Early immunologic and virologic predictors of clinical HIV-1 disease progression

Mahnke, Yolanda D.; Song, Ki Duk; Sauer, Mariana M.; Nason, Martha; Giret, María Teresa Maidana; Carvalho, Karina I.; Costa, Priscilla R.; Kallás, Esper G.

doi:10.1097/qad.0b013e32835ce2e9

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…Individuals included in this study had a low CD4 count which was directly related with high viral load. These features are consistent with the reported absence of ART [46] , [47] .…”

Section: Discussionsupporting

confidence: 92%

HIV-1 Diversity, Transmission Dynamics and Primary Drug Resistance in Angola

et al. 2014

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ObjectivesTo assess HIV-1 diversity, transmission dynamics and prevalence of transmitted drug resistance (TDR) in Angola, five years after ART scale-up.MethodsPopulation sequencing of the pol gene was performed on 139 plasma samples collected in 2009 from drug-naive HIV-1 infected individuals living in Luanda. HIV-1 subtypes were determined using phylogenetic analysis. Drug resistance mutations were identified using the Calibrated Population Resistance Tool (CPR). Transmission networks were determined using phylogenetic analysis of all Angolan sequences present in the databases. Evolutionary trends were determined by comparison with a similar survey performed in 2001.Results47.1% of the viruses were pure subtypes (all except B), 47.1% were recombinants and 5.8% were untypable. The prevalence of subtype A decreased significantly from 2001 to 2009 (40.0% to 10.8%, P = 0.0019) while the prevalence of unique recombinant forms (URFs) increased>2-fold (40.0% to 83.1%, P<0.0001). The most frequent URFs comprised untypable sequences with subtypes H (U/H, n = 7, 10.8%), A (U/A, n = 6, 9.2%) and G (G/U, n = 4, 6.2%). Newly identified U/H recombinants formed a highly supported monophyletic cluster suggesting a local and common origin. TDR mutation K103N was found in one (0.7%) patient (1.6% in 2001). Out of the 364 sequences sampled for transmission network analysis, 130 (35.7%) were part of a transmission network. Forty eight transmission clusters were identified; the majority (56.3%) comprised sequences sampled in 2008–2010 in Luanda which is consistent with a locally fuelled epidemic. Very low genetic distance was found in 27 transmission pairs sampled in the same year, suggesting recent transmission events.ConclusionsTransmission of drug resistant strains was still negligible in Luanda in 2009, five years after the scale-up of ART. The dominance of small and recent transmission clusters and the emergence of new URFs are consistent with a rising HIV-1 epidemics mainly driven by heterosexual transmission.

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“…Individuals included in this study had a low CD4 count which was directly related with high viral load. These features are consistent with the reported absence of ART [46] , [47] .…”

Section: Discussionsupporting

confidence: 92%

HIV-1 Diversity, Transmission Dynamics and Primary Drug Resistance in Angola

et al. 2014

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“…Interestingly enough, many studies have established a link between HIV-specific memory CD8 + T-cell differentiation and disease progression [16], [40], [41]. Additionally, differentiation of total CD8 + T-cells is also skewed in HIV infection and related to progression [6], [16], [19], [42], [43]. In this context, our results reinforce the level of knowledge into this field providing further support into these notions.…”

Section: Discussionsupporting

confidence: 85%

Early Skewed Distribution of Total and HIV-Specific CD8+ T-Cell Memory Phenotypes during Primary HIV Infection Is Related to Reduced Antiviral Activity and Faster Disease Progression

et al. 2014

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The important role of the CD8+ T-cells on HIV control is well established. However, correlates of immune protection remain elusive. Although the importance of CD8+ T-cell specificity and functionality in virus control has been underscored, further unraveling the link between CD8+ T-cell differentiation and viral control is needed. Here, an immunophenotypic analysis (in terms of memory markers and Programmed cell death 1 (PD-1) expression) of the CD8+ T-cell subset found in primary HIV infection (PHI) was performed. The aim was to seek for associations with functional properties of the CD8+ T-cell subsets, viral control and subsequent disease progression. Also, results were compared with samples from Chronics and Elite Controllers. It was found that normal maturation of total and HIV-specific CD8+ T-cells into memory subsets is skewed in PHI, but not at the dramatic level observed in Chronics. Within the HIV-specific compartment, this alteration was evidenced by an accumulation of effector memory CD8+ T (TEM) cells over fully differentiated terminal effector CD8+ T (TTE) cells. Furthermore, higher proportions of total and HIV-specific CD8+ TEM cells and higher HIV-specific TEM/(TEM+TTE) ratio correlated with markers of faster progression. Analysis of PD-1 expression on total and HIV-specific CD8+ T-cells from PHI subjects revealed not only an association with disease progression but also with skewed memory CD8+ T-cell differentiation. Most notably, significant direct correlations were obtained between the functional capacity of CD8+ T-cells to inhibit viral replication in vitro with higher proportions of fully-differentiated HIV-specific CD8+ TTE cells, both at baseline and at 12 months post-infection. Thus, a relationship between preservation of CD8+ T-cell differentiation pathway and cell functionality was established. This report presents evidence concerning the link among CD8+ T-cell function, phenotype and virus control, hence supporting the instauration of early interventions to prevent irreversible immune damage.

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“…35 The capacity to rapidly express or down-regulate activation markers on CM and EM CD8 cell subsets suggests that assessment of discrete T cell populations has utility in monitoring immune activation in HIV-infected patients on cART as the extent of CD38 expression within CD8 subsets and levels of cell-associated virus predict disease progression in untreated HIV-infected adults. 36 A surprising result among the youth with sustained viral suppression after 48 weeks of cART was continued elevation in CD38 on CM and EM CD8 T cells and the failure to normalize CD28 when compared to uninfected controls. Longer duration of optimal viral suppression may be needed before these signs of T cell activation decline in younger individuals.…”

Section: Discussionmentioning

confidence: 99%

Immune Reconstitution but Persistent Activation After 48 Weeks of Antiretroviral Therapy in Youth With Pre-Therapy CD4 >350 in ATN 061

Rudy

Kapogiannis

Worrell

et al. 2015

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited. Design Adolescent Trials Network 061 examined changes over 48 weeks of cART in T cell subsets and markers of T cell and macrophage activation in subjects with pre-therapy CD4>350. All subjects had optimal viral suppression from weeks 24 through 48. Methods Subjects (n=48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls. Results Significant increases over 48 weeks were noted in all CD4 populations including total, naïve, central memory (CM), and effector memory RO (EM RO) and effector memory RA (EM RA) while numbers of CM and EMRO CD8 cells declined significantly. By week 48, CD4 naïve cells were similar to controls while CM CD4 cells remained significantly lower and EM RO and EM RA subsets were significantly higher. CD38 and HLA DR expression, both individually and when co-expressed, decreased over 48 weeks of cART on CD8 cells but remained significantly higher than controls at week 48. In contrast, markers of macrophage activation measured by sCD14 and sCD163 in plasma did not change with cART and were significantly higher than controls. Conclusion In youth initiating early cART, CD4 cell reconstitution is robust with decreases in CD8 cells. However CD8 T cell and macrophage activation persists at higher levels than uninfected controls.

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Early immunologic and virologic predictors of clinical HIV-1 disease progression

Cited by 13 publications

References 34 publications

HIV-1 Diversity, Transmission Dynamics and Primary Drug Resistance in Angola

HIV-1 Diversity, Transmission Dynamics and Primary Drug Resistance in Angola

Early Skewed Distribution of Total and HIV-Specific CD8+ T-Cell Memory Phenotypes during Primary HIV Infection Is Related to Reduced Antiviral Activity and Faster Disease Progression

Immune Reconstitution but Persistent Activation After 48 Weeks of Antiretroviral Therapy in Youth With Pre-Therapy CD4 >350 in ATN 061

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