A man seemingly cured of HIV was reported at the International AIDS Conference in 2020, sparking debate (Diaz et al, J Int AIDS Soc, 2020; 23(4):OAXLB0105). The patient had been subjected to a 5-drug antiretroviral regimen + nicotinamide, a drug aimed at disrupting HIV latency and boosting cell-mediated immunity (NCT02961829). He had been in antiretroviral analytical treatment interruption (ATI) for 68 weeks with viral loads (VL) below detection limits (BDL), progressively declining HIV-1, but not CMV, antibody titers. The present report investigates the long-term stability of post-ATI control.
Cell-mediated immune responses were evaluated in stored PBMC by ELISPOT using the patient-specific GAG peptides, generic HIV peptides (GAG-p6, p17, NEF, VIF, gp160), and CMV peptides at baseline, weeks (W) 12, 24, 36, and 48 (study period), W116 (regular ART), and W64 and W68 post-ATI. HIV-1 VL was determined monthly.
MHC profiling showed no alleles associated with HIV-1 control and one allele associated with increased infection susceptibility (DRB1*150:03). The patient displayed increasing cell-mediated responses against two highly conserved Gag epitopes predicted to optimally bind his Class I HLA during experimental therapy. After ATI, these responses progressively disappeared, in parallel to the linear decline of anti-HIV-1 Abs, whereas CMV ELISPOT remained high. At W74 post-ATI (September 11th 2020) patient was diagnosed with secondary syphilis. VL remained BDL until W76 post-ATI becoming detectable at W79 and W81 (both log10=3.8 cp/mL on Nov 9th and 23rd 2020). Emerging HIV strain has the Brazilian GWGR motif at the tip of the V3 loop of gp120, whereas baseline strain presented the GPGR motif and had an incomplete N-linked glycosylation site suggesting a strain subjected to evolution and immune escape. The gag sequence from the emerging strain had amino acid substitutions compared to the original strain, but not in motifs corresponding to epitopes towards which cell-mediated immunity was directed. C2-V3-C3 sequences from baseline and after viremia are 17.3% different, whereas gag sequences are 11.4% different (Figure).
Anti-Gag cell-mediated immunity was associated with unprecedented post-therapy VL control in the chronic phase of the disease. Analyses are ongoing to investigate if the viral rebound source is the reactivation of a mutated virus or a new infection.