Two Distinct Mechanisms Leading to Loss of Virological Control in the Rare Group of Antiretroviral Therapy-Naive, Transiently Aviremic Children Living with HIV.

HIV-specific CD8+ T cells play a central role in immune control of adult HIV, but their contribution in pediatric infection is less well characterized. Previously, we identified a group of ART-naive children with persistently undetectable plasma viremia, termed "elite controllers," and a second group who achieved aviremia only transiently. To investigate the mechanisms of failure to maintain aviremia, we characterized in three transient aviremic individuals (TAs), each of whom expressed the disease-protective HLA-B*81:01, longitudinal HIV-specific T-cell activity, and viral sequences. In two TAs, a CD8+ T-cell response targeting the immunodominant epitope TPQDLNTML (Gag-TL9) was associated with viral control, followed by viral rebound and the emergence of escape variants with lower replicative capacity. Both TAs mounted variant-specific responses, but only at low functional avidity, resulting in immunological progression. In contrast, in TA-3, intermittent viremic episodes followed aviremia without virus escape or a diminished CD4+ T-cell count. High quality and magnitude of the CD8+ T-cell response were associated with aviremia. We therefore identify two distinct mechanisms of loss of viral control. In one scenario, CD8+ T-cell responses initially cornered low-replicative-capacity escape variants, but with insufficient avidity to prevent viremia and disease progression. In the other, loss of viral control was associated with neither virus escape nor progression but with a decrease in the quality of the CD8+ T-cell response, followed by recovery of viral control in association with improved antiviral response. These data suggest the potential for a consistently strong and polyfunctional antiviral response to achieve long-term viral control without escape. IMPORTANCE Very early initiation of antiretroviral therapy (ART) in pediatric HIV infection offers a unique opportunity to limit the size and diversity of the viral reservoir. However, only rarely is ART alone sufficient to achieve remission. Additional interventions that likely include contributions from host immunity are therefore required. The HIV-specific T-cell response plays a central role in immune control of adult HIV, often mediated through protective alleles such as HLA-B*57/58:01/81:01. However, due to the tolerogenic and type 2 biased immune response in early life, HLA-I-mediated immune suppression of viremia is seldom observed in children. We assessed a rare group of HLA-B*81:01-positive, ART-naive children who achieved aviremia, albeit only transiently, and investigated the role of the CD8+ T-cell response in the establishment and loss of viral control. We identified a mechanism by which the HIV-specific response can achieve viremic control without viral escape that can be explored in strategies to achieve remission.

Strong sex bias in elite control of paediatric HIV infection

BACKGROUND: Reports of posttreatment control following antiretroviral therapy (ART) have prompted the question of how common immune control of HIV infection is in the absence of ART. In contrast to adult infection, where elite controllers have been very well characterized and constitute approximately 0.5% of infections, very few data exist to address this question in paediatric infection. METHODS: We describe 11 ART-naive elite controllers from 10 cohorts of HIV-infected children being followed in South Africa, Brazil, Thailand, and Europe. RESULT: All but one of the elite controllers (91%) are females. The median age at which control of viraemia was achieved was 6.5 years. Five of these 11 (46%) children lost control of viraemia at a median age of 12.9 years. Children who maintained control of viraemia had significantly higher absolute CD4þ cell counts in the period of elite control than those who lost viraemic control. On the basis of data available from these cohorts, the prevalence of elite controllers in paediatric infection is estimated to be 5­10-fold lower than in adults. CONCLUSION: Although conclusions are limited by the study design, these data suggest that, whilst paediatric elite control can be achieved, compared with adult elite controllers, this occurs rarely, and takes some years after infection to achieve. Also, loss of immune control arises in a high proportion of children and often relatively rapidly. These findings are consistent with the more potent antiviral immune responses observed in adults and in females

Strong sex bias in elite control of paediatric HIV infection.

BACKGROUND: Reports of posttreatment control following antiretroviral therapy (ART) have prompted the question of how common immune control of HIV infection is in the absence of ART. In contrast to adult infection, where elite controllers have been very well characterized and constitute approximately 0.5% of infections, very few data exist to address this question in paediatric infection. METHODS: We describe 11 ART-naive elite controllers from 10 cohorts of HIV-infected children being followed in South Africa, Brazil, Thailand, and Europe. RESULTS: All but one of the elite controllers (91%) are females. The median age at which control of viraemia was achieved was 6.5 years. Five of these 11 (46%) children lost control of viraemia at a median age of 12.9 years. Children who maintained control of viraemia had significantly higher absolute CD4 cell counts in the period of elite control than those who lost viraemic control. On the basis of data available from these cohorts, the prevalence of elite controllers in paediatric infection is estimated to be 5-10-fold lower than in adults. CONCLUSION: Although conclusions are limited by the study design, these data suggest that, whilst paediatric elite control can be achieved, compared with adult elite controllers, this occurs rarely, and takes some years after infection to achieve. Also, loss of immune control arises in a high proportion of children and often relatively rapidly. These findings are consistent with the more potent antiviral immune responses observed in adults and in females.

Practical considerations for managing patients with diabetes and dementia.

INTRODUCTION: Diabetes and dementia appear to be linked epidemiologically and share a common pathogenetic mechanism. The development of dementia in older people with diabetes will have a significant impact on diabetes self-care and will increase the risk of hypoglycaemia and frailty which ultimately lead to disability and poor outcome. Areas covered: We performed a Medline and Embase search from 1997 to present on relevant dementia and diabetes studies published in English language. Expert commentary: Older people with comorbid diabetes and dementia are functionally heterogeneous and interventions should be proportionate to patients 'functional capacity. Metabolic targets can be tightened in fit persons and relaxed when cognitive abilities continue to decline and overall function deteriorates. A holistic multidisciplinary team approach that involves patients, their carers and integrated primary and secondary care services at one point of care that focuses on improving function and maintaining quality of life is needed.