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Attenuated viruses and protective immuneresponse in European long-term surviving hiv infected children

Objective

- To examine the frequency of possibly attenuated HIV variants in long term surviving (LTS) HIV infected children and to characterize these viruses on a biological and molecular level.
- To analyze the HIV specific humoral and cellular immunity in LTS HIV infected children in order to characterize presumably HIV protective immunity.

At least two different clinical courses can be observed in vertical HIV-1 infected infants. One group progress to AIDS within the first two years of life whereas a second one experience a slower disease progression. Within this latter group, epidemiological surveys have identified children defined as Long Term Survivors (LTS) experiencing very slow or no disease progression. In the frame of the European Concerted Action on "Determinants of disease progression in HIV-1 infected infants" a large cohort of HIV-1 infected children who can be defined as LTS have been identified. The analysis of genetical, immunological, as well as virological characteristics of this group of infected children may shed light on the mechanisms of protection from disease progression and ultimately be used to tailor immunological therapies. The following virologic and immunologic factors contributing to clinical and biological steady state possibly present in LTS children will be evaluated: 1) quantitative viral RNA and DNA content in specimens 2) differential content of viral mRNA species 3) isolate susceptibility to inhibitory by chemokines 4) levels of neutralizing antibodies to autologous virus isolates 5) levels of CD8+ T cell/chemokine mediated virus replication inhibition. These analyses will classify the children in the LTS cohort in groups according to the level of time-associated changes in viral parameters. Individuals with the lowest and the highest changes in viral expression pattern will be considered the two extreme categories for further detailed analysis of virus characteristics. Correlation between the different parameters will also be evaluated with respect to clinical and immunological progression. The detailed virologic analysis will include evaluation of: 1) frequency of infectious viruses by limiting dilution analysis 2) kinetics of replication of HIV biological clones by analysis of antigen release and quantitation of proviral DNA load. Children having highest levels of neutralizing antibodies and CD8-mediated inhibitory activity are anticipated to harbour the most attenuate virus variants. In the select cases of this kind the following analysis are planned to be perform: 1) genotypic analysis of individual HIV-1 regulatory and structural genes and 2) functional studies of recombinant viruses expressing isolated gene fragments.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

KAROLINSKA INSTITUTE
Address
13,Doktorsringen
171 77 Stockholm
Sweden

Participants (8)

EuroEspes
Spain
Address
Santa Marta De Babio
15080 La Coruna
Fondazione Centro San Raffaele del Monte Tabor
Italy
Address
Stamira D'ancona, 20
20132 Milano
Hospital Universitario de la Fe 'Sevasa'
Spain
Address
21,Avenida Campanar
46009 Valencia
INSTITUT CATALA DE LA SALUT
Spain
Address
119-129,Paseo Valle De Hebron 119-129
08035 Barcelona
Paediatric Hospital Bambino Ges
Italy
Address
Via Di Tor Vergata
00133 Roma
Swedish Institute for Infectious Disease Control
Sweden
Address
2,Lundagatan
171 63 Solna
THE UNIVERSITY OF MILANO
Italy
Address
9,Via Delle Commenda 9
20122 Milano
UNIVERSITY OF FLORENCE
Italy
Address
Via Luca Giordano 13
50132 Firenze