HIV post-treatment controllers have distinct immunological and virological features

Abstract

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4 + and CD8 + T cell activation, lower CD4 + T cell exhaustion, and more robust Gag-specific CD4 + T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4 + T cell% and CD4 + /CD8 + ratio, more functional NK cells, and a lower CD4 + T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Early antiretroviral therapy favors post-treatment SIV control associated with expansion of enhanced memory CD8+ T cells. pVISCONTI study

“…Additional analyses are ongoing to study the impact of early-and late-ART initiation on the innate immune response. Nevertheless, our study showed that post-treatment control, as reported for PWH 13,16 , was not related to the presence of protective MHC traits associated with natural control of infection (e.g. HLA-B*27 or B*57 alleles in PWH or MHC-M6 haplotype in CyMs).…”

“…Identifying immunologic or virologic signatures that could predict the time to viral rebound after stopping ART and understanding the mechanisms leading to post-treatment control is a priority to guide the development of innovative strategies for sustained HIV remission. Several markers such as low cell-associated HIV DNA levels, high CD4/CD8 ratios, loss of functional plasmacytoid dendritic cells or low expression of immune checkpoint molecules have been associated with delayed viral rebound after ART discontinuation 4,13,[16][17][18][19] and distinctive transcriptomic and metabolomic signatures have been observed in post-treatment controllers 20,21 . However, the mechanisms underlying durable HIV control after ART interruption remain elusive.…”

Antiviral capacity of the early CD8 T-cell response is predictive of natural control of SIV infection

“…k . can thus vary with time due to clonal expansion, memory recall, exhaustion, and/or viral evolution 14, 30, 31, 32 . Here, we focused on untreated infection, where the quality of CD8 T-cells is expected to rise during early infection and eventually plateau 33, 34, 35, 36, 37 .…”

Impact of early antiretroviral therapy, early life immunity and immune sex differences on HIV disease and posttreatment control in children

“…In addition, they tend to bind with strong avidity to the leucocyte immunoglobulin like receptors LILRB1 and LILRB2, that has the effect of dampening down the initiation of virus-specific CD8+ T-cell responses [71]. Second, consistent with the HLA-I associations, HIV-specific CD8+ T-cell responses among PTC are unremarkable [67,72 ▪▪ ]. Third, low levels of immune activation are associated with PTC [67,72 ▪▪ ], whereas immune control of ART-naive infection correlates with the speed and extent of immune activation [48].…”

“…The fourth feature of PTC is the central role played by NK responses. Although NK cell activity contributes to immune control in ART-naive infection in adults [38–42] and plays a major part in preventing disease progression among children LWH [37 ▪ ], NK responses appear to play a central role in PTC, both in adults [72 ▪▪ ,77–80] and in children. In particular, it has been proposed that PTC is associated with an HLA-I signature that combines disease-susceptible HLA molecules with HLA haplotypes that mediate a KIR-biased education of NK cells [77].…”