Immune Checkpoint Therapy in HIV

Human immunodeficiency virus (HIV) infection destroys the host immune system and makes the infected individual increasingly more vulnerable to a range of infections and cancers. Recent studies have shown that the single expression or co-expression of immune checkpoint proteins is a key mechanism for the functional impairment of HIV-specific T-cells. Immune checkpoints extensively participate in HIV infection via their role in inhibiting T-cell function. The two main ways in which they act are by causing T-cell exhaustion and helping to establish HIV-latency reservoirs.

Antiretroviral therapy (ART) has dramatically reduced HIV-related morbidity and mortality, but only 40% of people living with HIV globally are receiving ART, and there is no vaccine or cure. Once treatment is stopped, the virus rapidly rebounds. Considering the social and economic impact of the lifelong medical care required for people living with HIV, finding a cure has become a major global priority. Utilizing immune checkpoint blockade could potentially be exploited as a strategy to achieve the treatment.

Fig.1 Immune checkpoint molecule expression in HIV infection. (Marra, 2017)

T Cell Exhaustion in HIV Infection

T-cell exhaustion is a deterioration of T-cell function caused by exposure to persistent stimulation with high levels of antigen in chronic viral infection. T cell exhaustion is a hallmark of many chronic viral infections, and HIV is also included. The exhaustion of CD8⁺ T-cells in HIV-infected individuals has been found to accompany the upregulated expression of various immune checkpoint proteins such as TIM-3, PD-1, LAG-3, and TIGIT. Blockade of the PD-1/PD-L1 pathway significantly reduces HIV viral load and reinvigorates exhausted CD8⁺ T-cells in bone marrow-liver-thymus (BLT) humanized mice. Besides, a blockade targeting BTLA and TIM-3 partially augmented the proliferation of HIV-specific CD8⁺ T-cells. Combined blockades of PD-1 and TIM-3 or BTLA enhanced the proliferation of CD8⁺ T-cells and the production of cytokines such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-13.

Table.1 Summary of the roles of immune checkpoints in HIV infection. (Cai, 2020)

Manifestation	Checkpoints Involved	Functions
Establishment of HIV latency reservoirs	PD-1, CTLA-4, LAG-3, TIGIT	Participate in HIV infection and assist to virus escape from immune clearance
CD4⁺ T-cell dysfunction	PD-1, CTLA-4, LAG-3, TIGIT	Cause many CD4⁺ T-cells dysfunction and loss
CD8⁺ T-cell exhaustion	PD-1, TIM-3, LAG-3, TIGIT	Lead to CD8⁺ T-cell functional impacts such as decreased IL-2 secretion and T-cell proliferation
Improved Treg proliferation	TIM-3, CTLA-4, PD-1	Decrease the HIV-specific immune responses, contributing to virus persistence

Immune Checkpoint Proteins in HIV Infection

HIV was significantly enriched in sorted cells obtained from individuals infected with HIV on ART that expressed PD-1, TIGIT, and LAG-3 compared with cells that expressed none of these immune checkpoint proteins. Along with other exciting results, these observations are now being exploited by using immune checkpoint blockers to potentially reverse latency, allowing for the expression of HIV proteins on the surface of the cell, which would lead to immune clearance of the virus or virus-induced cytolysis. Through the use of CD4⁺ T cells from individuals with HIV infection on ART, the ex vivo administration of antiPD1 antibody together with the latencyreversing agent led to a significant increase in HIV RNA released into the supernatant. A phase II doseescalation study of antiPD-L1 antibody therapy was recently ceased after administration of the lowest dose to six individuals with HIV infection on ART. The study was stopped due to retinal toxicity observed in a simultaneous macaque study. Several clinical trials in the US are currently evaluating the effects of antiPD-1 and antiCTLA-4 antibodies either alone or in combination on HIV-associated malignancies.

Table.2 Clinical trials on immune checkpoint inhibitors targeting HIV infection. (Cai, 2020)

Target	NCT ID	Research Title/Objective	Status
PD-1	NCT03239899	PD-1 inhibition to determine CNS reservoir of HIV-infection	Phase I
PD-1	NCT03787095	Safety and immunotherapeutic activity of an anti-PD-1 antibody in HIV-1-infected participants on suppressive cART	Phase I
IMC	NCT03354936	Assess the safety of the use of immune checkpoint inhibitors in HIV infected patients	Recruiting
PD-1	NCT03367754	A single dose in HIV-infected people	Phase II

Immune Checkpoint blockade is a very active area of research at Creative Biolabs. We continue to make great strides in increasing its effectiveness and expanding its use in HIV therapy research. Our outstanding research services are widely acclaimed by worldwide customers. Our popular services include immune checkpoint antibody development, immune checkpoint targeted peptide development, immune checkpoint targeted small molecule drug development, and so forth. For more information, please feel free to contact us for information.

References

Marra, A.; et al. Immune checkpoint inhibitors in melanoma and HIV infection. The open AIDS journal. 2017, 11, p.91.
Cai, H.; et al. Immune Checkpoints in Viral Infections. Viruses. 2020, 12(9): 1051.
Cai, H.; et al. Immune Checkpoints in Viral Infections. Viruses. 2020, 12(9): 1051.

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