Susan M. Pedersen

BACKGROUND: Approaches to achieving antiretroviral therapy–free (ART-free) remission from HIV-1 must consider that people over 50 years now comprise the majority of people with HIV (PWH) on ART in various regions, including the United States. METHODS: We report a double-blind, randomized trial in which PWH on ART, aged 21–60 years, received modified vaccinia Ankara–vectored (MVA-vectored) vaccines, MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4), either alone or in combination ( n = 7/group), or saline placebo ( n = 3). M3 and M4 contain complementary HIVconsvX immunogens that each span the same regions in HIV-1 Gag and Pol but differ by approximately 8% at the amino acid level. RESULTS: M3, M4, and M3M4 regimens were well tolerated and all significantly increased both the frequency (peak median increase ~3-fold) and breadth of the HIVconsvX-specific T cell response while redirecting T cells to target conserved regions in HIV-1 for up to 10 weeks after vaccination. We also demonstrated that vaccination increased frequencies of T cells targeting participant autologous HIV-1 sequences. Vaccination mostly expanded preexisting HIV-1–specific T cells and did not impact CD4 ⁺ T cell activation, low-level viremia, or integrated HIV-1 provirus. Linear regression indicated that age was independently and negatively associated with the change in T cell frequency at 1, 2, and 10 weeks after vaccination (~1.41-fold decrease per 10 years older). After adjusting for age, years on ART was positively associated with HIVconsvX-specific T cell frequencies at 1 and 2 weeks following vaccination. CONCLUSION: In PWH receiving ART, MVA.HIVconsvX vaccines significantly increased T cells targeting conserved regions of HIV-1. Novel strategies may be required to enhance anti–HIV-1 immunity in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03844386 FUNDING: NIH National Institute of Allergy and Infectious Diseases (NIAID) grants U01AI131310, HHSN272201100021I/HHSN27200037 (subcontract OX-14007.004.0037-212), UM1TR004406, P30AI050410, and P30CA016086; International AIDS Vaccine Initiative; European and Developing Countries Clinical Trials Partnership SRIA2015-1066; European Commission’s Horizon 2020 Research and Innovation Programme 681137.

Human gastrointestinal (GI) tissues are a major site of HIV-1 viral persistence, but the nature of the GI reservoir remains poorly described. To characterize the GI HIV reservoir, we profiled cells from GI tissue and matched PBMCs from 10 people with HIV on antiretroviral therapy using single-cell RNA sequencing. We identified distinct compartment-specific patterns of gene expression, highlighting key differences between blood and colon CD4 ⁺ T cell populations. vRNA ⁺ cells from both blood and GI tissue were heterogeneous and found in multiple subtypes of CD4 ⁺ T cells, although vRNA ⁺ cells were particularly enriched in cells with Th17 or Treg17 phenotypes. Transcriptomic comparison of HIV vRNA ⁺ and vRNA ^– T cells revealed 116 differentially expressed genes that were associated with HIV infection, including ZBED2 , MAF , and IL17F . These data provide what we believe to be new information regarding the GI-resident HIV reservoir and suggest that compartment-specific patterns of gene expression are associated with HIV infection.