Sustained virologic suppression of multidrug-resistant HIV in an individual treated with anti-CD4 domain 1 antibody and lenacapavir

Abstract

The clinical management of people with multidrug-resistant (MDR) human immunodeficiency virus (HIV) remains challenging despite continued development of antiretroviral agents. A 58-year-old male individual with MDR HIV and Kaposi sarcoma (KS) was treated with a new antiretroviral regimen consisting of anti-CD4 domain 1 antibody UB-421 and capsid inhibitor lenacapavir. The individual experienced delayed but sustained suppression of plasma viremia and a substantial increase in the CD4⁺ T cell count. A longitudinal examination of plasma HIV and infectious isolates showed no evidence of viral evolution or the emergence of UB-421- or lenacapavir-resistant viruses. The individual received three cycles of liposomal doxorubicin and five doses of anti-programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab that resulted in improvement in KS with flattening of lesions. Our data demonstrate that combination therapy with UB-421 could provide sustained virologic suppression in people harboring MDR HIV with limited therapeutic alternatives.

Extended Data Fig. 1 |. Neutralization and suppression capacity of bNAbs and anti-CD4 antibodies against replication-competent viral isolates derived from the patient with MDR HIV.

a, The y axis indicates percentage suppression over control, as determined by the TZM-bl neutralization assay. Measurements for each viral isolate were performed in duplicate. Black bars represent the median values. b, The IC₈₀ values of ibalizumab against the infectious clones obtained from the patient. Measurements for each viral isolate were performed in duplicate. The P value was determined using the two-tailed Mann–Whitney test.

Extended Data Fig. 2 |. High-dimensional phenotypic profiling of B and T cells following initiation of UB-421 and lenacapavir.

a,b, UMAP and heatmaps of the patient CD19⁺ B cells (a) and CD3⁺ T cells (b). The heatmaps show intensities of expression for individual markers in each of the 15 clusters shown. Only the top 15 of 20 clusters are shown for B cells. UMAP plots show intensity of expression for each marker (left) and identification of B and T cell clusters generated by FlowSOM (right).

Extended Data Fig. 3 |. Within-host gag and gp120 phylogenies in rectangular format.

These are the same rooted trees as shown in Fig. 2c. Asterisks denote nodes with bootstrap support values ≥ 70%. Scale in estimated substitutions per nucleotide site.

Extended Data Fig. 4 |. Root-to-tip distances of pre- versus post-therapy sequences.

Horizontal black lines denote medians. Each measurement was performed once at each time point. P values were computed using the two-tailed Mann–Whitney U test.

Fig. 1 |. Clinical parameters, pharmacodynamics and efficacy findings in the patient with KS and MDR HIV following initiation of UB-421 and lenacapavir.

a, The patient’s longitudinal HIV plasma viremia and CD4⁺ T cell count. The green triangles and purple diamonds indicate the administration of UB-421 and lenacapavir, respectively. The red dotted horizontal line indicates the limit of detection of the assay (20 copies of HIV RNA per ml). The white triangles indicate undetectable plasma viremia. The timing of liposomal doxorubicin and pembrolizumab administration is shown (teal/black diamonds and orange/brown down-pointing triangles, respectively). b, KS lesions on the ankle of the patient over time. c, The percent receptor occupancy of UB-421 on CD4⁺ T cells (left) and the in vitro sensitivity to UB-421 of autologous, replication-competent HIV isolates derived from the patient at baseline and week 12 (right). Measurements of percent receptor occupancy were performed once at each time point. Measurements of IC₈₀ values were performed in duplicate for each viral isolate. d, The plasma pharmacokinetics of lenacapavir over time (left) and the in vitro sensitivity to lenacapavir of autologous, replication-competent HIV isolates derived from the patient at baseline and week 12 (right). Measurements of lenacapavir concentration in plasma were performed once at each time point. Measurements of IC₈₀ values were performed in duplicate for each viral isolate. P values were determined using the two-tailed Mann–Whitney test.

Fig. 2 |. Immunologic and virologic analyses of the peripheral blood and plasma of the patient following the initiation of UB-421 and lenacapavir.

a, High-dimensional immunophenotyping of B and T cells over time. High-dimensional immunophenotyping was conducted by spectral flow cytometry to identify B and T cell populations in PBMCs. b, The longitudinal frequency of CD4⁺ T cells carrying intact and defective HIV proviral DNA (top) and cell-associated HIV RNA (bottom). c, Maximum-likelihood phylogenies inferred from HIV gag and HIV env sequences derived from longitudinal plasma HIV RNA, with baseline and post-therapy sequences denoted by unique symbols. The phylogenetic trees are outgroup-rooted using the subtype B sequence KU678055, which is the genetically closest publicly available full-genome HIV sequence to the patient. Scale bars are shown in estimated substitutions per nucleotide site. The clade branching near the root of the env tree that contains one week 25 and one week 32 sequence, which is mentioned in the population genetic structure analysis, is highlighted in blue. The bottom graphs show the root-to-tip distances of HIV gag and HIV env sequences sampled post-therapy, analyzed using simple linear regression.