Immunotherapeutic Approaches to HIV Cure and Remission

Ming J. Lee; S. Fidler; John Frater


Curr Opin Infect Dis. 2022;35(1):31-41. 

In This Article

The Latent HIV Reservoir

Over the past few years, progress has been made in understanding the mechanisms of persistent infection, and possible strategies towards cure. The HIV reservoir refers to a long-lived latently infected pool of CD4 positive cells that contain HIV deoxyribonucleic acid (DNA) integrated into their genome. In the absence of expression of viral antigens these cells are invisible to effective immune responses and persist in a dormant state in the presence of ART. Figure 2 summarises the mechanisms of persistence and latency discussed in this section.

Figure 2.

The latent HIV reservoir and mechanisms of persistence.

Memory CD4 T cells form the majority of the latently infected cell population.[4] The transition from an effector to quiescent memory phenotype may allow the establishment of HIV latency, through temporary up-regulation of CCR5 expression and rapid downregulation of HIV gene transcription, whereas allowing completion of the HIV life cycle through integration.[5] Clonal proliferation also plays a significant role in reservoir persistence,[6] which needs to be addressed in cure strategies. Immune checkpoint molecules (e.g. PD-1, CTLA-4, LAG3, TIGIT) dampen T cell activation and may be associated with HIV latency.[7] Other cellular reservoirs have been described, including myeloid cells such as monocytes, tissue-resident macrophages, and follicular dendritic cells,[8] but there is on-going discussion around their significance, with most cure approaches still directed towards the CD4+ T-cell reservoir.

Other mechanisms of persistence include avoidance of cytotoxic T lymphocyte (CTL) mediated cell death; latently infected cells that survive ART initiation may as a result have a greater ability to persist after peak viraemia.[9] Cellular resistance mechanisms may include upregulation of Fas Ligand on infected cells leading to apoptotic cell death of uninfected CTLs,[10] the up-regulation of BCL-2, an inhibitor of apoptosis,[11] or distraction of CTL through defective virion 'decoys'.[12] The vast majority (~98%) of HIV proviral DNA is defective[13] with fatal defects such as deletions or hypermutations. Although these defective proviruses are unlikely to contribute to the replication-competent latent HIV reservoir, they may be transcriptionally active, and express proteins that may distract and reduce CTL-mediated cytotoxicity of cells containing replication-competent virus.[12] The ability to find and measure replication-competent virus amongst the vast amount of defective proviral genome has implications for evaluating cure strategies. Recently, novel polymerase chain reaction (PCR) assays such as the high-throughput intact proviral DNA assay[14] have replaced the previous gold standard quantitative viral outgrowth assay due to advantages over turnover, cost, and labour requirements. Whilst multiple assays are available to characterise and quantify the HIV reservoir, none to date have been able to accurately predict viral control (to < 50 copies HIV RNA/ml) after interruption of ART.

After treatment interruption, recrudescence of rebound plasma viraemia from activation of the latent reservoir is expected in the absence of viral control. Rebounding viral populations are diverse and have been found in multiple tissue compartments.[15] Analytical treatment interruption (ATI) is currently the only effective way to test the efficacy of HIV therapeutic interventions for posttreatment virological control as there are no validated predictive biomarkers.[16] Consensus recommendations for conducting ATI in HIV research trials have been reported to minimise risk to research participants,[16] and further risk mitigation strategies should be considered when designing ATI studies to address the challenges brought by the COVID-19 pandemic.[17]