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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., Competing Interests: Competing interests: R.Y., R.R. and K.L. report receiving research support from Celgene (now Bristol-Myers Squibb), CTI BioPharma (a Sobi A.B. Company), PDS Biotech, and Janssen Pharmaceuticals, drugs for clinical trials from Merck, EMD-Serano and Eli Lilly, and preclinical material from Lentigen Technology through CRADAs or MTAs with the NCI. R.Y. is a co-inventor of US Patent 10,001,483 entitled ‘Methods for the treatment of Kaposi’s sarcoma or KSHV-induced lymphoma using immunomodulatory compounds and uses of biomarkers’. An immediate family member of R.Y. is a co-inventor on patents or patent applications related to internalization of target receptors, epigenetic analysis and ephrin tyrosine kinase inhibitors. All rights, title, and interest to these patents have been assigned to the U.S. Department of Health and Human Services; the government conveys a portion of the royalties it receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-502). The other authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Certain infected individuals suppress human immunodeficiency virus (HIV) in the absence of anti-retroviral therapy (ART). Elucidating the underlying mechanism(s) is of high interest. Here we present two contrasting case reports of HIV-infected individuals who controlled plasma viremia for extended periods after undergoing analytical treatment interruption (ATI). In Participant 04, who experienced viral blips and initiated undisclosed self-administration of suboptimal ART detected shortly before day 1,250, phylogenetic analyses of plasma HIV env sequences suggested continuous viral evolution and/or reactivation of pre-existing viral reservoirs over time. Antiviral CD8 + T cell activities were higher in Participant 04 than in Participant 30. In contrast, Participant 30 exhibited potent plasma-IgG-mediated neutralization activity against autologous virus that became ineffective when he experienced sudden plasma viral rebound 1,434 d after ATI due to HIV superinfection. Our data provide insight into distinct mechanisms of post-treatment interruption control and highlight the importance of frequent monitoring of undisclosed use of ART and superinfection during the ATI phase., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

The antigenic polymorphism of HIV-1 is a major obstacle in developing an effective vaccine. Accordingly, we screened random peptide libraries (RPLs) displayed on phage with antibodies from HIV-infected individuals and identified an array of HIV-specific epitopes that behave as antigenic mimics of conformational epitopes of gp120 and gp41 proteins. We report that the selected epitopes are shared by a collection of HIV-1 isolates of clades A-F. The phage-borne epitopes are immunogenic in rhesus macaques, where they elicit envelope-specific antibody responses. Upon intravenous challenge with 60 MID50 of pathogenic SHIV-89.6PD, all monkeys became infected; however, in contrast to the naive and mock-immunized monkeys, four of five mimotope-immunized monkeys experienced lower levels of peak viremia, followed by viral set points of undetectable or transient levels of viremia and a mild decline of CD4+ T cells, and were protected from progression to AIDS-like illness. These results provide a new approach to the design of broadly protective HIV-1 vaccines.