Influence of host genotype on progression to acquired immunodeficiency syndrome among children infected with human immunodeficiency virus type 1

doi:10.1016/S0022-3476(95)70110-9

The Journal of Pediatrics

Volume 127, Issue 4, October 1995, Pages 544-549

https://doi.org/10.1016/S0022-3476(95)70110-9 Get rights and content

Abstract

Objective: To study the role of host genotype in pediatric infection with human immunodeficiency virus type 1 (HIV-1) and progression to acquired immunodeficiency syndrome (AIDS). Methods: Human leukocyte antigen (HLA) class II and complement C4 genotypes were determined by means of molecular genetic techniques for 243 black children born to HIV-1-infected mothers in New York City and San Francisco. Survival, cumulative incidences of opportunistic infections and encephalopathy, and rates of CD4⁺ T cell decline were compared in children of different genotypes. Results: Among HIV-1-infected children, the HLA-DR3 haplotype (DRB1*0301-DQA1*0501-DQB1*0201) was associated with increased incidence of encephalopathy, faster rate of CD4⁺ cell decline, and death before 2 years of age. Deletion of the C4A gene was independently associated with increased incidences of encephalopathy and early death. DPB1*0101 was associated with survival to at least 2 years of age. The presence of DQB1*0604 was associated with increased risk of HIV infection. Conclusions: These results are consistent with previously reported associations between HLA genotypes and faster progression to AIDS among HIV-infected adults. The DR3 haplotype and C4A deletion may reflect the same underlying mechanism of susceptibility in that the DR3 haplotype is in linkage disequilibrium with other C4A null alleles. In addition, the class II locus DPB1 may have an independent effect on survival. (J PEDIATR 1995;127:544-9)

Section snippets

Study population

Participants were drawn from cohorts at Harlem Hospital Center in New York City and at San Francisco General Hospital and affiliated member hospitals of the Bay Area Pediatric AIDS Cohort. Signed, informed consent was obtained from a parent or guardian of the HIV-1-exposed children to participate in this study. A total of 243 black children born to HIV-infected mothers were enrolled between December 1989 and 1992 and followed through March 1994. The 149 children born in 1989 or earlier were

Risk of perinatal HIV-1 infection

Among the 94 children born in 1990 or later, the genotypes of 42 HIV-infected children were compared with those of 52 children with seroreversion. Genotype at the class II HLA-DQB1 locus was significantly associated with HIV-1 serostatus: 5 (12%) of the 42 infected children carried DQB1*0604, but none of the 52 children with seroreversion carried this allele (p <0.02).

Clinical outcomes and treatment protocols for HIV-1-infected children

Clinical and genetic data were available for 96 HIV-infected children from both prospective (n = 37) and prevalent (n = 59)

DISCUSSION

Survival of children perinatally infected with HIV-1 is associated with their genotype at class II and class III MHC loci; HIV-infected children who carry the HLA class II DR3 haplotype (DRB1*0301-DQB1*0201-DQA1*0501) or a deletion of the complement C4A gene are more likely to die before 2 years of age than are HIV-infected children who do not carry these genotypes. Associations of the DR3 haplotype and C4A deletion with increased risk of having encephalopathy and a rapid loss of CD4⁺ cells

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Even with the unfortunate increase in cohorts of chronically infected individuals with stable phenotypes (e.g., human immunodeficiency virus (HIV) viral load), linkage studies with sufficient power to identify host genes associated with variation in susceptibility to viral infections, though possible, were still rare. Though these studies often found variants associated with the HLA complex to be critical for variation in viral susceptibility (Carbonara et al., 1983; Cramp et al., 1998; Just et al., 1995; Kaslow et al., 1990; Kruskall, Alper, Awdeh, Yunis, & Marcus-Bagley, 1992; Shaw & Biddison, 1979; Uno, Kawano, Matsuoka, & Tsuda, 1988), the identification of variants at other loci was limited (Hohler et al., 1998, reviewed overall in Hill, 1998). Furthermore, for acute viral infections, which lack the stable phenotypes associated with chronic infections, such as viral load, these types of approaches have very poor success for identifying variant host genes associated with susceptibility to viral infections.
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Once the diagnosis of HIV-1 infection has been established, transition of care to a multidisciplinary pediatric HIV clinic is recommended. Multiple risk factors have been associated with more rapid disease progression in HIV-infected infants and children, including intrauterine transmission, specific HLA genotypes (HLA-DR3, C4A, and DQB1*0604), presence and maintenance of HIV-1–specific CD4 responses, higher HIV-1 RNA concentrations in infants, thymic dysfunction, lack of perinatal zidovudine (AZT) prophylaxis, enhanced viral fitness, and poorer maternal health.15–21 HIV-1–infected infants constitute possibly the only age group in which there is a generalized consensus among HIV experts that early initiation of antiretroviral therapy (ART) (before 12 weeks of age) rather than deferring it decreases the disease progression and mortality.
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We made an attempt to find out whether Human Leucocyte Antigen (HLA)-DQB1 and -DPB1 alleles are associated with susceptibility or resistance to Human Immunodeficiency Virus (HIV) infection and development of pulmonary tuberculosis (PTB) in HIV infected patients. The allelic profile of HLA-DQB1 and -DPB1 was studied among HIV patients without pulmonary tuberculosis (HIV+PTB−) (n = 115), HIV patients with pulmonary TB (HIV+PTB+) (n = 59), HIV negative PTB patients (HIV−PTB+) (n = 110) and healthy controls (n = 112) by polymerase chain reaction and sequence specific oligonucleotide probe method. Increased frequency of HLA-DQB1*050301 was observed in HIV+PTB− [p = 0.024, Odds Ratio (OR) 2.30, 95% Confidence Interval (CI) 1.11–4.90] and HIV+PTB+ patients (p = 0.044, OR 2.41, 95% CI 1.01–5.73) compared to healthy controls, suggesting that DQB1*050301 may be associated with susceptibility to HIV infection as well as development of PTB in HIV patients. Underrepresentation of HLA-DPB1*1501 was observed in HIV−PTB+ (p = 0.002, P_c = 0.034) and HIV+PTB+ (p = 0.036) patients compared to healthy controls, suggesting that DPB1*1501 may be associated with protection against PTB development both in HIV positive and negative subjects. Analysis on the amino acid variation in the peptide binding pocket at β69 position of HLA-DPB1 molecules revealed that the β69 arginine containing HLA-DPB1 alleles and the genotype lysine/arginine were underrepresented in HIV−PTB+ (allele: p = 0.003, P_c = 0.009; genotype: p = 0.0002, P_c = 0.001) and HIV+PTB+ (allele: p = 0.016, P_c = 0.048; genotype: p = 0.026). This suggests that HLA-DPB1 alleles with arginine may be associated with protection against development of PTB in both HIV infected as well as uninfected individuals. Further, the haplotypes HLA-DRB1*1502-DPB1*0201 and HLA-DQB1*0601-DPB1*0201 (P_c < 0.001) and HLA-DRB1*1502-DQB1*0601-DPB1*0201 (p = 0.006, OR 5.09, 95% CI 1.42–22.66) were significantly overrepresented in HIV+PTB+ patients compared to healthy controls suggesting that genetic susceptibility to PTB development in HIV patients may be modulated by interplay between HLA class II alleles, besides HLA class I alleles.
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^☆: From the School of Public Health and Department of Molecular and Cell Biology, University of California, Berkeley; the Department of Pediatrics, Harlem Hospital, New York, New York; the Department of Pediatrics, University of California, San Francisco; the G. H. Sergievsky Center, Columbia University, New York, New York; and New York Psychiatric Institute, New York

^☆☆: Supported by National Institutes of Health grant RO1 HD/A1 25792.

^★: Reprint requests: Mary Claire King, PhD, Division of Medical Genetics, University of Washington, Box 357720, Seattle, WA 98195-7720.

^★★: 0022-3476/95/$5.00 + 0 9/20/66741

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Influence of host genotype on progression to acquired immunodeficiency syndrome among children infected with human immunodeficiency virus type 1☆,☆☆,★,★★

Abstract

Section snippets

Study population

Risk of perinatal HIV-1 infection

Clinical outcomes and treatment protocols for HIV-1-infected children

DISCUSSION

Lancet

Mol Immunol

Lancet

Hum Immunol

Lancet

Hum Immunol

Lancet

Am J Med Sci

Gastroenterology

J PEDIATR

Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery

N Engl J Med

Trends in survival for children reported with maternally transmitted acquired immunodeficiency syndrome in New York City, 1982 to 1989

Pediatr Infect Dis J

Rapid increases in load of human immunodeficiency virus correlate with early disease progression and loss of CD4 cells in vertically infected infants

J Infect Dis

Markedly reduced mortality associated with corticosteroid therapy of Pneumocystis carinii pneumonia in children with acquired immunodeficiency syndrome

Arch Pediatr Adolesc Med

Classification system for human immunodeficiency virus (HIV) infection in children under 13 years of age

MMWR Morb Mortal Wkly Rep

Oncogenes and human breast cancer

Am J Hum Genet

Molecular cloning: a laboratory manual

Isotypic and allotypic variation of human class II histocompatibility antigen alpha-chain genes

Nature

Polymorphism of the human complement C4 and steroid 21-hydroxylase genes

J Clin Invest

Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus

Proc Natl Acad Sci USA