Persistent immune dysfunction during suppressive antiretroviral therapy: implications for analytical treatment interruption trials for chronic HIV infections in sub-Saharan Africa

Background Despite the success of long-term antiretroviral therapy (ART), immune dysfunction—including incomplete T helper cell recovery, immune activation, and inflammation—persists and may affect the benefits of analytical ART treatment interruption (ATI) trials among people living with human immunodeficiency virus (HIV) (PLHIV) in sub-Saharan Africa (SSA). This narrative review summarizes evidence of incomplete immune function recovery among PLHIV on long-term ART and potential interventions to enhance their ability to participate in ATI trials with immunotherapies in the quest for an HIV cure in SSA. Methods A PubMed search query was used “([Immunity, Innate{MeSH Terms}] OR [Adaptive Immunity{MeSH Terms}] AND [HIV{MeSH Terms}] AND [Anti-HIV Agents{MeSH Terms}] AND [function{Title/Abstract} OR dysfunction{Title/Abstract} OR recovery{Title/Abstract} OR restoration{Title/Abstract} OR reconstitution{Title/Abstract} OR regeneration{Title/Abstract}])”, which retrieved 165 articles. These articles were filtered using an English-language filter, resulting in 160 papers. This query was translated to Web of Science and Google Scholar. In addition, we conducted a specific literature search on documented “cured” HIV cases globally to understand innate and adaptive immune functions relevant to supporting post-ART immunological viral control. Results Persistent dysfunction of host innate and adaptive immunity during suppressive ART is reported in SSA HIV treatment cohorts. Natural killer (NK) cells, dendritic cells, and monocyte dysfunction potentially limit post-ART viral control. In addition, persistently impaired CD4 and CD8 T-cell proliferation capacity, immune activation, and exhaustion during ART may limit host HIV-specific responses during ATI trials with broadly neutralizing antibodies (bNAbs) and therapeutic vaccines, thereby increasing the risk of post-ART viral rebound. Similarly, adjunct therapies with TLR7 agonists, such as vesatolimod, could potentially increase cytotoxic capabilities of dendritic and natural killer cells to improve HIV latency reversal and viral clearance during ART. Conclusion Innovative combination immunotherapies to avert persistent immune dysfunction, such as therapeutic vaccines, combination bNabs, enhancer of zeste homolog 2 (EZH2) inhibitors to boost CD8 + T-cell function and augment post-ART viral control, and latency reversal agents to increase cytotoxicity potential of dendritic cell and natural killer cells, among others, could potentially optimize HIV-specific CD8 T-cell cytotoxicity and viral clearance, and delay viral rebound during ATI trials in SSA.