Abstract
Upon interruption of antiretroviral therapy, HIV-infected patients usually show viral load rebound to pre-treatment levels. Four patients, hereafter referred to as secondary controllers (SC), were identified who initiated therapy during chronic infection and, after stopping treatment, could control virus replication at undetectable levels for more than six months. In the present study we set out to unravel possible viral and immune parameters or mechanisms of this phenomenon by comparing secondary controllers with elite controllers and non-controllers, including patients under HAART. As candidate correlates of protection, virus growth kinetics, levels of intracellular viral markers, several aspects of HIV-specific CD4+ and CD8+ T cell function and HIV neutralizing antibodies were investigated. As expected all intracellular viral markers were lower in aviremic as compared to viremic subjects, but in addition both elite and secondary controllers had lower levels of viral unspliced RNA in PBMC as compared to patients on HAART. Ex vivo cultivation of the virus from CD4+ T cells of SC consistently failed in one patient and showed delayed kinetics in the three others. Formal in vitro replication studies of these three viruses showed low to absent growth in two cases and a virus with normal fitness in the third case. T cell responses toward HIV peptides, evaluated in IFN-γ ELISPOT, revealed no significant differences in breadth, magnitude or avidity between SC and all other patient groups. Neither was there a difference in polyfunctionality of CD4+ or CD8+ T cells, as evaluated with intracellular cytokine staining. However, secondary and elite controllers showed higher proliferative responses to Gag and Pol peptides. SC also showed the highest level of autologous neutralizing antibodies. These data suggest that higher T cell proliferative responses and lower replication kinetics might be instrumental in secondary viral control in the absence of treatment.
Highlights
Once infected with human immunodeficiency virus (HIV), the large majority of individuals are unable to control the virus
Clinical characteristics of the study population Within the HIV cohort of the Institute of Tropical Medicine of Antwerp, including over 1700 patients, we identified 160 subjects, excluding pregnant women, who had been successfully treated for progressive HIV infection with full highly active antiretroviral therapy (HAART), but at some point decided to stop treatment against medical advice
Most patients were infected with HIV-1 subtype B or the closely related subtype D, with the exception of secondary controllers (SC) P4 (A1) and HAART P17 (CRF-02)
Summary
Once infected with human immunodeficiency virus (HIV), the large majority of individuals are unable to control the virus. Exceptional patients, so-called elite controllers (EC), continue to have an ‘‘undetectable’’ plasma viral load (VL, copies/ml) without treatment [1]. Strong HIV-specific adaptive immunity, genetic factors and/or viral defects have been invoked to explain controller status. Elite controllers appear to harbor HIV-1 variants that encode Gag, Pol, Env and or Nef proteins that are less efficient than their counterparts of HIV-1 in typical/chronic progressors. Particular HLA B MHC antigens, including B27, B5701 and B58, are enriched in EC. This has been explained by the fact that CD8+ T cells restricted by these HLA molecules, recognize very conserved epitopes in Gag and that escape comes at a high fitness cost for the virus [5,6]
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