Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Host Genes Important to HIV Replication and Evolution Amalio Telenti1 and Welkin E. Johnson2 1Institute of Microbiology, University Hospital and University of Lausanne, 1011 Lausanne, Switzerland 2New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, Massachusetts 01772 Correspondence: [email protected] Recent years have seen a significant increase in understanding of the host genetic and genomic determinants of susceptibility to HIV-1 infection and disease progression, driven in large part by candidate gene studies, genome-wide association studies, genome-wide transcriptome analyses, and large-scale in vitro genome screens. These studies have iden- tified common variants in some host loci that clearly influence disease progression, charac- terized the scale and dynamics of gene and protein expression changes in response to infection, and provided the first comprehensive catalogs of genes and pathways involved in viral replication. Experimental models of AIDS and studies in natural hosts of primate lentiviruses have complemented and in some cases extended these findings. As the relevant technology continues to progress, the expectation is that such studies will increase in depth (e.g., to include host whole exome and whole genome sequencing) and in breadth (in par- ticular, by integrating multiple data types). ost genetics has been of considerable allowed the identification of a host genetic con- Hinterest to the field of HIV/AIDS since tribution to .50% of the observed differences the identification of the role of CCR5D32 in cell susceptibility to transduction with a (Dean et al. 1996; Huang et al. 1996; Liu et al. vesicular stomatitis virus (VSV)-pseudotyped 1996) in resistance to infection and of human HIV-1 vector (Loeuillet et al. 2008). In the www.perspectivesinmedicine.org leukocyte antigen (HLA) alleles in disease pro- larger context of infection by simian immuno- gression (Kaslow et al. 1996). Further ob- deficiency viruses, host genetic variation influ- servations confirm that there is a significant ences transmission between species as well as component of heredity in the susceptibility to replication and pathogenesis within individ- HIV-1. Identical twins infected with the same uals of the same species (Kirmaier et al. 2010). viral strain progressed at a similar pace, whereas Host genetic variation includes fixed differ- their fraternal twin had a different clinical ences between species (divergence) and vari- course (Draenert et al. 2006). In vitro, the study ation within populations (polymorphism). of cells from large pedigrees—immortalized B Genetic barrierstoviral transmission and spread lymphocytes from multigeneration families— can arise owing to variation in genes required Editors: Frederic D. Bushman, Gary J. Nabel, and Ronald Swanstrom Additional Perspectives on HIV available at www.perspectivesinmedicine.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a007203 Cite this article as Cold Spring Harb Perspect Med 2012;2:a007203 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press A. Telenti and W.E. Johnson for optimal viral replication (e.g., receptors, of very precise study traits (Evangelou et al. transcription factors, chaperones, etc.) as well 2011). In addition, only common variation as variation in genes that actively thwart viral (present in .5% in a given population) is inves- replication and pathogenesis (e.g., innate and tigated in GWASs. The need for large popula- adaptive immune effectors such as antibody tions (power) is determined by the statistical and cytotoxic T lymphocyte (CTL) responses, requirements that impose a very strict threshold and restriction factor loci such as TRIM5a, of significance (i.e., defined by P , 5 Â 1028 the APOBEC3 cluster, and tetherin). The influ- owing to correction for multiple comparisons) ence of host selection on viral evolution mani- and by the limited contribution of any given fests as changes in primary sequence (escape genetic variant to the population phenotype. and reversion variants) in the viral genome The study traits need to be defined by strict cri- structure, and over the long term, in the acquis- teria to avoid heterogeneity in the phenotype— ition of accessory functions. In this article, we an important consideration because the field begin with an overview of the current under- uses study outcomes, such as time to AIDS or standing of genes and gene variants influencing death, which represent composite end points. susceptibility to HIV-1 in humans, and suscept- Finally, the genotyping arrays used in GWASs ibility to HIV/simian immunodeficiency virus target common variants that tag other variants; (SIV) in nonhuman primate models of infec- the actual causal variant or functional polymor- tion. This includes data from candidate gene phism is unlikely to be interrogated directly. studies, genome-wide association studies, and Current arrays are generally adequate to capture other genome-wide screens. We then analyze common variation in Caucasians and Asians, notable data on host genome pressure on the although less effective in individuals of African viral genome structure. Finally, we present a ancestry. global view on the evolutionary genomics of Eight GWASs have been published during susceptibility to HIV-1 and other retroviruses. the period 2007–2010 (Table 1). The first study (Fellay et al. 2007) investigated the genomic determinants of viral set point after seroconver- KEY ADVANCES sion—the relatively steady state of viral replica- tion in the 3 years following a documented Human Genomics infection. As a secondary end point, the study evaluated disease progression, as defined by Genome-Wide Association Studies time to CD4þ T-cell count less than 350 cells/ The HIV field was one of the first to embrace mL, or else initiation of treatment. This study www.perspectivesinmedicine.org the opportunities offered by new technologies identified three variants in chromosome 6: a that allowed genome-wide association studies variant in HCP5 that tagged the protective allele (GWASs). This approach, which assesses 500,000 HLA-BÃ5707, a variant upstream of HLA-C to 1 million genetic variants (single nucleotide associated with difference in HLA-C expression polymorphism, SNP) for each individual, had levels, and a variant in ZNRD1 that may be advantages and limitations (Telenti and Gold- merely associated with other influences from stein 2006). First, it allowed for the first time the major histocompatibility complex (MHC) the non–a priori analysis, at genome-wide scale, locus, or contribute directly to pathogenesis of possible genetic determinants of a trait. This (Ballana et al. 2010). Extension of this work would allow discovery, unbiased validation of by the same group of researchers (Fellay et al. all previously reported variants, and scoring 2009) confirmed the various associations and the contribution of the genetic variant in the ruled out major variants elsewhere in the context of other possible genome influences. genome with the exception of those in the However, the limitations of the approach in- CCR5-CCR2 locus (Fig. 1). The overall variance clude the need for sufficient power, requiring explained by the genome-wide significant hits large numbers of subjects, and the identification was close to 20%—much larger than what has 2 Cite this article as Cold Spring Harb Perspect Med 2012;2:a007203 Downloaded from www.perspectivesinmedicine.org http://perspectivesinmedicine.cshlp.org/ Cite this article as Table 1. Genome-wide association studies, 2007–2010 Study/year Trait N Population Genome-wide significant hitsa Comment Fellay et al. 2007 Viral load set point, 486 (seroconverters) Caucasian rs2395029 (HCP5/ disease progression HLA-BÃ57:01), rs9264942 (HLA-C), rs9261174 Cold Spring Harb Perspect Med (ZNRD1) Dalmasso et al. Plasma HIV- 605 (seroconverters) Caucasian rs10484554, rs2523619, and 2008 RNA levels rs2395029 (HLA-C, HLA-B and cellular locus) HIV-DNA levels Limou HIV nonprogression 275 (HIV-1þ Caucasian rs2395029 (HCP5/ Subset study (Limou et al. 2010) Ã et al. 2009 nonprogressors), and HLA-B 57:01) used to validate candidate onSeptember26,2021-PublishedbyColdSpringHarborLaboratory 1352 (negative rs2234358 (CXCR6) in three Press controls) independent cohort studies (n ¼ 1028) 2012;2:a007203 Le Clerc Rapid disease 85 (HIV-1þ rapid Caucasian – et al. 2009 progression progressors), and 2049 (negative controls) Fellay et al. 2009 Viral load set point, 2554 (seroconverters and Caucasian rs2395029, rs9264942, Failed to validate previously disease progression seroprevalent) rs259919, rs9468692, reported candidate genes with rs9266409 (MHC locus), and the exception of CCR5/CCR2 rs333(CCR5D32) variants Herbeck et al. Disease progression 156 (rapid, moderate, and Caucasian – Among the 25 top-ranking 2010 nonprogressors) variants, rs17762192 (PROX1) was validated in an independent replication cohort of 590 seroconverters Pelak et al. 2010 Viral set point 515 (seroconverters) African American HLA-BÃ57:03 (rs2523608) In contrast with the tagged HLA, rs2523608 does not reach genome-wide significance International HIV nonprogression 974 (HIV controllers), Caucasian, African 313 SNPs in the MHC locus Arg97, Cys67, Gly62, and Glu63, all HIV 2648 (HIV progressors)