Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

Soares, Rui; Tendeiro, Rita; Foxall, Russell B.; Baptista, António P.; Cavaleiro, Rita; Gómes, Perpétua; Camacho, Ricardo Jorge; Valadas, Emília; Doroana, Manuela; Lucas, Margarida; Antúnes, Francisco; Victorino, Rui M. M.; Sousa, Ana E.

doi:10.1128/jvi.01921-10

Cited by 45 publications

(42 citation statements)

References 62 publications

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“…Compared to data for HIV-1-infected individuals, less data are available about the relationship between the progression toward overt disease and the presence of an IFN state in HIV-2-infected individuals at different stages of the disease. However, in marked contrast to HIV-1-infected individuals, HIV-2-infected individuals do generally display low viral loads (44)(45)(46)(47). The reasons for these differences are unknown at present.…”

Section: A Lpha and Beta Interferons (Ifn-␣ And Ifn-␤) Collectively mentioning

confidence: 85%

“…One of the major differences that exists between HIV-1 and HIV-2 infections in vivo is that while the former is characterized by high viral loads in the majority of untreated patients, a high proportion of HIV-2-infected patients present with relatively low viral loads for decades (44)(45)(46)(47). In light of the results presented here, it would be tempting to speculate that the higher susceptibility of HIV-2 to IFN-␣ is at least in part responsible for the presence of lower viral loads, while the partial resistance displayed by HIV-1 allows the virus to replicate despite the presence of chronic type I interferon responses.…”

Section: Discussionmentioning

confidence: 99%

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Evidence for a Different Susceptibility of Primate Lentiviruses to Type I Interferons

Cordeil

Nguyen

Berger

et al. 2013

J Virol

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Type I interferons induce a complex transcriptional program that leads to a generalized antiviral response against a large panel of viruses, including human immunodeficiency virus type 1 (HIV-1). However, despite the fact that interferons negatively regulate HIV-1 ex vivo, a chronic interferon state is linked to the progression of AIDS and to robust viral replication, rather than protection, in vivo. To explain this apparent contradiction, we hypothesized that HIV-1 may have evolved a partial resistance to interferon, and to test this hypothesis, we analyzed the effects of alpha interferon (IFN-␣) on the infectivity of HIV-1, human immunodeficiency virus type 2 (HIV-2), and rhesus monkey simian immunodeficiency virus (SIVmac). The results we obtained indicate that HIV-1 is more resistant to an IFN-␣-induced response than are HIV-2 and SIVmac. Our data indicate that the accumulation of viral DNA is more compromised following the infection of IFN-␣-treated cells with HIV-2 and SIVmac than with HIV-1. This defect correlates with a faster destabilization of HIV-2 viral nucleoprotein complexes (VNCs), suggesting a link between VNC destabilization and impaired viral DNA (vDNA) accumulation. The differential susceptibilities to IFN-␣ of the primate lentiviruses tested here do not map to the capsid protein (CA), excluding de facto a role for human tripartite motif protein isoform 5 alpha (Trim5␣) in this restriction; this also suggests that an additional restriction mechanism differentially affects primate lentivirus infection. The different behaviors of HIV-1 and HIV-2 with respect to IFN-␣ responses may account at least in part for the differences in pathogenesis observed between these two virus types.

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Section: A Lpha and Beta Interferons (Ifn-␣ And Ifn-␤) Collectively mentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Evidence for a Different Susceptibility of Primate Lentiviruses to Type I Interferons

Cordeil

Nguyen

Berger

et al. 2013

J Virol

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“…In antiretroviral-treated adults, total HIV DNA in resting CD4 T cells is strongly associated with CD4 and CD8 T cell activation, whereas there is no association between cell activation and integrated DNA or IUPM coculture results (254). Cell-associated HIV RNA load, which reflects the level of viral transcription, including abortive transcription, also correlates with immune activation in untreated patients, patients on cART, and natural controllers (204,255,256,257). In patients on cART with undetectable viremia, HIV transcript loads correlate negatively with the CD4 T cell count (257) and positively with lymphoproliferative responses to HIV p24 antigen (258).…”

Section: Discussionmentioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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“…If the former is true, it is necessary to develop quantitative virological biomarkers to monitor these effects. Further studies are warranted to establish whether CA HIV-1 RNA can be used as a reliable surrogate marker of such effects, but several reports already point to a direct correlation of CA HIV RNA levels with markers of immune activation in untreated patients, natural controllers, and patients on ART [127-129]. …”

Section: Reviewmentioning

confidence: 99%

Cell-associated HIV RNA: a dynamic biomarker of viral persistence

2013

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In most HIV-infected individuals adherent to modern antiretroviral therapy (ART), plasma viremia stays undetectable by clinical assays and therefore, additional virological markers for monitoring and predicting therapy responses and for measuring the degree of HIV persistence in patients on ART should be identified. For the above purposes, quantitation of cell-associated HIV biomarkers could provide a useful alternative to measurements of viral RNA in plasma. This review concentrates on cell-associated (CA) HIV RNA with the emphasis on its use as a virological biomarker. We discuss the significance of CA HIV RNA as a prognostic marker of disease progression in untreated patients and as an indicator of residual virus replication and the size of the dynamic viral reservoir in ART-treated patients. Potential value of this biomarker for monitoring the response to ART and to novel HIV eradication therapies is highlighted.

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Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

Cited by 45 publications

References 62 publications

Evidence for a Different Susceptibility of Primate Lentiviruses to Type I Interferons

Evidence for a Different Susceptibility of Primate Lentiviruses to Type I Interferons

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

Cell-associated HIV RNA: a dynamic biomarker of viral persistence

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