Enhanced CD4+ T-Cell Recovery with Earlier HIV-1 Antiretroviral Therapy

Le, Tuan; Wright, Edwina; Smith, Davey M.; He, Weijing; Catano, Gabriel; Okulicz, Jason F.; Young, Jason A.; Clark, Robert A.; Richman, Douglas D.; Ahuja, Sunil K.

doi:10.1056/nejmoa1110187

Cited by 307 publications

(341 citation statements)

References 27 publications

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“…All participants were CMV and EBV seropositive. The estimated date of infection (EDI) for HIV was calculated using established algorithms [19]. Stored samples were selected retrospectively from participants who started ART and achieved complete suppression of HIV RNA (defined as <50 or <200 copies/mL depending on assay sensitivity) during study follow-up.…”

Section: Participants Samples and Clinical Laboratory Testsmentioning

confidence: 99%

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

et al. 2016

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Background. A low CD4/CD8 ratio in human immunodeficiency virus (HIV)-infected individuals is associated with inflammation and higher risk of non-AIDS morbidity and mortality. In this study, we investigated the effect of subclinical cytomegalovirus (CMV) and Epstein-Barr virus (EBV) replication on CD4 + and CD8 + T-cell dynamics when antiretroviral therapy (ART) is started during early infection.Methods. We investigated 604 peripheral blood mononuclear cell samples from 108 CMV-and EBV-seropositive HIV-infected men who have sex with men, who started ART within a median of 4 months from their estimated date of infection and were followed for a median of 29.1 months thereafter. Levels of CMV and EBV DNA were measured at each timepoint. Mixed-effects asymptotic regression models were applied to characterize CD4 + and CD8 + T-cell dynamics, and Bayesian hierarchical models were used to quantify individual differences in CMV and EBV DNA replication.Results. Higher levels of subclinical CMV replication were associated with lower predicted maximum levels of CD4/CD8 ratio (P < .05), which was driven by higher levels of CD8 + T-cell counts (P < .05), without affecting CD4 + T-cell counts (P > .1). Age was negatively associated with CD4/CD8 levels (P < .05), and this effect was independent of the CMV association (P < .05 for both CMV and age in a multivariate model).Conclusions. Subclinical CMV replication in blood cells during early HIV infection and younger age were associated with lower CD4/CD8 ratios during suppressive ART. These findings suggest that active CMV infection in the setting of treated HIV may represent an attractive potential target for therapeutic intervention.

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Section: Participants Samples and Clinical Laboratory Testsmentioning

confidence: 99%

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

et al. 2016

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“…Thus using these two factors and a comprehensive set of clinical data, we are able to estimate the relative contributions of both direct killing and RN collagenation in HIV, the subsequent reversal which occurs. We also show that this reversal is dependent on the timing of ART introduction, as in [47], with earlier ART leading to closer to full recovery.…”

Section: Discussionmentioning

confidence: 60%

“…Given this information on the distinct roles of direct killing and collagenation, it is then possible to estimate the values of these parameters during HIV. Taking the data of [47] to make a first estimate we target an initial reduction of 57% from baseline after 1 year of HIV (CD4 + count declining from ∼ 1000 cells/mm 3 to ∼ 430 cells/mm 3 ) and a subsequent recovery of 31% after 4 years of ART (CD4 + count recovering from ∼ 430 cells/mm 3 to ∼ 740 cells/mm 3 ). Using this calibration we find µ HIV = 5.4 × 10 −3 /day and κ = 3.8 × 10 −4 /day 2 , and the results of this simulation are given by the solid black curve in Fig.…”

Section: Hiv Infection and Artmentioning

confidence: 99%

“…4. Here we can also easily test the effects of introducing ART relatively earlier or later, as considered by [47], shifting the HIV exposure time by 120 days in each direction; of course greater exposure time without ART results in greater CD4 + count decline during this phase, but also the recovery is altered because of the level of RN damage from collagenation, with changes of ±120 days resulting in ±6.5% changes in recovery, respectively.…”

Section: Hiv Infection and Artmentioning

confidence: 99%

“…The HIV-active rates µ HIV and κ are fitted to the data of [47]. The FRC length is chosen to align with experimental data, e.g.…”

Section: B the Steady State Of The Heterogeneous Population Modelmentioning

confidence: 99%

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T cell and reticular network co-dependence in HIV infection

Donovan

Lythe

2016

Journal of Theoretical Biology

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Fibroblastic reticular cells (FRC) are arranged on a network in the T cell zone of lymph nodes, forming a scaffold for T cell migration, and providing survival factors, especially interleukin-7 (IL-7). Conversely, CD4 + T cells are the major producers of lymphotoxin-β (LT-β), necessary for the construction and maintenance of the FRC network. This interdependence creates the possibility of a vicious cycle, perpetuating loss of both FRC and T cells. Furthermore, evidence that HIV infection is responsible for collagenation of the network suggests that long term loss of network function might be responsible for the attenuated recovery in T cell count seen in HIV patients undergoing antiretroviral therapy (ART). We present computational and mathematical models of this interaction mechanism and subsequent naive CD4 + T-cell depletion in which (1) collagen deposition impedes access of naive T cells to IL-7 on the FRC and loss of IL-7 production by loss of FRC network itself, leading to the depletion of naive T cells through increased apoptosis; and (2) depletion of naive T cells as the source of LT-β on which the FRC depend for survival, leads to loss of the network, thereby amplifying and perpetuating the cycle of depletion of both naive T cells and stromal cells. Our computational model explicitly includes an FRC network and its cytokine exchange with a heterogeneous T-cell population. We also derive lumped models, in terms of partial differential equations and reduced to ordinary differential equations, that provide additional insight into the mechanisms at work. The central conclusions are that 1) damage to the reticular network, caused by HIV infection, is a plausible mechanism for attenuated recovery post-ART; 2) within this, the production of T cell survival factors by FRCs may be the key ratelimiting step; and 3) the methods of model reduction and analysis presented are useful for both immunological studies and other contexts in which agent-based models are severely limited by computational cost.

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