Immune and Viral Correlates of “Secondary Viral Control” after Treatment Interruption in Chronically HIV-1 Infected Patients

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.

HIV-1 transcriptional activity during frequent longitudinal sampling in aviremic patients on antiretroviral therapy

“…Antiretroviral therapy (ART) in HIV-1-infected individuals suppresses plasma HIV-1 RNA below limits of detection by standard clinical assays within 3-6 months. However, despite long-term ART, some infected cells continue to transcribe viral RNA as indicated by the presence of cellular HIV-1 transcripts and low-level viremia detected by ultrasensitive single-copy assay (SCA) [14][15][16][17]. The decay kinetics of viral transcriptional activity, measured as cell-associated unspliced HIV-1 RNA (CA-US HIV-1 RNA), in peripheral blood mononuclear cells (PBMCs) and lymphocytes residing in lymph nodes, follow roughly the same pattern as the decay kinetics of plasma HIV-1 RNA [18,19], although the reduction only occurs over 1-2 log 10 compared to the 3-6 log 10 reduction in plasma HIV-1 RNA [18].…”

Brief Report: Prevalence of Posttreatment Controller Phenotype Is Rare in HIV-Infected Persons After Stopping Antiretroviral Therapy

“…The circumstances leading to a similar phenomenon among those started on ART during CHI are unclear. Immunologic studies of previously identified PTCs who started ART during CHI have reported low levels of HIV unspliced RNA in peripheral blood mononuclear cells compared to other ART-treated patients 20 . Further study of PTCs who started ART during CHI is needed to better delineate their underlying genetic, immunologic, and virologic characteristics.…”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…The frequency of PTCs is estimated at between 5% and 15% of patients beginning cART shortly after primary HIV infection [17][18][19][20], which is significantly higher than the proportion of HICs [21,22]. Such a significant proportion of PTCs has been observed only after early initiation of treatment and not when therapies were begun during the chronic phase, in which reported cases are even scarcer [23]. The rarity of PTCs worldwide may be explained by the fact that only a very small proportion (approx.…”