Abstract
Very early after the identification of the human immunodeficiency virus (HIV), host genetics factors were anticipated to play a role in viral control and disease progression. As early as the mid-1990s, candidate gene studies demonstrated a central role for the chemokine co-receptor/ligand (e.g., CCR5) and human leukocyte antigen (HLA) systems. In the last decade, the advent of genome-wide arrays opened a new era for unbiased genetic exploration of the genome and brought big expectations for the identification of new unexpected genes and pathways involved in HIV/AIDS. More than 15 genome-wide association studies targeting various HIV-linked phenotypes have been published since 2007. Surprisingly, only the two HIV-chemokine co-receptors and HLA loci have exhibited consistent and reproducible statistically significant genetic associations. In this chapter, we will review the findings from the genome-wide studies focusing especially on non-progressive and HIV control phenotypes, and discuss the current perspectives.
Highlights
After the discovery of human immunodeficiency virus (HIV)-1 as the etiologic agent for AIDS, it became apparent that this infection was exhibiting a considerable phenotypic heterogeneity at different levels:(i) Virus acquisition: some individuals, named highly exposed HIV-seronegatives, remain uninfected even after repeated exposure to the virus
Cohorts: ACS, Amsterdam cohort study; ALIVE, AIDS link to intravenous experience; CHAVI, center for HIV/AIDS vaccine immunology; COS, Couples Observational Study; DCG, DC gay; DoD HIV NHS, Department of Defense HIV Natural History Study; GISHEAL, genetic and immunological study on HIV+ European and African longterm non-progressors (LTNP); GRIV, genomics of resistance to immunodeficiency virus; HGDS, Hemophilia Growth and Development Study; LSOCA, longitudinal studies of the ocular complications of AIDS; MACS, multicenter AIDS cohort study; MHCS, multicenter Hemophilia cohort study; PPHHTS, Partners in Prevention HSV/HIV Transmission Study; PRIMO, primo infection; SFCC, San Francisco city clinic
The motivation for identifying genes associated with HIV/AIDS has gained momentum as effective vaccines and curative treatments have failed to materialize
Summary
After the discovery of human immunodeficiency virus (HIV)-1 as the etiologic agent for AIDS, it became apparent that this infection was exhibiting a considerable phenotypic heterogeneity at different levels:. As illustrated by this result, host factors controlling viral load are likely to be correlated with stable high CD4+ T-cell count Likewise, this explains the abundance of HLA SNPs (46 out of the 50 top signals) in the meta-analysis between the GRIV LTNP and the Euro-CHAVI HIV-RNA GWAS. Comparable to the Euro-CHAVI study, signals approaching genome-wide significance were identified independently from HCP5 rs2395029 for ZNRD1/RNF39 SNPs. The only GWAS addressing rapid progression to date was performed by comparing the GRIV rapid progressors, defined by a drop of CD4+ T-cell count below 300/μL within 3 years after the last seronegative test, with 1,352 seronegative controls (Figure 3) (Le Clerc et al, 2009). Some of these studies will be further discussed in Santa-Marta et al (2013)
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