Abstract Body

GS-6207 is a potent, first in class, multistage inhibitor of HIV-1 capsid function with the potential to be used as a subcutaneous (SC) long-acting agent with dosing every 3 months or longer. In the clinic, a single SC injection of GS-6207 (50 mg to 450 mg) in people living with HIV (PLWH) showed a rapid and strong antiviral effect, with a >1.8 mean log10 decrease in HIV-1 RNA at day 10. Mutations in HIV-1 gag near protease (PR) cleavage sites have emerged with the use of protease inhibitors (PIs), resulting in increased fitness and/or PI-resistance. Here we have characterized the activity of GS-6207 in mutants with HIV-1 gag cleavage site mutations, as well as mutants with resistance to other drug classes.

HIV mutations were inserted into the pXXLAI infectious clone either by site-directed mutagenesis or by cloning of plasma samples. Infectious clones with HIV gag cleavage site mutations, or HIV gag-PR fragments from treatment-naïve or experienced PLWH were evaluated using a standard 5-day antiviral assay (MT-2-cells). Isolates with resistance mutations against the 4 major drug classes (NRTI, NNRTI, PI, INSTI) were tested phenotypically using a single-cycle assay (Monogram Biosciences).

In all, 19 HIV gag cleavage site mutants (single and double mutants with L363F/M, A364V, Q430R, A431V, K436E, I437T/V, L449H/V/F, P453L, and/or PR mutations V82A and I84V) as well as 55 patient derived clones were analyzed phenotypically. GS-6207 EC50 fold-change compared to wild-type (WT) ranged from 0.3 to 2.1 in these mutants, similar to the control drug. In contrast, high levels of reduced susceptibility to PIs (>500 fold) and maturation inhibitors (MIs) (>70 fold) were noted in some mutants. Testing of isolates with resistance mutations against the 4 main classes of drugs (n=40) indicated WT susceptibility to GS-6207 (fold-change ranging from 0.3 to 1.1), while highly reduced susceptibility was observed for control drugs of each class.

HIV gag cleavage site mutations did not impact the activity of GS-6207, while some conferred resistance to MIs and PIs. Similarly, GS-6207 activity was not affected by naturally occurring variations in HIV gag, in contrast to the loss of activity observed for MIs in nearly half of the mutants. Finally, the activity of GS-6207 was not affected by the presence of resistance mutations to the 4 main ARV classes. These data support the evaluation of GS-6207 in PLWH with multi-class resistance.