Speaker
Description
Heterogenous HIV-like particle (HLP) is a targeted, potent HIV latency reversal agent (LRA) for people living with HIV (PLWH) on ART. When using samples derived from over 50 PLWH on treatment for 2 to 22 years, HLPs at least 100-fold more effective than other latency reversal agents in clinical development. HIV primarily infects activated CD4+ T cells whose T cell receptor (TCR) recognizes HIV peptide presented by MHC class II, a cell population that also holds latent HIV upon antiretroviral treatment. A heterogenous HLP induces high level latency reversal by providing this HIV-1 peptide presentation through MHC class II. Potency of HLP as an LRA is dependent on the match of MHC class II-restricted HLP peptides and those class II-restricted peptides presented by the infecting HIV. Using a pipeline program (classIIhiv) built on NetMHCIIpan, the heterogenous HLP and the participant’s HIV-1 genome sequence and HLA class II alleles are entered into classIIhiv to compare the match between class II-restricted HIV-1 peptides of the participant’s virus and that of HLP. We factored in exact sequence matches at amino acid positions 1,2,4,6,9 of the 9 mer peptides, i.e. sites that bind the MHC II cleft. Sequence diversity at one position of 3,5,7,8 was allowed for the match since these peptides could still accommodate TCR binding. Using HIV-1 sequence and HLA class II alleles of 100 infected individuals, we predicted an >80% match of class II-restricted peptides between the infecting HIV-1 and our “off-the-shelf” HLP. For every 1 of 10 individuals, a <80% match has prompted our development of autologous HLPs for these PLWH. Interestingly, slight increases in latency reversal (2 to 3-fold) were observed with autologous compared to “off-the-shelf” HLP in samples from these individuals. More details of the development and processes of this predictive algorithm will be presented at the meeting.
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