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ELECTRONIC ARTICLE: Silvia Sánchez-Ramón, José Ma Bellón, Salvador Resino, Carmen Cantó-Nogués, Dolores Gurbindo, José-Tomás Ramos, and MaAngeles Muñoz-Fernández Low Blood CD8+ T-Lymphocytes and High Circulating Monocytes Are Predictors of HIV-1-Associated Progressive Encephalopathy in Children Pediatrics 2003; 111: e168-e175 [Abstract] [Full text] [PDF]

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Marker of HIV Disease Progression in infants

Javier Chinen   (12 February 2003)

CD3+ T-LYMPHOCYTES BY 6-MONTHS OF AGE AND HIV-1-ASSOCIATED PROGRESSIVE ENCEPHALOPATHY IN CHILDREN

Muñoz Fernandez MªAngeles, Silvia Sánchez-Ramón, Salvador Resino and Mª Angeles Muñoz-Fernández   (9 April 2003)

Marker of HIV Disease Progression in infants 12 February 2003
Javier Chinen, Staff Clinician NHGRI-NIH Send letter to journal: Re: Marker of HIV Disease Progression in infants jchinen{at}nhgri.nih.gov Javier Chinen	Dear Editor, I read with much interest the article: Low Blood CD8 T- Lymphocytes and High circulating Monocytes are Predictors of HIV-1-Associated Progressive Encephalopathy in Children, published in the February issue of the Journal. Markers of disease progression in HIV-infected infants and children are important to direct and reinforce the care of the subgroup of patients presenting accelerated disease. Most pediatricians would rely in the follow-up of viral loads and CD4 T- cell counts for the identification of these patients. We recently described that CD3 T-cell counts by 6 month of age is also a marker of HIV disease progression (1). This finding takes into account the decline of both CD4 and CD8 T-cells with the implication of a diminished capacity to control viral infection, as the authors of the present report also discuss. It would be of interest if Dr. Sanchez-Ramon and collaborators find that CD3 T-cell counts at or around 6 months of age are also predictive of progressive encephalopathy, which could validate the importance of this newly identified marker. (1) Chinen J, Easley KA, Mendez H, Shearer WT. Decline of CD3-positive T-cell counts by 6 months of age is associated with rapid disease progression in HIV-1--infected infants. J Allergy Clin Immunol. 2001 Aug;108(2):265-8.
CD3+ T-LYMPHOCYTES BY 6-MONTHS OF AGE AND HIV-1-ASSOCIATED PROGRESSIVE ENCEPHALOPATHY IN CHILDREN 9 April 2003
Muñoz Fernandez MªAngeles, head of laboratorio Inmuno-Biología Molecular Hospital General Universitario Gregorio Marañón, Silvia Sánchez-Ramón, Salvador Resino and Mª Angeles Muñoz-Fernández Send letter to journal: Re: CD3+ T-LYMPHOCYTES BY 6-MONTHS OF AGE AND HIV-1-ASSOCIATED PROGRESSIVE ENCEPHALOPATHY IN CHILDREN mmunoz{at}cbm.uam.es Muñoz Fernandez MªAngeles, et al.	Although we agree with Dr. Chinen and colleagues that the analysis of the decline of CD3+ T-lymphocytes account for the decline of both CD4+ and CD8+ T-lymphocytes (1), we think that it represents a less accurate estimation that quantifying any of both subsets. As we noted in our article, among all of the immunologic and virologic variables assessed within the 6 months of age in our observational study were the CD8+ T-lymphocytes’ counts, the only significant difference with respect to HIV-1-infected children that did not undergo HIV-associated progressive encephalopathy (2). Thus, CD4+ T-lymphocytes by 6-months of age did not define a subgroup of children presenting a higher risk of this neurological complication. As suggested by Dr Chinen, we evaluated whether decreased numbers of CD3+ T-lymphocytes is a predictive factor of HIV-associated progressive encephalopathy in our cohort of 19 out of 58 HIV-1-infected children who underwent HIV-associated progressive encephalopathy, for whom we have CD3+ T-lymphocytes counts by 6-months of age. All 19 infants were given combination antiretroviral therapy and followed by the same paediatrician. The same analysis was performed in a control group of 27 HIV-infected children without any neurological symptoms during follow-up, within the same time-lapse and therefore with similar therapeutical approach. Time to progress to PE was assessed by Kaplan-Meier estimates for median CD3+ T-lymphocytes of all 47 HIV-1-infected children (65% of CD3+ lymphocytes) (Figure 1A). Children with CD3+ T-lymphocytes below the median value progressed to progressive encephalopathy faster than those with CD3+ T-lymphocytes above the median (P = 0.06) (Figure 1A). By Cox regression analysis, children with low CD3+ T-lymphocytes (T-lymphocytes < 65%) were 2.54-fold more likely to progress to progressive encephalopathy than children with CD3+ T-lymphocytes above 65% (CI95%: 0.9; 7.18; P=0.07). The survival of children in group CD3+ T-lymphocytes >65% from birth was significantly longer as determined by Kaplan-Meier log rank analysis (Figure 1B) (P <0.03), with a median survival time of 9.9 years (95% CI: 7.8 to 12.11) versus a mean of 3.24 years (95% C: I0.11 to 6.37) for group CD3+ T-lymphocytes<65% (Figure 1B). The observed number of deaths during follow-up was 14 (56%) in group CD3+ T-lymphocytes <65% and 5 (24%) in group CD3+ T-lymphocytes >65%. Cox regression univariant analysis to estimate the RR of progression to death for CD3+ T-lymphocytes <65% by 6-months of age showed that these children had a relative risk (RR) for progressing to death of 2.85-fold higher than those of group CD3+ T-lymphocytes >65% (95% CI: 1.02 to 7.96) (P =0.04). Restricting the estimates to total CD3+ T-lymphocytes seem to be insufficient to explain the susceptibility to develop neurological HIV disease and may raise a few problems of interpretation. It mostly verifies the failure of the immune system of the child to overcome HIV infection. By contrast, the role of CD8+ T-lymphocytes in the control of HIV-1 infection is well established, and the suppression of HIV-1 replication is dependent on the presence of HIV-1-specific CD8+ T-lymphocytes. We hypothesised in our paper that the duration of the neurologically asymptomatic phase for any given child may depend mostly on the magnitude of specific CD8+ T-lymphocyte responses, and correlated the finding of a significant low CD8+ T-lymphocytes numbers with the significant peak of circulating monocytes observed before the onset of encephalopathy. Although, a decline of CD3+ T-lymphocytes by 6-months of age show a trend towards a higher susceptibility for developing progressive encephalopathy, we believe that CD8+ T-lymphocytes are a more reliable marker in terms of predicting HIV-associated progressive encephalopathy early in life, and that may be used as a putative biological marker of neuropathogenicity. References 1. Chinen J, Easly KA, Mendez H, Shearer WT. Dcline of CD3-positive T-cell counts by 6-months of age is associated with rapid disease progression in HIV-1-infected infants. J Allergy Clin Immunol 2001 Aug; 108(2): 265-8. 2. Sánchez-Ramón S, Bellón JM, Resino S, Cantó C, Ramos JT, Gurbindo D, and MA Muñoz-Fernández. Low CD8+ T-cells may trigger CNS spread of HIV-1-activated monocytes in HIV-1-associated progressive encephalopathy in children. Pediatrics 2003 Feb; 111: 168–75. Figure 1. Kaplan-Meier curves of progression to encephalopathy (A) and death (B), according to median CD3+ T-lymphocytes counts. A B