Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection

Abstract

HIV-1 elite controllers (EC) maintain undetectable viral load (VL) in the absence of antiretroviral treatment. However, these subjects have heterogeneous clinical outcomes including a proportion loosing HIV-1 control over time. In this work we compared, in a longitudinal design, transient EC, analyzed before and after the loss of virological control, versus persistent EC. The aim was to identify factors leading to the loss of natural virological control of HIV-1-infection with a longitudinal retrospective study design. Gag-specific T-cell response was assessed by intracellular poly-cytokine production quantified by flow cytometry. Viral diversity and sequence-dating were performed in proviral DNA by PCR amplification at limiting dilution in and genes. The expression profile of 70 serum cytokines and chemokines was assessed by multiplex immunoassays. We identified transient EC as subjects with low Gag-specific T-cell polyfunctionality, high viral diversity and high proinflammatory cytokines levels before the loss of control. Gag-specific T-cell polyfunctionality was inversely associated with viral diversity in transient controllers before the loss of control (r=-0.8;=0.02). RANTES was a potential biomarker of transient control. This study identified, virological and immunological factors including inflammatory biomarkers associated with two different phenotypes within EC. These results may allow a more accurate definition of EC, which could help in a better clinical management of these individuals and in the development of future curative approaches. There is a rare group of HIV-infected patients who have the extraordinary capacity to maintain undetectable viral load levels in the absence of antiretroviral treatment, the so called HIV-1 elite controllers (EC). However, there is a proportion within these subjects that eventually loses this capability. In this work we found differences in virological and immune factors including soluble inflammatory biomarkers between subjects with persistent control of viral replication and EC that will loss the virological control. The identification of these factors could be a key point for a right medical care of those EC who are going to lose the natural control of viral replication, and for the design of future immunotherapeutic strategies using as a model the natural persistent control of HIV-infection.

Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure

“…This could be due to the previous long-term story of HCV infection, and in fact, sCD163 has been proposed as a marker of liver fibrosis 46 . This is a substantial difference with previously published EC profiles where despite the viral control, inflamation levels were maintained over www.nature.com/scientificreports www.nature.com/scientificreports/ time 10,47 . Whether this could be a distinctive marker easy to assay for EEC needs to be examined in extended populations, but previous works with persistent EC suggested this idea 10,48 .…”

“…This is a substantial difference with previously published EC profiles where despite the viral control, inflamation levels were maintained over www.nature.com/scientificreports www.nature.com/scientificreports/ time 10,47 . Whether this could be a distinctive marker easy to assay for EEC needs to be examined in extended populations, but previous works with persistent EC suggested this idea 10,48 . The interplay of T cells with the preserved number and functions of innate cells might have been a critical factor for the maintenance of the high HIV-1-specific T-cell responses in these subjects 49 .…”

“…All study subjects showed the lowest viral diversity values among comparative groups of subjects on ART or LTNP with viral load control. In addition, in a previous study we showed that low diversity and lack of viral evolution was highly correlated with permanent viral control in persistent EC 10 . On the contrary, transient EC who lost control during the follow-up showed higher levels of genetic diversity 10 (Fig.…”

“…Likewise, both frequency and poly-functionality of Gag-specific CD8 + T-cell responses were higher in EEC when compared with subjects on ART (Fig. 3A) and similar or above the median of a group of persistent EC (with more than 18 years of controlled infection) and higher than those of transient EC 10 . The CTL responses supported the capacity of the immune system to mount effective adaptive immune responses as confirmed by the ex vivo viral inhibition assay.…”

HIV control: Is getting there the same as staying there?

“…In a multicenter study of controllers (Collaboration of Observational HIV Epidemiological Research Europe [COHERE]), progression was rare and was predicted by a low CD4/CD8 ratio and intermittent viremia [ 67 ]; similar findings were noted in a French study [ 68 ]. In smaller pathogenesis-oriented studies, heightened inflammation and T-cell activation predated and often predicted virologic progression [ 17 , 69 , 70 ].…”