Synopsis of the R&D plan proposed by Girish N. Vyas, Ph.D., F.R.C. Path.
The combined passive-active immunization of neonates with HBIG and HBsAg vaccine, implemented since 1995, has virtually eliminated mother to child transmission of HBV in China and Taiwan (Stevens CA et al., Biologicals, 2017). This remarkable success serves as a paradigm for immune-based prevention and cure of HIV-1 infection, which remains a formidable challenge despite four decades of sustained effort and more than $20 billion invested in research and development of preventive antibodies and vaccines.
Every HIV infections is (1) initiated by the founder/transmitted (F/T) R5-HIV phenotype, (2) followed by both T and B cell immune responses, including antibody response to the viral envelope proteins, (3) not eliminated by autologous immune responses and result in persistent infection, and (4) not preventable by polyclonal IgG isolated from pooled plasma of infected blood donors. These data indicate a specific immune tolerance lesion at the B cell level.
The HIV-1 envelope gene (Env) encodes gp160, which is post-translationally cleaved into gp120 and gp41. The cysteine residues in the cytoplasmic tail of gp41 form a trimeric structure that enables noncovalent assembly of three molecules of gp120, (gp41-gp120) X3, in the infectious virions of diverse genotypes (A-H and their recombinant forms). We postulate that T cell independent quaternary conformational antigenic determinant/s (QCAD), expressed by (gp41-gp120) X3, can be bound to a QCAD-specific B cell receptor. This in turn enables HIV infection of a B cell clone amongst the immune repertoire with receptors specific to HIV-pan-neutralizing antibodies (HIV-PNAB). Such infection compromises the host’s ability to achieve immune elimination of any HIV infection. When HIV infects that clone of B cells, persistent infection inevitably gets established.
A consortium of research investigators from UCSF, Gladstone, and Vitalant Research Institutes, led by GNVie LLC in San Francisco, has proposed an innovative strategy to rapidly develop a pair of licensable biological products for immune-based prevention of HIV. Approximately 1% of Caucasians carrying a homozygous 32-basepair deletion in their CCR5 gene (CCR5-delta32) are genetically resistant to the F/T R5-HIV, which requires CCR5 as a coreceptor. Following CCR5-delta32 genotype confirmation and in vitro validation of HIV-1/R5 resistance, such individuals could consent to be immunized with infection-free trimeric envelope glycoprotein subunits (iTEGS) derived from HIV-1/R5 virions (Vyas et al., Biologicals, 2012). Regulatory approval of iTEGS as an investigational new drug (IND), produced under cGMP conditions, is an essential first step. Safe and successful immunization of such donors, with added protection of Lanacapavir, would validate the safety of iTEGS as an HIV vaccine candidate (HIVAX), and enable the production of hyperimmune HIV immunoglobulins (hyHIVIG), analogous to HBIG, for passive prophylaxis against F/T HIV-1/R5. These two biological products, hyHIVIG and HIVAX, could then be deployed for a combined passive-active protection of neonates born to HIV-infected mothers. The twin biological products could prove useful in the ultimate prevention and cure of HIV infection worldwide.
A lymphoblastoid B cell line that is continuously producing F/T R5-HIV in quantities 10-times more than primary human lymphocytes is proprietary, and the Patents issued in Australia, Europe, and USA (#11267872 issued on March 8, 2022) are owned by GNVie LLC. I am available for discussion of the safety, efficacy, and developmental plans for the twin biologicals as life-saving products useful for immune elimination and potential cure of HIV-1 infection.
(E-mail Contact: girish.vyas@gnvie.com)
GNVie llc 