James McMahon

The session focuses on adults and children who naturally control HIV replication including HIV elite controllers (EC - control viral replication and never received ART) and post-treatment controllers (PTC - control viral replication after ceasing ART). Immunological and virological features of these people are described.

The Visconti PTC cohort update reported 5/25 have resumed ART and all had viral load blips >400 copies/mL. Other PTC features are decreasing reservoir size and p24 production, low HIV-specific CD8+ T-cell responses, poorly neutralising antibodies and HLA B35/53 genotype leading to NK-cell mediated viremic control. HIV proviral sequencing of ECs and an ART-treated reference cohort reported the intact and total HIV reservoir is 10 and 20 fold less respectively in ECs. Also, EC proviruses were much more likely in non-genic regions such as satellite DNA implying very deep latency for virus in sites where transcription and subsequent viral rebound aren’t expected. Dr Yu also proposed the provocative question of whether ‘exceptional long-term’ ECs have been cured by natural immunity? Provocative, as cure implies an intervention has occurred. Detailed analysis of 2 billion PBMCs in one man with undetectable viral load for 24 years without ART found no intact virus.

The speakers presented detailed descriptions of ECs and PTCs including very intensive evaluation of some ECs in the United States. The small numbers of individuals and variability in immunological and virological findings within these groups make it difficult to draw clear conclusions about what aspects of the immune response, or the virus tell us where to target interventions for HIV cure. However, the detailed assessment of these rare individuals could provide us with valuable clues to identify interventions that could benefit the broader population with HIV.

Aurelio Orta-Reséndiz

The topics presented in this session included some of the viral and immunological profiles that have been described in HIV elite controllers (ECs), post-treatment controllers (PTCs) and pediatric cases of viral control while discussing hypothesis based on the measurement of markers of replication, intact provirus and HLA alleles among others.

Dr. Saez-Cirion discussed the decrease of p24 expression in PTCs over time, the association of HLA-B*35/53 and Bw4TTC2 with control among early treated and how KIR ligands-carrying HLA are enriched in B35/53 PTCs. Dr. Persaud explained the differences between adult and perinatal cases of viral control such as longer time to viral set point and highlighted cases of smaller proviral reservoir in pediatric PTCs. Dr. Streeck described the CD8 and CD4 T-cells specific responses in long-term control, the impact of HLA-DRB1 type on control and the presence in lymph nodes of cytolytic CD4 T-cells lacking perforin and granzyme B expression. Dr. Xu Yu described different frequencies of intact sequences among ECs, how integration sites within centromeric regions are related to control despite intact proviral genomes and the an exceptional EC case with negative viral outgrowth tests after 24 years of undetectable viremia, which is the first report of natural remission.

In contrast to ECs, PTCs require treatment to initially control viremia but durably maintain control if the therapy is interrupted. The immune and viral characteristics between PTC, EC and perinatal pediatric controllers are widely different. However, we can identify some that are associated with an increased probability of viral control. Although promising, the studies discussed in this session showed that low proviral reservoir size is insufficient to confer a post-treatment controller status and that the genetically silent location of intact provirus in EC, and the role of HLA specific alleles in spontaneous control needs to be further characterized.