Immunological Responses in HIV Infection

The immunological response to HIV infection unfolds in distinct phases, beginning with innate defences and progressing to adaptive cellular and humoral immunity. Early in infection, dendritic cells and macrophages detect viral particles through pattern recognition receptors, triggering production of type I interferons and pro-inflammatory cytokines. Natural killer cells exert cytotoxic pressure on infected cells, while antigen presentation via major histocompatibility complex molecules primes HIV-specific CD8+ cytotoxic T lymphocytes (CTLs) and CD4+ helper T cells. Robust CTL responses can temporarily contain viraemia, but ongoing viral replication, high mutation rates and depletion of CD4+ T cells undermine long-term control. Persistent antigen exposure drives T cell exhaustion, marked by expression of inhibitory immune checkpoint molecules, and establishes a latent viral reservoir in memory CD4+ T cells. Chronic immune activation, microbial translocation from damaged gut mucosa and immune senescence contribute to non-AIDS comorbidities such as cardiovascular disease and neurocognitive impairment. Although antiretroviral therapy (ART) suppresses plasma viraemia and partially restores CD4+ counts, residual inflammation and the stable reservoir present formidable barriers to eradication. Recent advances seek to characterise reservoir cell phenotypes, enhance immune clearance of infected cells and develop strategies to reverse latency, with the dual aims of achieving durable remission and informing functional cure approaches.

Research from Nature Portfolio

Single-cell profiling of HIV-1 reservoir cells in treated individuals has revealed compartment-specific phenotypic signatures that promote cell survival and resistance to cytotoxic clearance. In peripheral blood, intact provirus-harbouring CD4+ T cells express elevated immune checkpoint markers and survival receptors, whereas lymph node reservoir cells upregulate surface proteins such as CD44, CD28 and IL-21 receptor. These findings illuminate how small subsets of optimally adapted cells persist under long-term ART. In a rare case of HIV cure following CCR5Δ32/Δ32 stem cell transplantation, in-depth virological and immunological analyses showed undetectable replication-competent virus despite sporadic HIV DNA traces. Low immune activation and waning HIV-specific responses indicated absence of ongoing antigen production, providing strong evidence for sustained remission and guiding future curative interventions.

Immunological Responses in HIV Infection publication trend

The graph below shows the total number of articles in immunological responses in hiv infection across all publications each year (not limited to Nature Index journals).

Technical terms

Latent reservoir: Resting memory CD4+ T cells harbouring replication-competent but transcriptionally silent virus.

Immune checkpoint: Inhibitory receptor on T cells that modulates activation and contributes to T cell exhaustion.

Latency reversal: Pharmacological induction of viral gene expression in latently infected cells to expose them to immune clearance.

Microbial translocation: Passage of bacterial products from the gut lumen into systemic circulation, fuelling chronic immune activation.

Cytotoxic T lymphocyte (CTL): Antigen-specific CD8+ T cell capable of killing infected cells via perforin and granzyme release.

Functional cure: Sustained viral remission without eradication of all proviral DNA, achieved through immune control or genetic interventions.

References

1. Anti-PD-L1 antibody ASC22 in combination with a histone deacetylase inhibitor chidamide as a “shock and kill” strategy for ART-free virological control: a phase II single-arm study. Signal Transduction and Targeted Therapy (2024).
2. Phenotypic signatures of immune selection in HIV-1 reservoir cells. Nature (2023).
3. In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation. Nature Medicine (2023).
4. Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART. Viruses (2019).
5. CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART. PLOS Pathogens (2016).