 [25]. The Clidinium Bromide glycan N332 residue in the V3 base has been demonstrated to represent an important supersite of vulnerability for comprehensive antibody mediated virus neutralization and is currently aiding design and development of Clidinium Bromide an effective vaccine. In the case of mAbs PGT121 and PGT128 that target the V3-glycan supersite, loss of the glycan at position 332 is often associated with resistance [26]. Recently, Goo et al. and Sok et al. [26,27] reported that some viruses despite the presence of key N301 and N332 V3 glycans were found to be resistant to the potent and broadly neutralizing mAbs, PGT121 and PGT128. They suggested that altered conformation Clidinium Bromide of Env due to unknown mechanisms resulted in neutralization resistance of viruses to these mAbs. Recently, van den Kerkhof et al. [14] showed Mouse monoclonal to Fibulin 5 association of elongated V1 loop length with resistance to patient derived primary Envs to PGT135 mAb. In the present study, we examined the basis of resistance of HIV-1 clade C Envs to contemporaneous BCN plasma (INDO-SA 2007) obtained from a slow progressing Indian patient whose specificity mapped to the N332 at the V3 base. By examining HIV-1 Envs obtained from BCN plasma of an Indian patient, we found that longer V1 loop length hinders the bnAbs such as PGT121 and PGT128 to access the N332 glycan epitope. Our observation provides information that explains the basis of resistance of HIV-1 variants that are naturally resistant to bnAbs targeting N332 glycan epitope. We screened 100 HIV-1 positive plasma samples obtained from antiretroviral therapy (ART) nave slow progressing Indian donors with a CD4 count >350 mm3for the presence of broadly neutralizing antibodies to HIV-1 clade C viruses from India (n = 9) and South Africa (n = 8). Of the 21 plasma samples that were found to cross neutralize >50 % of the pseudoviruses at 1:100 dilution, we identified an Indian donor (INDO-SA 2007) whose plasma showed the maximum breadth and potency with median ID50 of 770 (Fig.1a). The INDO-SA 2007 plasma showed geometric mean titer of >749 when tested against a larger panel of Clidinium Bromide 28 HIV-1 Env pseudotyped viruses primarily comprising Envs of Indian and.