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Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS.

Savarino A, Shytaj IL - Retrovirology (2015)

Bottom Line: However, one main source of clinical concern is the persistence of immune hyperactivation in individuals under ART.Chronically enhanced levels of T-cell activation are associated with several deleterious effects which lead to faster disease progression and slower CD4(+) T-cell recovery during ART.If the quinoline-based strategies should nevertheless be pursued in future studies, particular care must be devoted to the dosage selection, in order to maximize the chances to obtain effective in vivo drug concentrations.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. andrea.savarino@iss.it.

ABSTRACT
The restoration of the immune system prompted by antiretroviral therapy (ART) has allowed drastically reducing the mortality and morbidity of HIV infection. However, one main source of clinical concern is the persistence of immune hyperactivation in individuals under ART. Chronically enhanced levels of T-cell activation are associated with several deleterious effects which lead to faster disease progression and slower CD4(+) T-cell recovery during ART. In this article, we discuss the rationale, and review the results, of the use of antimalarial quinolines, such as chloroquine and its derivative hydroxychloroquine, to counteract immune activation in HIV infection. Despite the promising results of several pilot trials, the most recent clinical data indicate that antimalarial quinolines are unlikely to exert a marked beneficial effect on immune activation. Alternative approaches will likely be required to reproducibly decrease immune activation in the setting of HIV infection. If the quinoline-based strategies should nevertheless be pursued in future studies, particular care must be devoted to the dosage selection, in order to maximize the chances to obtain effective in vivo drug concentrations.

No MeSH data available.


Related in: MedlinePlus

Comparison of the susceptibility to chloroquine/hydroxychloroquine and auranofin of the cellular subsets involved in HIV production and persistence. Shown in the figure is a schematic depiction of a activation and b differentiation stages of CD4+ T-lymphocytes and their correlation with viral production, latency and viral reactivation. Both chloroquine/hydroxychloroquine and auranofin can influence these transitions by exerting a pro-apoptotic effect, the efficacy of which is graphically exemplified by the intensity of the blue color in the corresponding rectangles. Efficacy gradients are based on data derived from Refs. [45, 48, 50].
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Fig2: Comparison of the susceptibility to chloroquine/hydroxychloroquine and auranofin of the cellular subsets involved in HIV production and persistence. Shown in the figure is a schematic depiction of a activation and b differentiation stages of CD4+ T-lymphocytes and their correlation with viral production, latency and viral reactivation. Both chloroquine/hydroxychloroquine and auranofin can influence these transitions by exerting a pro-apoptotic effect, the efficacy of which is graphically exemplified by the intensity of the blue color in the corresponding rectangles. Efficacy gradients are based on data derived from Refs. [45, 48, 50].

Mentions: A recent study showed that hydroxychloroquine selectively induces apoptosis in the memory T-cell compartment (CD45RA− CD45RO+) [45]. As, upon activation, naïve T-cells (CD45RA+ CD45RO−) acquire a CD45RA− CD45RO+ phenotype, the “antimemory” effect should limit immune activation (Figure 2) [46]. There is growing consensus that induction of apoptosis in the memory T-cell compartment might have a detrimental effect on the viral reservoir [47–49]. In this light, chloroquine/hydroxychloroquine should have an anti-reservoir potential. This view is supported by another recent study which shows that chloroquine sensitizes to apoptosis the latently infected cells upon viral reactivation, likely by removing the anti-apoptotic effect of the virus structural gag gene products [50]. These effects are potentially interesting, since it has been well demonstrated that viral reactivation from latency does not necessarily result in cell death [51].Figure 2


Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS.

Savarino A, Shytaj IL - Retrovirology (2015)

Comparison of the susceptibility to chloroquine/hydroxychloroquine and auranofin of the cellular subsets involved in HIV production and persistence. Shown in the figure is a schematic depiction of a activation and b differentiation stages of CD4+ T-lymphocytes and their correlation with viral production, latency and viral reactivation. Both chloroquine/hydroxychloroquine and auranofin can influence these transitions by exerting a pro-apoptotic effect, the efficacy of which is graphically exemplified by the intensity of the blue color in the corresponding rectangles. Efficacy gradients are based on data derived from Refs. [45, 48, 50].
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4472405&req=5

Fig2: Comparison of the susceptibility to chloroquine/hydroxychloroquine and auranofin of the cellular subsets involved in HIV production and persistence. Shown in the figure is a schematic depiction of a activation and b differentiation stages of CD4+ T-lymphocytes and their correlation with viral production, latency and viral reactivation. Both chloroquine/hydroxychloroquine and auranofin can influence these transitions by exerting a pro-apoptotic effect, the efficacy of which is graphically exemplified by the intensity of the blue color in the corresponding rectangles. Efficacy gradients are based on data derived from Refs. [45, 48, 50].
Mentions: A recent study showed that hydroxychloroquine selectively induces apoptosis in the memory T-cell compartment (CD45RA− CD45RO+) [45]. As, upon activation, naïve T-cells (CD45RA+ CD45RO−) acquire a CD45RA− CD45RO+ phenotype, the “antimemory” effect should limit immune activation (Figure 2) [46]. There is growing consensus that induction of apoptosis in the memory T-cell compartment might have a detrimental effect on the viral reservoir [47–49]. In this light, chloroquine/hydroxychloroquine should have an anti-reservoir potential. This view is supported by another recent study which shows that chloroquine sensitizes to apoptosis the latently infected cells upon viral reactivation, likely by removing the anti-apoptotic effect of the virus structural gag gene products [50]. These effects are potentially interesting, since it has been well demonstrated that viral reactivation from latency does not necessarily result in cell death [51].Figure 2

Bottom Line: However, one main source of clinical concern is the persistence of immune hyperactivation in individuals under ART.Chronically enhanced levels of T-cell activation are associated with several deleterious effects which lead to faster disease progression and slower CD4(+) T-cell recovery during ART.If the quinoline-based strategies should nevertheless be pursued in future studies, particular care must be devoted to the dosage selection, in order to maximize the chances to obtain effective in vivo drug concentrations.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy. andrea.savarino@iss.it.

ABSTRACT
The restoration of the immune system prompted by antiretroviral therapy (ART) has allowed drastically reducing the mortality and morbidity of HIV infection. However, one main source of clinical concern is the persistence of immune hyperactivation in individuals under ART. Chronically enhanced levels of T-cell activation are associated with several deleterious effects which lead to faster disease progression and slower CD4(+) T-cell recovery during ART. In this article, we discuss the rationale, and review the results, of the use of antimalarial quinolines, such as chloroquine and its derivative hydroxychloroquine, to counteract immune activation in HIV infection. Despite the promising results of several pilot trials, the most recent clinical data indicate that antimalarial quinolines are unlikely to exert a marked beneficial effect on immune activation. Alternative approaches will likely be required to reproducibly decrease immune activation in the setting of HIV infection. If the quinoline-based strategies should nevertheless be pursued in future studies, particular care must be devoted to the dosage selection, in order to maximize the chances to obtain effective in vivo drug concentrations.

No MeSH data available.


Related in: MedlinePlus