Activation of latent HIV-1 expression by protein kinase C agonists. A novel therapeutic approach to eradicate HIV-1 reservoirs.
The persistence of latent HIV-infected cellular reservoirs represents the major hurdle to virus eradication in patients treated with highly active antiretroviral therapy. The molecular mechanisms by which integrated HIV-1 is repressed during latency have been partially identified in different models of HIV-1 latency, and the involvement of multiple processes has been demonstrated. Therefore, several molecular targets amenable to pharmacological manipulation have emerged to antagonize HIV-1 latency in the viral reservoirs. In this context, it has been suggested that successful depletion of such latent reservoirs will require a combination of therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. HIV-1 reactivation therapy is a potential therapeutic option to purge the viral reservoirs. The goal of this therapy is to enhance the transcriptional activity of the latent HIV-1 without inducing the polyclonal activation of non-infected cells. In this sense natural or semisynthetic protein kinase C agonists lacking tumour-promoter activities clearly fulfil this criterion, thereby opening new research avenues to purge HIV-1 reservoirs. In this review article, we have succinctly summarized the known effects of "natural products", focusing on phorboids like prostratin and ingenols, macrolides like bryostatin 1, and macrocyclic polyesters like ingols and jatrophanes. A comprehensive view on the molecular mechanisms underlying the principle of HIV-1 reactivation from latency is provided, discussing the combination of "natural products" with other experimental or conventional therapeutics.
Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Medicina. Avda. de Menéndez Pidal s/n, Universidad de Córdoba, Córdoba, Spain. fi1muble@uco.es
Gonzalo
G
Sánchez-Duffhues
Minh Q
MQ
Vo
Moisés
M
Pérez
Marco A
MA
Calzado
Santiago
S
Moreno
Giovanni
G
Appendino
Eduardo
E
Muñoz
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use; D020536:Enzyme Activators / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D058990:Molecular Targeted Therapy; D011493:Protein Kinase C / Q000378:metabolism*; D011533:Proviruses / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D014775:Virus Activation / Q000187:drug effects*; D016662:Virus Integration / Q000187:drug effects
D019380:Anti-HIV Agents; D001688:Biological Products; D020536:Enzyme Activators; D011493:Protein Kinase C