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Host Genetic Determinants of Human Immunodeficiency Virus Infection

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Host Genetic Determinants of Human Immunodeficiency Virus Infection 0031-3998/09/6505-0055R Vol. 65, No. 5, Pt 2, 2009 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2009 International Pediatric Research Foundation, Inc. Host Genetic Determinants of Human Immunodeficiency Virus Infection and Disease Progression in Children KUMUD K. SINGH AND STEPHEN A. SPECTOR Department of Pediatrics, University of California, San Diego, La Jolla, California 92093 ABSTRACT: Increasing data support host genetic factors as an viruses that use CCR5 as a coreceptor, CXCR4 using virus is important determinants of human immunodeficiency virus type-1 often identified in persons with more advanced disease and is (HIV-1) susceptibility, mother-to-child transmission (MTCT), and associated with more rapid disease progression. To enter disease progression. Of these genetic mediators, those impacting target cells, HIV interacts with the CD4 receptor via its gp120 innate and adaptive immune responses seem to play a critical role in protein, thereby stimulating a conformational change in viral infectivity and pathogenesis. During primary infection, CCR5 gp120, which exposes a portion of transmembrane glycopro- using virus is predominantly transmitted and polymorphisms that tein gp41, and allows access of the gp120 V-loop to either affect the expression of CCR5 alter the risk for MTCT and rate of disease. Chemokines that naturally bind to coreceptors alter infectiv- CCR5 or CXCR4. Subsequently, a peptide in gp41 causes the ity and viral pathogenesis. Additional genes that affect innate immu- fusion of the viral envelope and host cell membrane, and nity including those encoding for MBL2 and those modulating the allows the viral capsid to enter the target cell.1 adaptive immune response including CX3CR1 and human leukocyte Host factors are important determinants of susceptibility antigen types can significantly modify susceptibility and response to and pathogenesis of infectious diseases in children and adults. HIV-1 infection. As young children develop, the dependence on Identifying genetic variants that influence the response to certain arms of the immune system varies and can alter the effect of HIV-1 can provide insights into approaches to predict disease genetic variants. Additionally, host genetic factors may alter the re- progression, can lead to development of new treatments, and sponse to antiretrovirals. Finally, because HIV-infected children can provide new immunologic targets for vaccine develop- progress more rapidly than adults and have fewer background cofactors, ment. In this review, we summarize the available data on the such as drug use and coinfections, the effects of host factors on HIV-1 impact of host genetics on MTCT and treatment of HIV- disease may be more clearly identified. In this review, we summarize available data on the impact of host genetics on MTCT and disease infected children. Where appropriate the differences between progression of HIV-infected children. (Pediatr Res 65: 55R–63R, findings in children compared with adults are discussed. Ad- 2009) ditionally, we describe the role a particular variant may play in the control of HIV-1 through innate vs. adaptive immunity. emarkable progress has been made in the interruption of Genetic Variants of Coreceptors and Their Ligands R human immunodeficiency virus type-1 (HIV-1) mother-to- Alter HIV-Related Disease Progression child transmission (MTCT) and treatment for HIV-infected chil- dren. However, despite these advances many challenges remain Host and microbial genetics are important determinants of to eliminate MTCT through the safest ways possible and in infection and disease outcome. Viruses subvert the immune optimizing antiretroviral therapy for pregnant women and chil- system by mimicking cellular genes to gain entry into cells dren in developed and developing countries. Infants and children and to avoid immunologic detection. With the identification can be particularly susceptible to the long-term effects of antiret- that HIV-1 uses chemokine receptors for cell binding and roviral exposure. Therefore, approaches that lead to optimal drug entry, variants in genes encoding these receptors and their exposure with the least potential for toxicity for the individual natural ligands have been shown to modify the risk for patient are critical if HIV-infected and -exposed children are to infection and disease progression. Several single nucleotide lead healthy and productive lives. Moreover, the recent HIV-1 polymorphisms (SNPs) within the CC chemokine receptor 5 vaccine failures dramatically demonstrate the need to further (CCR5) coding and regulatory region seem to affect HIV-1 understand the interactions between host and virus. disease. For HIV-1 infection of adults and children, CCR5 is HIV usually uses CD4 and a coreceptor to infect cells. The a critical coreceptor modulating perinatal transmission (1–3) most common HIV coreceptors are the chemokine receptors CCR5 and CXCR4. Although most primary infections involve Abbreviations: APOBEC3G, apolipoprotein B mRNA editing catalytic polypeptide 3G; CCR2, chemokine (C-C motif) receptor 2; CCR5, chemo- Received November 11, 2008; accepted December 17, 2008. kine (C-C motif) receptor 5; CCL3L1, chemokine (C-C motif) ligand 3-like Correspondence: Stephen A. Spector, M.D., Department of Pediatrics, University of 1; CXCR4, chemokine (C-X-C motif) receptor 4; CX3CR1, chemokine California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0672; e-mail: saspector@ (C-X3-C motif) receptor 1; HIV-1, human immunodeficiency virus type-1; ucsd.edu; [email protected] IL4, interleukin-4; MBL, mannose-binding lectin; MCP-1, monocyte che- This work was supported by Grants from the National Institute of Allergy and Infectious Diseases, The International Maternal Pediatric Adolescent AIDS Clinical motactic protein-1; MTCT, mother-to-child transmission; SDF-1, stromal Trials (IMPAACT) Network (AI-069536). cell-derived factor-1 55R 56R SINGH AND SPECTOR with a deletion of 32-bp from the coding region of the CCR5 almost 50% increase in disease progression when compared gene (⌬32) providing almost complete protection against with those with the G/A or G/G genotype. Therefore, on a HIV-1 infection in individuals with the homozygous mutant population basis, the CCR5-59029-G/A genetic variants have genotype (CCR5-⌬32/⌬32) (4–7). Individuals heterozygous a greater overall impact on HIV-related disease in children for CCR5-wt/⌬32 are less likely to be infected with HIV-1 and than the CCR5-wt/⌬32 variant. Another variant in the CCR5 show a slower rate of disease progression (2,3,5,6,8,9). Sev- promoter region at position 59353-C/T was found to have an eral SNPs in the regulatory region of the CCR5 gene, includ- almost 40% greater risk for children with the C/C genotype ingaGtoApolymorphism at position 59029,aTtoC having a cognitive-index score of Ͻ70 compared with those polymorphism at position 59353 andaCtoTpolymorphism with the T allele. at position 59356 have been reported to alter the rate of The impact of CCR2 on HIV-related disease remains con- disease progression to AIDS (8,10). troversial. Although CCR2 is recognized as a minor corecep- A polymorphism in the coding region of the CC chemokine tor for HIV-1 in vitro, whether it serves as a coreceptor in receptor 2 (CCR2), a minor HIV-1 coreceptor, at position 180 humans remains to be clarified. However, several studies in (G to A polymorphism) leads to expression of an isoleucine adults have identified that a CCR2 variant, CCR2-64I, alters replacing a valine at amino acid position 64 (designated as disease progression (9,11,13). In contrast, we have found no CCR2-64I) and has been associated with slower disease pro- association between disease progression and death with any of gression of HIV-1–infected adults (9,11). Similarly, in the the CCR2 genotypes. The reason(s) for the different effects 3Ј-untranslated region of the gene encoding the CXC chemo- observed in children vs. adults with the CCR2 variants are kine SDF-1␣, the only natural ligand of the HIV-1 coreceptor unclear. However, it is likely that the alteration in disease CXCR4,aGtoApolymorphism at position 801 has been progression found in adults results from modulation of the reported to delay the rate of disease progression to AIDS in its immune response to HIV-1 as related to the binding of CCR2 with homozygous (A/A) form in an initial report (12), but not by its ligand MCP1 (CCL2). It is possible that the broad immaturity of others (13–15). The SDF1-3Ј-A polymorphism has also been the immune system of young children compared with adults masks reported to be associated with increased perinatal transmission any effect this interaction may have on viral control. of HIV-1 (16). Some of the studies demonstrating these effects The natural ligand for CXCR4, SDF-1, has also been are discussed below and are summarized in Table 1 and associated with HIV-1 disease in some studies of adults and Figures. 1 and 2. children. In our own research, children with the CCR5- In a cohort of over 1000 HIV-infected children, who par- wt/wt genotype and the SDF1-3Ј-A/A variant were more ticipated in Pediatric AIDS Clinical Trials Group 152 or 300 likely to experience disease progression than those with protocols and received mono- or dual-nucleoside reverse tran- either the G/A or G/G genotypes. These findings are con- scriptase inhibitor treatment before the availability of effective sistent with other studies in children that reported slower antiretroviral therapy, we studied the effects of CCR2-V64I, disease progression associated with the SDF1-3Ј-A/A ge- CCR5-wt/⌬32, CCR5-59029-G/A, CCR5-59353-T/C, CCR5- notype (22,23). However, only a small number of individ- 59356-C/T and SDF1-3Ј-G/A polymorphisms on the rate of uals within a given population have the SDF1-3Ј-A/A disease progression and neurologic impairment (17). These genotype (Ͻ2% in our studies).
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