There is great variation in the age when signs of HIV-associated illness first appear in children infected perinatally. In long-term survivors a combination of specific, innate virologic properties and host immune responses keep the infection """"""""in check"""""""", as compared to virologic parameters in other infected infants who develop rapidly progressive disease. We will detail the relationships that exist between the biologic characteristics (viral phenotype) displayed by primary pediatric isolates of HIV-1 in vitro and clinical manifestations of disease. We will determine whether sequential isolates become more pathogenic as the infection progresses and whether pediatric long-term survivors have viral isolates which display phenotypes associated with decreased pathogenicity. We will attempt to cultivate all isolates in monocyte-derived macrophages to learn how this growth property evolves and if it correlates with changes in the pace of clinical illness or with CNS disease. We will determine whether there are consistent associations between specific sequences in the V1, V2 and V3 loops of env and viral phenotype. We will also study the degree to which the genotype of virus isolates passaged in culture conforms with the genotype of feral virus strains that are isolated de novo from blood mononuclear cells and plasma. In order to study in greater detail the relationships between genotype and phenotype, infectious proviral DNA clones of a small number of mother and child isolates will be obtained and their biologic behavior examined. Portions of the env region of these clones will be sequenced. We will look for genetic features that are associated with particular phenotypes. In these studies we will make extensive use of an archive of samples (virus stocks, culture supernatant fluids, frozen PBMC, plasma, etc) that have been collected from 70 HIV-1 infected children in Connecticut, including 27 long-term survivors, and of new specimens that we will collect prospectively. Most of our patients are also enrolled in a prospective, longitudinal cohort study; hence, demographic and clinical data are available to define associations between phenotype, genotype and clinical expression of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039015-04
Application #
2887100
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Hoff, Rodney
Project Start
1996-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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