Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy.
Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs.IMPORTANCEThough antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is persistently maintained in reservoirs of latently infected cells. Consequently, lifelong therapy is required to maintain viral suppression. Ultimately, new therapies that specifically target and eliminate the latent HIV reservoir are needed. Toll-like receptor agonists are potent enhancers of innate antiviral immunity that can also improve the adaptive immune response. Here, we show that a highly selective TLR7 agonist, GS-9620, activated HIV from peripheral blood mononuclear cells isolated from HIV-infected individuals with suppressed infection. GS-9620 also improved immune effector functions that specifically targeted HIV-infected cells. Previously published studies on the compound in other chronic viral infections show that it can effectively induce immune activation at safe and tolerable clinical doses. Together, the results of these studies suggest that GS-9620 may be useful for treating HIV-infected individuals on suppressive antiretroviral therapy.
Gilead Sciences, Foster City, California, USA.
Angela
A
Tsai
Gilead Sciences, Foster City, California, USA.
Alivelu
A
Irrinki
Gilead Sciences, Foster City, California, USA.
Jasmine
J
Kaur
Gilead Sciences, Foster City, California, USA.
Tomas
T
Cihlar
Gilead Sciences, Foster City, California, USA.
George
G
Kukolj
Gilead Sciences, Foster City, California, USA dsloan@agenovir.com jeff.murry@gilead.com.
Derek D
DD
Sloan
Gilead Sciences, Foster City, California, USA dsloan@agenovir.com jeff.murry@gilead.com.
Jeffrey P
http://orcid.org/0000-0002-3716-1460
JP
Murry
D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D006678:HIV / Q000276:immunology* / Q000502:physiology*; D015658:HIV Infections / Q000821:virology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007370:Interferon Type I / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D010586:Phagocytes / Q000187:drug effects / Q000502:physiology; D011621:Pteridines / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects*
D044966:Anti-Retroviral Agents; D007155:Immunologic Factors; D007370:Interferon Type I; D011621:Pteridines; D012367:RNA, Viral; D051199:Toll-Like Receptor 7; C582524:vesatolimod
TLR7; broadly neutralizing antibodies; cytotoxic T lymphocytes; human immunodeficiency virus; interferon alpha; interferons; latency; plasmacytoid dendritic cells; reservoir