Immune responses and fewer uninfected cells to target deplete viral numbers in blood plasma sharply within a few weeks."
Answers
Answer:
Hey mate...
Explanation:
Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial. At age 9.5 years, diagnostic tests for HIV are negative and the child has characteristics similar to uninfected children that include a high CD4:CD8 ratio, low T cell activation and low CCR5 expression. Virus persistence (HIV-1 DNA and plasma RNA) is confirmed with sensitive methods, but replication-competent virus is not detected. The child has weak HIV-specific antibody and T cell responses. Furthermore, we determine his HLA and KIR genotypes. This case aids in understanding post-treatment control and may help design of future intervention strategies.
Introduction
Rapid formation of persistent viral reservoirs follows acute HIV-1 infection. This early establishment of latently HIV-1-infected CD4+ T cells harbouring replication-competent virus remains the major obstacle to HIV cure or remission1,2,3. As antiretroviral therapy (ART), even when given within days of infection, usually fails to clear these reservoirs4,5,6, it is unlikely that ART alone can lead to HIV remission. It is, however, hypothesized that ART given very soon after infection may enable a more effective immune response and, together with other strategies, lead to sustained control of viral replication.
Current approaches to HIV cure or remission have focused on either reversing latency (e.g. “shock and kill”), enhancing immune responses or preventing immune activation (e.g. vaccines and other immunotherapies)7. Central to the question of HIV remission is the interaction between viral reservoir, immune activation, host genetics and immune response.
Several adult cases of post-treatment control have been described8,9,10,11,12,13,14,15,16. These individuals are unlike elite controllers (<1%) who control HIV-1 to undetectable levels in the absence of ART17,18, probably through distinct immunological mechanisms8.
In children, data are extremely limited. In 2013, the report of the “Mississippi baby” suggested that very early ART, here within 30 h of birth, could lead to prolonged (27 months) virological control off-treatment19,20, raising hope for a feasible HIV-1 remission strategy. Unfortunately, this girl “relapsed” after almost 2 years without ART due to return of high levels of viral replication, and required ART. Subsequently, a French girl was reported who started ART at 3 months of age, stopped treatment between 5 and 7 years of age and controlled virus to undetectable levels for over 12 years21.
Reports of post-treatment controllers who initiated ART and then discontinued by design or unintentionally may help our understanding of key host determinants of HIV replication control, and inform interventions for HIV remission and cure.
Here we report a detailed virological and immunological analysis of a child at 9.5 years of age, originally enroled in the Children with HIV Early antiRetroviral therapy (CHER) trial22,23 who was randomized to the immediate, time-limited 40 weeks of ART study arm. The CHER trial was initiated at a time when the best strategy on when to initiate and how to maintain treatment in infants was unclear. This child, one of 227 early treated children (0.4%), is the only one maintaining long-term sustained virological control post-ART cessation. At 9.5 years, virus persists at low levels (plasma RNA 6.6 copies per mL), cell-associated DNA is 5 copies per million peripheral blood mononuclear cells and replication-competent virus is not detected. Immunologically, he is not unlike healthy children of similar age, evidenced by high CD4:CD8 ratio, low T cell activation and low CCR5 expression. He has weak HIV-specific antibody and CD4+ T cell responses indicating memory of prior/current virus encounter, and together with possession of some host genotypes, these provide clues for future studies to inform what constitutes long-term post-treatment control.
Results
Clinical case
The child, born in 2007, had a positive HIV-1 DNA PCR at age 32 days. At 39 days, HIV-1 RNA was >750,000 copies per mL (upper limit of quantitation of the assay) confirming infection; at 60 days, plasma HIV RNA had declined to 151,000 copies per mL. He commenced zidovudine, lamivudine and lopinavir-ritonavir one day later (Fig. 1, Supplementary Table 1). He was born at term, of normal birth weight (3700g), did not receive nevirapine prophylaxis, and was not breastfed. CD4+ T cell count and per cent at 61 days, prior to ART start, were 2249 cells per µL and 41.6%. These values fell within the respective baseline interquartile ranges (IQRs) for all early treated children who stopped ART in the CHER trial.