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    • In this issue of Vranckx and colleagues

    2018-10-23

    In this issue of , Vranckx and colleagues show that a LEDGIN termed CX014442 specifically alters HIV-1 genomic integration in a manner that is similar to that associated with LEDGF depletion (). The authors carefully characterized HIV integration sites in the presence of various concentrations of CX014442 and found that this compound caused a dose-dependent shift that now favored GC-rich regions for integration instead of actively transcribed genomic regions (). However, the preferential DNA sequences targeted for integration did not change, and Vranckx verified that CX014442 did not favor HIV integration within genomic regions that are identified as unsafe integration sites (), consistent with the notion that HIV integration does not result in cellular transformation, although HIV integration at sites close to genes involved in cellular survival has been linked to cellular clonal expansion without oncogenesis (). The authors further showed that integration events, in the presence of CX014442, were more likely to be localized deeper within the cellular nucleus (), consistent with a similar effect of LEDGF knockdown (). The use of the INSTI raltegravir or a catalytically inactive form of integrase had similar effects (). Most remarkably, using an latency model with a dual-reporter virus, the scientists showed that post-latency reactivation was also inhibited in the presence of CX014442. Accordingly, they argue that LEDGINs may target HIV integration within genomic regions that are less favorable for reactivation than those that are targeted in the presence of a functional integrase–LEDGF interaction. In support of this, the authors also showed that latent infection in LEDGF-depleted gnrh agonist is less susceptible to reactivation by various latency reversing agents including a combination of the protein kinase C activator prostratin together with SAHA, a histone deacetylase inhibitor. This is important as latency reversing agents are being actively investigated as part of the “Shock and Kill” cure strategy. The authors conclude that LEDGINs may help reduce the portion of the HIV reservoir that is susceptible to reactivation and suggest that LEDGINs might have utility early in treatment strategies aimed at reducing the size of the reservoir. One caveat may be that the use of INSTIs or reverse transcriptase inhibitors may actually be more beneficial during early treatment, since the LEDGINs may, in fact, be most active post-integrationally. Further research is needed to better understand the molecular mechanism(s) whereby LEDGINs inhibit HIV replication and to better distinguish between their -integrase versus post-integration effects. In addition, CX014442 also seemed to be effective at different concentrations in different cell types and this also needs to be further studied as should the reasons for the LEDGIN- and raltegravir-dependent relocalization of integration to sites that are deeper within the nucleus. And, clarification is needed to understand the link between integration sites within specific genomic regions and susceptibility to latency reversal. The use of non-human primate and/or humanized mouse models might also provide much needed insights in regard to the possible role of LEDGINs in HIV eradication. Disclosure
    Chronic elevation in markers of immune activation is a hallmark of HIV infection, even when viral replication has been suppressed by antiretroviral therapy (ART) (). The Strategies for the Management of Antiretroviral Therapy (SMART) study demonstrated that plasma levels of interleukin-6 (IL-6), C-reactive protein, and D-dimer are independent predictors of mortality in HIV infection, including deaths related to cardiovascular disease (CVD) (). The predictive value of markers of immune activation and inflammation has been confirmed in several studies (). Potential mechanisms have also been identified that may contribute to increased activation of both the innate and the adaptive immune systems in chronic HIV infection, including: copathogens, microbial translocation, pro-inflammatory lipids, low level viral replication, and the immune system\'s response to cytopenia ().