Human Immunodeficiency Virus-Specific CD8+ T-Cell Activity Is Detectable from Birth in the Majority of In Utero-Infected Infants

ABSTRACT Human immunodeficiency virus (HIV)-infected infants in sub-Saharan Africa typically progress to AIDS or death by 2 years of life in the absence of antiretroviral therapy. This rapid progression to HIV disease has been related to immaturity of the adaptive immune response in infants. We screened 740 infants born to HIV-infected mothers and tracked development and specificity of HIV-specific CD8+ T-cell responses in 63 HIV-infected infants identified using gamma interferon enzyme-linked immunospot assays and intracellular cytokine staining. Forty-four in utero-infected and 19 intrapartum-infected infants were compared to 45 chronically infected children >2 years of age. Seventy percent (14 of 20) in utero-infected infants tested within the first week of life demonstrated HIV-specific CD8+ T-cell responses. Gag, Pol, and Nef were the principally targeted regions in chronic pediatric infection. However, Env dominated the overall response in one-third (12/36) of the acutely infected infants, compared to only 2/45 (4%) of chronically infected children (P = 0.00083). Gag-specific CD4+ T-cell responses were minimal to undetectable in the first 6 months of pediatric infection. These data indicate that failure to control HIV replication in in utero-infected infants is not due to an inability to induce responses but instead suggest secondary failure of adaptive immunity in containing this infection. Moreover, the detection of virus-specific CD8+ T-cell responses in the first days of life in most in utero-infected infants is encouraging for HIV vaccine interventions in infants.

[1]  B. Walker,et al.  High frequency of rapid immunological progression in African infants infected in the era of perinatal HIV prophylaxis , 2007, AIDS.

[2]  G. Pantaleo,et al.  Functional patterns of HIV-1-specific CD4 T-cell responses in children are influenced by the extent of virus suppression and exposure , 2007, AIDS.

[3]  David Heckerman,et al.  CD8+ T-cell responses to different HIV proteins have discordant associations with viral load , 2007, Nature Medicine.

[4]  Mario Roederer,et al.  HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. , 2006, Blood.

[5]  M. Altfeld,et al.  Differential immunogenicity of HIV-1 clade C proteins in eliciting CD8+ and CD4+ cell responses. , 2005, The Journal of infectious diseases.

[6]  E. Holmes,et al.  Unique Acquisition of Cytotoxic T-Lymphocyte Escape Mutants in Infant Human Immunodeficiency Virus Type 1 Infection , 2005, Journal of Virology.

[7]  E. Rosenberg,et al.  Early proliferation of CCR5(+) CD38(+++) antigen-specific CD4(+) Th1 effector cells during primary HIV-1 infection. , 2005, Blood.

[8]  S. Rowland-Jones,et al.  Longitudinal Assessment of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon Responses during the First Year of Life in HIV-1-Infected Infants , 2005, Journal of Virology.

[9]  Philip J. R. Goulder,et al.  HIV-1 Viral Escape in Infancy Followed by Emergence of a Variant-Specific CTL Response1 , 2005, The Journal of Immunology.

[10]  Andrew K. Sewell,et al.  Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA , 2005, The Journal of experimental medicine.

[11]  Bette Korber,et al.  Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA , 2004, Nature.

[12]  Galit Alter,et al.  Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells , 2004, The Journal of experimental medicine.

[13]  B. Walker,et al.  Immune Escape Precedes Breakthrough Human Immunodeficiency Virus Type 1 Viremia and Broadening of the Cytotoxic T-Lymphocyte Response in an HLA-B27-Positive Long-Term-Nonprogressing Child , 2004, Journal of Virology.

[14]  Philip J. R. Goulder,et al.  HIV and SIV CTL escape: implications for vaccine design , 2004, Nature Reviews Immunology.

[15]  Bette Korber,et al.  HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection despite a relatively high degree of genetic diversity , 2004, AIDS.

[16]  Alessandro Sette,et al.  Selection, Transmission, and Reversion of an Antigen-Processing Cytotoxic T-Lymphocyte Escape Mutation in Human Immunodeficiency Virus Type 1 Infection , 2004, Journal of Virology.

[17]  D. Cornforth,et al.  Association of strong virus-specific CD4 T cell responses with efficient natural control of primary HIV-1 infection , 2004, AIDS.

[18]  B. Walker,et al.  Reconstitution of Virus-Specific CD4 Proliferative Responses in Pediatric HIV-1 Infection 1 , 2003, The Journal of Immunology.

[19]  B. Walker,et al.  Progress in Defining CD4 Helper Cell Responses in Chronic Viral Infections , 2003, The Journal of experimental medicine.

[20]  Dorothy Bray,et al.  Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial , 2003, The Lancet.

[21]  Barbra A. Richardson,et al.  Comparison of Human Immunodeficiency Virus Type 1 Viral Loads in Kenyan Women, Men, and Infants during Primary and Early Infection , 2003, Journal of Virology.

[22]  S. Rowland-Jones,et al.  Mature CD8(+) T lymphocyte response to viral infection during fetal life. , 2003, The Journal of clinical investigation.

[23]  S. Furlan,et al.  HIV-Specific CD8+ T Cell Function in Children with Vertically Acquired HIV-1 Infection Is Critically Influenced by Age and the State of the CD4+ T Cell Compartment1 , 2003, The Journal of Immunology.

[24]  D. Strick,et al.  Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load , 2003, Journal of Virology.

[25]  B. Walker,et al.  Immunologic control of HIV-1. , 2002, Annual review of medicine.

[26]  R. Yogev,et al.  Infrequent Detection of HIV-1-Specific, But Not Cytomegalovirus-Specific, CD8+ T Cell Responses in Young HIV-1-Infected Infants1 , 2001, The Journal of Immunology.

[27]  E. Rosenberg,et al.  Immune control of HIV-1 after early treatment of acute infection , 2000, Nature.

[28]  G. Trinchieri,et al.  Association between HIV‐specific T helper responses and CTL activities in pediatric AIDS , 2000, European journal of immunology.

[29]  P Pezzotti,et al.  Longitudinal human immunodeficiency virus type 1 load in the italian seroconversion study: correlates and temporal trends of virus load. , 1999, The Journal of infectious diseases.

[30]  Dorothy Bray,et al.  Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial , 1999, The Lancet.

[31]  C. Rouzioux,et al.  Early HIV-specific cytotoxic T lymphocytes and disease progression in children born to HIV-infected mothers. , 1998, AIDS research and human retroviruses.

[32]  F. Buseyne,et al.  Cytotoxic T lymphocytes generation capacity in early life with particular reference to HIV. , 1998, Vaccine.

[33]  Rodney Phillips,et al.  Co‐evolution of human immunodeficiency virus and cytotoxic T‐lymphocyte responses , 1997, Immunological reviews.

[34]  P. Jagodziński,et al.  Diminished HIV-specific CTL activity is associated with lower type 1 and enhanced type 2 responses to HIV-specific peptides during perinatal HIV infection. , 1997, Journal of immunology.

[35]  L. Kalish,et al.  Viral load and disease progression in infants infected with human immunodeficiency virus type 1. Women and Infants Transmission Study Group. , 1997, The New England journal of medicine.

[36]  D. Weissman,et al.  Immunopathogenic Mechanisms of HIV Infection , 1996, Annals of Internal Medicine.

[37]  J. Sullivan,et al.  HIV-1-specific cytotoxic T lymphocyte responses in the first year of life. , 1995, Journal of immunology.

[38]  G. Shaw,et al.  Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection , 1994, Journal of virology.

[39]  R. Koup,et al.  Deficient human immunodeficiency virus type 1-specific cytotoxic T cell responses in vertically infected children. , 1991, The Journal of pediatrics.