Slow progressor of human immunodeficiency virus: 20 years follow-up of a case from North India.

A case of human immunodeficiency virus (HIV) infection from North India is described with a 20-year follow-up. Patient first reported in 1993 when he was detected HIV positive, remained healthy without treatment, married in 1999 and did not transmit the disease to his children or his wife and was lost to follow-up. He was thought to be an elite controller. After 15 years of the initial visit, his CD4 cells, however, were found to be low, with a viral load of 10,000/copies/ml. He was negative for human leukocyte antigen B57 and B27 alleles with a normal expression of CCR5 and CXCR4 on CD4 cells. Lymphocytes showed a significant production of tumour necrosis factor alpha and interferon γ, but not of interleukin (IL)-2, IL4 or IL10. It is possible that gut infection, common in India, could have triggered T cell activation in the ensuing years, resulting in activation of HIV. The case illustrates the significance of long-term follow-up of these patients for timely institution of anti-retroviral therapy.

Gene expression of cytokines (TNF-α, IFN-γ), serum profiles of IL-17 and IL-23 in paediatric systemic lupus erythematosus.

OBJECTIVE: Paediatric systemic lupus erythematosus (pSLE) exhibits an aggressive clinical phenotype and severe complications commonly renal involvement. This could be reflective of the ongoing chronic pro-inflammatory cytokine milieu. We examined relative gene expression of tumour necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ) and serum levels of interleukin-17 (IL-17) and IL-23 and their association with SLEDAI (SLE disease activity index) score and organ manifestations in pSLE. METHODS: We enrolled 40 pSLE patients (age 5-16 years, on treatment) and 20 age-matched healthy controls. Relative gene expression levels of IFN-γ and TNF-α in the peripheral blood were determined by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). ß actin gene was used for normalization of gene expression. Serum levels of IL-17 and IL-23 were determined by solid phase sandwich ELISA. Statistical analysis were carried out for comparing (Mann-Whitney U test) and correlating data (Univariate, multivariate analysis and Pearson correlation test) with SLEDAI scores and clinical manifestations. RESULTS: Over-expression of TNF-α and IFN-γ was found in 90% (36/40) and 80% (32/40) of pSLE patients, respectively. The relative gene expression of TNF-α and IFN-γ were significantly correlated with renal manifestations (p < 0.05). Further, relative expression of IFN-γ gene correlated significantly with skin manifestations and SLEDAI (p < 0.05). Serum levels of IL-17 (766.95 ± 357.83 pg/ml) and IL-23 (135.4 ± 54.23 pg/ml) in pSLE were significantly higher than in controls (IL-17, 172.7 ± 39.19 pg/ml and IL-23, 21.15 ± 10.99 pg/ml) (p < 0.05). Patients with cutaneous (p = 0.002) and haematological involvement (p = 0.003) had high serum IL-17 levels. Serum IL-17 levels correlated with SLEDAI (r = 0.447; p < 0.05). CONCLUSIONS: In this preliminary study, we observed a persistent, strong pro-inflammatory cytokine milieu in pSLE patients which reflects ongoing inflammatory damage in different organs. The gene expression profile of these cytokines may be used for assessing organ involvement in pSLE. IL-17 may also serve as a prognostic marker in pSLE. However, longitudinal studies on treatment of naïve patients are required to corroborate these findings.

Rapid effects of corticosterone in the mouse dentate gyrus via a nongenomic pathway.

Corticosterone activates two types of intracellular receptors in the rodent brain: the high affinity mineralocorticoid receptor (MR) and lower affinity glucocorticoid receptor (GR). These receptors act as transcriptional regulators and mediate slow changes in neuronal activity in a region-dependent manner. For example, in CA1 pyramidal cells, corticosterone slowly changes Ca(2+) currents and glutamate transmission but dentate granule cells appear to be resistant. Recent studies have shown that corticosteroids also exert rapid MR-dependent, nongenomic effects on hippocampal CA1 cells [e.g. increasing the frequency of miniature excitatory postsynaptic currents (mEPSCs)]. In the present study, we investigated whether dentate granule cells are also resistant to the rapid effects of corticosterone. We found that, comparable to the CA1 area, corticosterone quickly and reversibly increases mEPSC frequency but not amplitude of dentate cells. This effect did not require protein synthesis and displayed the pharmacological profile of an MR- rather than GR-dependent event. These data support the hypothesis that, unlike the slow gene-mediated effects of corticosterone, rapid hormonal actions are quite similar for CA1 and dentate cells.

High rate of mutation K103N causing resistance to nevirapine in Indian children with acquired immunodeficiency syndrome.

In north India the number of paediatric cases with acquired immunodeficiency syndrome (AIDS) is on the rise. Most drug combinations used for treatment of AIDS incorporate nevirapine, resistance to which develops very fast if given singly or because of unplanned interruptions. This paper investigates presence of mutations at codon 103 and codon 215 of the HIV pol gene causing resistance to nevirapine and zidovudine (AZT) respectively in 25 children with AIDS. Mutations T215Y and K103N were detected by a nested cum amplification refractory mutation system polymerase chain reaction (ARMS PCR) and the results were confirmed by direct sequencing in five randomly selected cases. Nineteen patients had received nevirapine containing regimen and six were drug naive. Mutation K103N was observed in 56% (14/25) of the children while mutation T215Y was found in none. Two of the six drug naïve children also showed K103N mutation. Thus, Indian children drug naïve or treated with nevirapine containing regimens show a high rate of mutation conferring resistance to nevirapine which calls for a judicious use of nevirapine both in antenatal and postnatal setting.

Serotype analysis of Indian patients with HIV infection.

HIV infection has established itself in India. Besides Bombay, Madras and Manipur it has assumed epidemic proportions in Punjab, where 24% of seropositives acquired infection through blood products. Preliminary observations on genetic analysis in 13 isolates revealed that the principal neutralizing determinant (PND) of the V3 loop was closely related to the South African isolate. Since serotyping can give reliable information about genotypic prevalence in the population, serotyping in the present study used 5 synthetic peptides (NOF, EL1, MN, IIIB, IND) of African, North American, European and Indian origin. The Indian consensus was derived from genotype analysis of 13 cases. Results of serotype analysis indicated that 82% of patients harboured a strain related to the South African type of HIV-1. These observations have a sinister significance for designing vaccine strategies for this region.