Abstract
BackgroundThe current treatment for HIV-1 is based on blocking various stages in the viral replication cycle using combination antiretroviral therapy (ART). Even though ART effectively controls the infection, it is not curative, and patients must therefore continue treatment life-long.AimHere we review recent literature investigating the single or combined effect of toll-like receptor (TLR) agonists and broadly neutralizing antibodies (bNAbs) with the objective to evaluate the evidence for this combination as a means towards an HIV-1 cure.ResultsMultiple preclinical studies found significantly enhanced killing of HIV-1 infected cells by TLR agonist-induced innate immune activation or by Fc-mediated effector functions following bNAb administration. However, monotherapy with either agent did not lead to sustained HIV-1 remission in clinical trials among individuals on long-term ART. Notably, findings in non-human primates suggest that a combination of TLR agonists and bNAbs may be able to induce long-term remission after ART cessation and this approach is currently being further investigated in clinical trials.ConclusionPreclinical findings show beneficial effects of either TLR agonist or bNAb administration for enhancing the elimination of HIV-1 infected cells. Further, TLR agonist-mediated stimulation of innate effector functions in combination with bNAbs may enhance antibody-dependent cellular cytotoxicity and non-human primate studies have shown promising results for this combination strategy. Factors such as immune exhaustion, proviral bNAb sensitivity and time of intervention might impact the clinical success.
Highlights
Overwhelming progress has been made in preventing and treating human immunodeficiency virus 1 (HIV-1)
The present review focuses on the involved mechanisms including Toll-like receptor (TLR) agonist-induced innate immune activation, bNAb-binding to infected cells, antibody-dependent cellular cytotoxicity (ADCC) capacity, viral reservoir size, and time to viral rebound during analytical treatment interruption (ATI)
JLAT10.6 cells stimulated with supernatant from GS-9620 stimulated peripheral blood mononuclear cells (PBMCs) (15) Ex vivo stimulation, p24 antigen (ELISA) as latency reversal measure PMBCs from aviremic HIV-1 positive donors on Antiretroviral therapy (ART)
Summary
Overwhelming progress has been made in preventing and treating human immunodeficiency virus 1 (HIV-1). Antiretroviral therapy (ART) can effectively control viral replication, prevent the development of acquired immunodeficiency syndrome (AIDS), reduce risk of transmission and restore normal life expectancy (1). Life-long compliance to ART is a requirement for virologic control until alternative treatment strategies can be developed enabling sustained ART-free virologic remission or complete eradication of the viral reservoir (6). One strategy aimed at eliminating the viral reservoir, hypothesize that the administration of latency reversing agents (LRAs), will reactivate HIV-1 transcription in latently infected cells, subsequently making cells sensitive to immune-mediated killing (7). Far this strategy has not been effective in eradicating the HIV-1 reservoir. Even though ART effectively controls the infection, it is not curative, and patients must continue treatment life-long
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