Absence of Lenacapavir (GS-6207) Phenotypic Resistance in HIV Gag Cleavage Site Mutants and in Isolates with Resistance to Existing Drug Classes

Abstract

Lenacapavir (LEN; GS-6207) is a potent first-in-class inhibitor of HIV-1 capsid with long-acting properties and the potential for subcutaneous dosing every 3 months or longer. In the clinic, a single subcutaneous LEN injection (20 mg to 750 mg) in people with HIV (PWH) induced a strong antiviral response, with a >2.3 mean log₁₀ decrease in HIV-1 RNA at day 10. HIV-1 Gag mutations near protease (PR) cleavage sites have emerged with the use of protease inhibitors (PIs). Here, we have characterized the activity of LEN in mutants with Gag cleavage site mutations (GCSMs) and mutants resistant to other drug classes. HIV mutations were inserted into the pXXLAI clone, and the resulting mutants (n = 70) were evaluated using a 5-day antiviral assay. LEN EC₅₀ fold change versus the wild type ranged from 0.4 to 1.9 in these mutants, similar to that for the control drug. In contrast, reduced susceptibility to PIs and maturation inhibitors (MIs) was observed. Testing of isolates with resistance against the 4 main classes of drugs (n = 40) indicated wild-type susceptibility to LEN (fold change ranging from 0.3 to 1.1), while reduced susceptibility was observed for control drugs. HIV GCSMs did not impact the activity of LEN, while some conferred resistance to MIs and PIs. Similarly, LEN activity was not affected by naturally occurring variations in HIV Gag, in contrast to the reduced susceptibility observed for MIs. Finally, the activity of LEN was not affected by the presence of resistance mutations to the 4 main antiretroviral (ARV) drug classes. These data support the evaluation of LEN in PWH with multiclass resistance.

Keywords: GS-6207; HIV-1; antiretroviral resistance; capsid inhibitor; cross-resistance.

FIG 1

Drug susceptibilities in HIV-1 isolates with resistance mutations to the 4 main ARV drug classes. Ten mutants with resistance to each of the 4 main drug classes were analyzed: NRTIs (A), NNRTIs (B), PIs (C), and INSTIs (D). Resistance-associated mutations found in each mutant are indicated in Table S1 in the supplemental material. Each point represents a single isolate tested singly (PhenoSense GT or PhenoSense IN CLIA-validated assays). The black lines indicate the median EC₅₀ fold change for each drug. NRTI, nucleotide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; INSTI, integrase strand transfer inhibitor.

FIG 2

Drug susceptibilities in treatment-naive (TN) HIV-1 isolates (n = 15) (A) and treatment-experienced (TE) HIV-1 isolates (n = 36) (B). Each symbol represents a single isolate. The black lines indicate the median EC₅₀ fold change for each drug. *, GSK-3532795/BMS-955176; CAI, capsid inhibitor; PI, protease inhibitor; MI, maturation inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor. Data are from n ≥ 3, conducted in triplicates.

FIG 3

Drug susceptibilities in site-directed mutant HIV-1 isolates (n = 19) (A) and treatment-experienced HIV-1 isolates (n = 24) (B) with Gag cleavage site mutations. Each symbol represents a single isolate. The black lines indicate the median EC₅₀ fold change for each drug. *, GSK-3532795/BMS-955176; CAI, capsid inhibitor; PI, protease inhibitor; MI, maturation inhibitor; NRTI, nucleos(t)ide reverse transcriptase inhibitor. Data are from n ≥ 3, conducted in triplicates.