Increased inflammation in sanctuary sites may explain viral blips in HIV infection

Abstract

Combined antiretroviral therapy (cART) is a powerful therapy to suppress HIV-1 viral replication. Although in treatment, viral load in plasma remains below the limit of detection in regular assays, 50copiesmL, intermittent episodes of transient viremia (viral blips) over the limit of detection occur in a significant set of HIV-patients under cART. Here, we develop a model-based study of a possible relation between ongoing replication in lymphoid-tissue-based sanctuary sites and viral blips. Given that follicular hyperplasia occurs during lymphoid inflammation as a normal response to infection, we hypothesize that when the diameter of the lymph node follicle increases and crosses a critical size, a viral blip occurs due to cryptic viremia. To demonstrate this we do a theoretical analysis of the model to find those conditions that guarantee that the virus is suppressed in all compartments, and simulate the model for different scenarios of lymph node follicle diameter changes. Thus, to have realistic viral blips, with duration of less than 30 days and with amplitudes relatively close to the limit of detection, the diameter rise rate should be between 0.02 and 0.03 days−1. Moreover, the final diameter of the site is directly related to the steady states of the virus load after the occurrence of a blip. When the steady state viral load after the blip is below the limit of detection, the median value of R0 is 1.45. However, when the median increases beyond 2.1, the steady state of the viral load after the blip often has a value above the limit of detection if the final maximum diameter is sufficiently small. In these cases, for a realistic blip, the maximum final diameters should be greater than 0.7mm so that there is a relative loss of connection between compartments.

Herpes DNAemia and TTV Viraemia in Intensive Care Unit Critically Ill Patients: A Single-Centre Prospective Longitudinal Study

“…The higher serum IL10 level in sepsis compared to all other ICU pathologies may suggest that EBV and CMV reactivation could be triggered by molecular events mediated by stress, local trauma, or unrelated infections ( 45 , 46 ), rather than associated with pre-existing immune suppression ( 11 , 45 , 47 ). Alternatively, we observed low-level viraemia or viral “blips” for herpesviruses rather than significant viral rebound; hence, reactivation may result from increased inflammation in sanctuary sites or reservoirs as described in HIV infection ( 48 , 49 ) or to immunosurveillance activities of neighbouring cells ( 50 ). The changes observed in TTV viraemia in ICU patients in this study indicate the need for further exploration of the process of reactivation/modulation of expression of TTV.…”

Identification of viral protein R of human immunodeficiency virus-1 (HIV) and interleukin-6 as risk factors for malignancies in HIV-infected individuals: A cohort study

“…First, there is evidence for residual viral replication due to the low concentrations of antiretroviral drugs in sanctuary sites are present throughout the body, including the lymph nodes, central nervous system, tissue macrophages, adipose tissue, and the gut-associated lymphoid tissue [65][66][67][68][69][70]. It has also been reported that temporal elevation of viral production, "viral blip", is induced by transient inflammation in the sanctuary sites [71,72]. In our study, the proportion of viral blips in the Vpr-positive patients was negligible both in the tumor group (5.2%, 6 of 115 patients) and the non-tumor group (6.1%, 4 of 66 patients) (Table 3) and none of factors including HIV viremia were predicted with Vpr emergence status (S3 Table ), further implying that the production of Vpr was not due to the viral blip.…”

Episomal HIV-1 DNA and its relationship to other markers of HIV-1 persistence

“…3 ), using infection dynamic rates and tissue transport rates derived from a number of human and animal studies. Analyzing this model leads to several interesting insights [ 55 , 56 ]. The model demonstrates that a lower limit in sanctuary size is necessary to sustain ongoing replication, even when no antiretrovirals are present.…”