Background:  TNX-355 is a humanized monoclonal antibody that binds to domain 2 of the CD4 receptor and prevents entry of HIV into target cells. In an ongoing blinded phase 2 clinical trial TNX-355 demonstrated potent antiviral activity when administered with optimized background regimen (OBR) vs a TNX-355 placebo with OBR. Both treatment emergent and preexisting decreased susceptibility to entry inhibitors has been described. The current study was initiated to assess the baseline susceptibility of HIV isolated from treatment experienced patients without prior exposure to entry inhibitors.

Methods:  Baseline plasma samples were obtained from 82 patients enrolled in the phase 2 clinical trial. HIV envelope RNA from each sample was amplified by RT-PCR and used to construct pseudotyped viruses. These viruses were tested for susceptibility to TNX-355 using the PhenoSense™ Entry assay.

Results:  Envelope genes from 78 of the 82 plasma samples were successfully amplified. All viruses were HIV-1 subtype B:  49 viruses were CCR5 tropic, 2 exhibited tropism for CXCR4 expressing cells only, and 27 were dual/mixed tropic. The susceptibility to TNX-355 was similar for all viruses, regardless of their tropism; IC₅₀ values for viruses capable of infecting CCR5 cells ranged from 0.01 to 0.16 µg/mL, while IC₅₀ values for viruses capable of infecting CXCR4 cells ranged from 0.07 to 0.23 µg/mL. In single-round infectivity assays, decreased susceptibility to antiviral agents that target cellular receptors is frequently manifested as a reduction in the percentage of maximal inhibition (PMI). PMI for the viruses tested in this study ranged from 71 to 100%. No association with chemokine co-receptor tropism was noted.

Conclusions:  Baseline susceptibility to TNX-355 was independent of chemokine coreceptor tropism.  In this investigation, HIV-1 subtype B viruses were susceptible at baseline.  Further studies to correlate baseline susceptibility with virologic outcome and establish clinical cutoffs are needed.