HIV-gp140-Specific Antibodies Generated From Indian Long-Term Non-Progressors Mediate Potent ADCC Activity and Effectively Lyse Reactivated HIV Reservoir.

Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV antibodies have shown an association with HIV control. We assessed if such antibodies can be generated in vitro and whether the generated antibodies can facilitate the reduction of reactivated HIV reservoir. We isolated HIV-1-gp140-specific memory B cells from HIV-1-infected long-term non-progressors (LTNPs) with or without plasma ADCC and cultured them to generate anti-HIV antibodies. The ability of the generated antibodies to mediate ADCC and facilitate NK cell-mediated lysis of reactivated HIV reservoir was assessed by the rapid fluorometric antibody-dependent cellular cytotoxicity assay and a flow-based novel latency reduction assay, respectively. All LTNPs showed the presence of gp140-specific memory B cells [median: 0.79% (0.54%-1.225%)], which were successfully differentiated into plasma cells [median 72.0% (68.7-82.2%)] in an in-vitro culture and secreted antibodies [median OD: 0.253 (0.205-0.274)]. The HIV-gp140-specific antibodies were generated from 11/13 LTNPs irrespective of their plasma ADCC status. The generated antibodies from LTNPs with plasma ADCC showed higher ADCC potency (median: 37.6%, IQR: 32.95%-51%) and higher reduction in reactivated HIV reservoir (median: 62.5%, IQR: 58.71%-64.92%) as compared with the antibodies generated from LTNPs without plasma ADCC (ADCC: median: 8.85%, IQR: 8%-9.7%; and % p24 reduction median: 13.84, IQR: 9.863%-17.81%). The potency of these antibodies to reduce latent reservoir was two-fold higher than the respective plasma ADCC. The study showed that the potent ADCC-mediating antibodies could be generated from memory B cells of the LTNPs with plasma ADCC activity. These antibodies also showed potent ability to facilitate NK cell-mediated lysis of reactivated HIV reservoirs. It also indicated that memory B cells from individuals with plasma ADCC activity should be preferentially used for such antibody generation. The important role of these antibodies in the reduction of latent reservoirs needs to be further evaluated as a useful strategy to obtain a functional cure for HIV infection.

Higher frequencies of functional HIV-envelope-specific memory B cells are associated with nonprogressive HIV infection in Indian population.

OBJECTIVE: The HIV-1-specific antibodies are being considered for prevention and therapy in HIV infection. For effective antibody response, presence of functionally competent memory B cells (MEBs) is important; however, HIV-infection is known to alter the B-cell functionality. Very limited data are available on the HIV-specific memory B-cell population in HIV-infected Indian population. METHODS: In this study, the frequencies of HIV-gp140-specific MEBs were measured in individuals with nonprogressive [long-term-nonprogressors (LTNPs), N = 20] and progressive (N = 19) HIV infection using multicolor flow cytometry. The activation and functional status of these MEBs were assessed as frequencies and mean fluorescence intensity (MFI) of the CD38 and CD40 expression, respectively. RESULTS: The percentages of gp140 + MEBs were higher in LTNPs than seen in progressors (P = 0.0475) and associated with higher CD4 cell count (P = 0.0312, r = 0.2833). As compared with the progressors, LTNPs also showed higher functional (CD40+) gp140 + MEBs both frequencies (P < 0.0001) and CD40 MFI (P = 0.0222), whereas the frequencies (<0.0001) and the MFI (P = 0.0047) of CD38 expression was significantly lower. Higher CD4 cell counts and lower plasma viral load values were associated with higher frequencies of CD40+ gp140 + MEBs (P < 0.0001, r = 0.4962) (P = 0.0036, r = -0.4202) and lower frequencies (P = 0.0008, r = -0.4231) and CD38 expression (MFI) (P = 0.004, r = -0.3719) (P = 0.0066, r = 0.4033). CONCLUSION: Our study suggests that LTNPs have functional HIV-specific memory B-cell compartment with reduced activation that may lead to effective HIV-specific humoral immune responses contributing to their nondisease progression status. These findings would help in better understanding of the characteristics of the HIV-specific memory B-cell population in nonprogressive HIV infection.