Downloaded from www.microbiologyresearch.org by IP: 54.70.40.11 On: Thu, 04 Jul 2019 04:39:13 Broad neutralization response in a subset of HIV-1 subtype C-infected viraemic non-progressors from southern India Paneerselvam Nandagopal, 1 Jayanta Bhattacharya, 2 Aylur K. Srikrishnan, 1 Rajat Goyal, 3 Chinnambedu Ravichandran Swathirajan, 1 Shilpa Patil, 2 Shanmugam Saravanan, 1 Suprit Deshpande, 2 Ramachandran Vignesh, 1,4 Sunil Suhas Solomon, 1,5 Nikhil Singla, 3 Joyeeta Mukherjee 3 and Kailapuri G. Murugavel 1, * Abstract Broadly neutralizing antibodies (bnAbs) have been considered to be potent therapeutic tools and potential vaccine candidates to enable protection against various clades of human immunodeficiency virus (HIV). The generation of bnAbs has been associated with enhanced exposure to antigen, high viral load and low CD4+ T cell counts, among other factors. However, only limited data are available on the generation of bnAbs in viraemic non-progressors that demonstrate moderate to high viraemia. Further, since HIV-1 subtype C viruses account for more than 50 % of global HIV infections, the identification of bnAbs with novel specificities is crucial to enable the development of potent tools to aid in HIV therapy and prevention. In the present study, we analysed and compared the neutralization potential of responses in 70 plasma samples isolated from ART-naïve HIV-1 subtype C-infected individuals with various disease progression profiles against a panel of 30 pseudoviruses. Among the seven samples that exhibited a neutralization breadth of 70 %, four were identified as ‘elite neutralizers’, and three of these were from viraemic non-progressors while the fourth was from a typical progressor. Analysis of the neutralization specificities revealed that none of the four elite neutralizers were reactive to epitopes in the membrane proximal external region (MPER), CD4-binding site and V1V2 or V3 glycan. However, two of the four elite neutralizers exhibited enhanced sensitivity towards viruses lacking N332 glycan, indicating high neutralization potency. Overall, our findings indicate that the identification of potent neutralization responses with distinct epitope specificities is possible from the as yet unexplored Indian population, which has a high prevalence of HIV-1 subtype C infection. INTRODUCTION The elicitation of potent neutralizing antibodies is the princi- pal correlate of protection for most preventable vaccines [1]. For rapidly evolving pathogens like human immunodefi- ciency virus (HIV), neutralizing antibodies elicited by vacci- nation or during natural infection are largely strain-specific and therefore non-protective against globally circulating viral strains [2]. However, 10–20 % of HIV-infected individuals elicit highly potent broadly neutralizing antibodies (bnAbs) that hold promise as potent therapeutic and prophylactic agents. Recent studies have shown that passively transferred bnAbs protect against simian/human immunodeficiency virus (SHIV) infection in non-human primates [3] and con- trol viraemia in HIV-infected individuals with chronic infec- tion [4–6]. In recent years, major advancements in HIV vaccine research have resulted in the isolation and characteri- zation of next-generation bnAbs that are able to neutralize around 70 to 90 % of circulating HIV-1 strains in vitro [7] Received 13 December 2017; Accepted 18 January 2018 Author affiliations: 1 YRG Center for AIDS Research and Education, Chennai, India; 2 HIV Vaccine Translational Research Laboratory, Translational Health Science and Technology Institute, Faridabad, India; 3 International AIDS Vaccine Initiative (IAVI), New Delhi, India; 4 Laboratory-based Department, UniKL-Royal College of Medicine Perak (UniKL-RCMP), Universiti Kuala Lumpur, Greentown, Ipoh 30450, Malaysia; 5 Johns Hopkins University School of Medicine, Baltimore, MD, USA. *Correspondence: Kailapuri G. Murugavel, murugavel@yrgcare.org Keywords: viremic non- progressors; bnAbs; broad neutralizers; HIV-1 Subtype C. Abbreviations: ART, antiretroviral therapy; ARV, antiretroviral drugs; bnAbs, broadly neutralizing antibodies; CATNAP, Compile, Analyse and Tally NAb Panels Database; CD4bs, CD4-binding site; DFID, United Kingdom Department for International Development; DMEM, Dulbecco’s modified Eagle’s medium; env, envelope; GMT, geometric mean titre; IAVI, International AIDS Vaccine Initiative; IBMT, Fraunhofer Institute for Biomedical Engineering; ID 50 , inhibitory dilution (ID 50 ); IRB, institutional review board; LANL, Los Alamos National Laboratory; LTR, long terminal repeat; LT*VC, long-term virae- mic controller; LTNP, long-term non-progressors; LT*VNP, long-term viraemic non-progressors; MLV, murine leukaemia virus; MPER, membrane proximal external region; NIHARRP, NIH AIDS Research and Reference Reagent Program; NORAD, Norwegian Agency for Development Cooperation; OPD, o-phenylenediamine dihydrochloride; PBST, phosphate-buffered saline with Tween 20; RLU, relative luminescence units; RSC3, resurfaced sta- bilized core 3; SHIV, simian/human immunodeficiency virus; SHM, somatic hypermutation; TP, typical progressors; USAID, United States Agency for International Development; YRG CARE, YRG Center for AIDS Research and Education. Three supplementary tables and one supplementary figures are available with the online version of this article. RESEARCH ARTICLE Nandagopal et al., Journal of General Virology 2018;99:379–392 DOI 10.1099/jgv.0.001016 001016 ã 2018 The Authors 379