Host variation in type I interferon signaling genes (MX1), C-C chemokine receptor type 5 gene, and major histocompatibility complex class I alleles in treated HIV+ noncontrollers predict viral reservoir size.

Humans HIV Infections / drug therapy Alleles CD8-Positive T-Lymphocytes Cross-Sectional Studies HIV-1 / genetics Histocompatibility Antigens Class I / genetics HLA Antigens RNA Major Histocompatibility Complex Receptors, Chemokine / genetics Interferon Type I / metabolism Viral Load Myxovirus Resistance Proteins

Journal

AIDS (London, England)

ISSN: 1473-5571

Titre abrégé: AIDS

Pays: England

ID NLM: 8710219

Informations de publication

Date de publication:
01 03 2023

Historique:

entrez: 25 1 2023

pubmed: 26 1 2023

medline: 27 1 2023

Statut: ppublish

Résumé

Prior genomewide association studies have identified variation in major histocompatibility complex (MHC) class I alleles and C-C chemokine receptor type 5 gene (CCR5Δ32) as genetic predictors of viral control, especially in 'elite' controllers, individuals who remain virally suppressed in the absence of therapy. Cross-sectional genomewide association study. We analyzed custom whole exome sequencing and direct human leukocyte antigen (HLA) typing from 202 antiretroviral therapy (ART)-suppressed HIV+ noncontrollers in relation to four measures of the peripheral CD4+ T-cell reservoir: HIV intact DNA, total (t)DNA, unspliced (us)RNA, and RNA/DNA. Linear mixed models were adjusted for potential covariates including age, sex, nadir CD4+ T-cell count, pre-ART HIV RNA, timing of ART initiation, and duration of ART suppression. Previously reported 'protective' host genetic mutations related to viral setpoint (e.g. among elite controllers) were found to predict smaller HIV reservoir size. The HLA 'protective' B∗57:01 was associated with significantly lower HIV usRNA (q = 3.3 × 10-3), and among the largest subgroup, European ancestry individuals, the CCR5Δ32 deletion was associated with smaller HIV tDNA (P = 4.3 × 10-3) and usRNA (P = 8.7 × 10-3). In addition, genomewide analysis identified several single nucleotide polymorphisms in MX1 (an interferon stimulated gene) that were significantly associated with HIV tDNA (q = 0.02), and the direction of these associations paralleled MX1 gene eQTL expression. We observed a significant association between previously reported 'protective' MHC class I alleles and CCR5Δ32 with the HIV reservoir size in noncontrollers. We also found a novel association between MX1 and HIV total DNA (in addition to other interferon signaling relevant genes, PPP1CB, DDX3X). These findings warrant further investigation in future validation studies.

Identifiants

DOI: 10.1097/QAD.0000000000003428 PMID: 36695358 PMC: PMC9894159

pubmed: 36695358

doi: 10.1097/QAD.0000000000003428

pii: 00002030-202303010-00011

pmc: PMC9894159

doi:

Substances chimiques

Histocompatibility Antigens Class I 0

HLA Antigens 0

RNA 63231-63-0

Receptors, Chemokine 0

Interferon Type I 0

MX1 protein, human 0

Myxovirus Resistance Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

Pagination

477-488

Subventions

Organisme : NIAID NIH HHS

ID : R01 AI143464

Pays : United States

Organisme : NIAID NIH HHS

ID : U19 AI096109

Pays : United States

Informations de copyright

Références

Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies . Clin Infect Dis 2010; 50:1387–1396.

Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication . Immunity 2012; 37:377–388.

Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, et al. Survival of persons with and without HIV infection in Denmark, 1995–2005 . Ann Intern Med 2007; 146:87–95.

Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection . Lancet 2010; 376:49–62.

Dalmasso C, Carpentier W, Meyer L, Rouzioux C, Goujard C, Chaix ML, et al. Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study . PLoS One 2008; 3:e3907.

Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, et al. A whole-genome association study of major determinants for host control of HIV-1 . Science 2007; 317:944–947.

Fellay J, Frahm N, Shianna KV, Cirulli ET, Casimiro DR, Robertson MN, et al. Host genetic determinants of T cell responses to the MRKAd5 HIV-1 gag/pol/nef vaccine in the step trial . J Infect Dis 2011; 203:773–779.

Fellay J, Ge D, Shianna KV, Colombo S, Ledergerber B, Cirulli ET, et al. Common genetic variation and the control of HIV-1 in humans . PLoS Genet 2009; 5:e1000791.

Herbeck JT, Gottlieb GS, Winkler CA, Nelson GW, An P, Maust BS, et al. Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS . J Infect Dis 2010; 201:618–626.

Le Clerc S, Limou S, Coulonges C, Carpentier W, Dina C, Taing L, et al. Genomewide association study of a rapid progression cohort identifies new susceptibility alleles for AIDS (ANRS Genomewide Association Study 03) . J Infect Dis 2009; 200:1194–1201.

Limou S, Le Clerc S, Coulonges C, Carpentier W, Dina C, Delaneau O, et al. Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02) . J Infect Dis 2009; 199:419–426.

Pelak K, Goldstein DB, Walley NM, Fellay J, Ge D, Shianna KV, et al. Host determinants of HIV-1 control in African Americans . J Infect Dis 2010; 201:1141–1149.

Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PI, et al. International HIVCS. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation . Science 2010; 330:1551–1557.

Petrovski S, Fellay J, Shianna KV, Carpenetti N, Kumwenda J, Kamanga G, et al. Common human genetic variants and HIV-1 susceptibility: a genome-wide survey in a homogeneous African population . AIDS 2011; 25:513–518.

de Roda Husman AM, Koot M, Cornelissen M, Keet IP, Brouwer M, Broersen SM, et al. Association between CCR5 genotype and the clinical course of HIV-1 infection . Ann Intern Med 1997; 127:882–890.

Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study . Science 1996; 273:1856–1862.

Rappaport J, Cho YY, Hendel H, Schwartz EJ, Schachter F, Zagury JF. 32b CCR-5 gene deletion and resistance to fast progression in HIV-1 infected heterozygotes . Lancet 1997; 349:922–923.

Kulkarni S, Lied A, Kulkarni V, Rucevic M, Martin MP, Walker-Sperling V, et al. CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome . Nat Immunol 2019; 20:824–834.

Levy CHS, Roychoudhury P, Reeves DB, Amstuz C, Zhu H, et al. A highly multiplexed droplet digital PCR assay to measure the intact HIV-1 proviral reservoir . Cell Rep Med 2021; 2:100243.

Ramirez CM, Sinclair E, Epling L, Lee SA, Jain V, Hsue PY, et al. Immunologic profiles distinguish aviremic HIV-infected adults . AIDS 2016; 30:1553–1562.

Boufassa F, Lechenadec J, Meyer L, Costagliola D, Hunt PW, Pereyra F, et al. Blunted response to combination antiretroviral therapy in HIV elite controllers: an international HIV controller collaboration . PLoS One 2014; 9:e85516.

Emu B, Sinclair E, Hatano H, Ferre A, Shacklett B, Martin JN, et al. HLA class I-restricted T-cell responses may contribute to the control of human immunodeficiency virus infection, but such responses are not always necessary for long-term virus control . J Virol 2008; 82:5398–5407.

Grebe E, Facente SN, Bingham J, Pilcher CD, Powrie A, Gerber J, et al. Interpreting HIV diagnostic histories into infection time estimates: analytical framework and online tool . BMC Infect Dis 2019; 19:894.

Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS . Nat Genet 2002; 31:429–434.

Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F, et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1 . Nat Genet 2007; 39:733–740.

Ho YC, Shan L, Hosmane NN, Wang J, Laskey SB, Rosenbloom DI, et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure . Cell 2013; 155:540–551.

Bruner KM, Murray AJ, Pollack RA, Soliman MG, Laskey SB, Capoferri AA, et al. Defective proviruses rapidly accumulate during acute HIV-1 infection . Nat Med 2016; 22:1043–1049.

Malnati MS, Scarlatti G, Gatto F, Salvatori F, Cassina G, Rutigliano T, et al. A universal real-time PCR assay for the quantification of group-M HIV-1 proviral load . Nat Protoc 2008; 3:1240–1248.

Chapman B, Kirchner R, Pantano L, Naumenko S, De Smet M, Beltrame L, et al . bcbio/bcbio-nextgen. In. v.1.2.8. ed: Zenodo. Available at https://doi.org/10.5281/zenodo.5781867 .

Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM . arXiv 2013.

Poplin R, Ruano-Rubio V, DePristo MA, Fennell TJ, Carneiro MO, Van der Auwera GA, et al. Scaling accurate genetic variant discovery to tens of thousands of samples . bioRxiv 2017; 201178.

Picard toolkit. 2019.

DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data . Nat Genet 2011; 43:491–498.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses . Am J Hum Genet 2007; 81:559–575.

Danecek P, Auton A, Abecasis G, Albers CA, Banks E, DePristo MA, et al. The variant call format and VCFtools . Bioinformatics 2011; 27:2156–2158.

Gogarten SM, Sofer T, Chen H, Yu C, Brody JA, Thornton TA, et al. Genetic association testing using the GENESIS R/Bioconductor package . Bioinformatics 2019; 35:5346–5348.

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data . Nucleic Acids Res 2010; 38:e164.

Chen H, Huffman JE, Brody JA, Wang C, Lee S, Li Z, et al. Efficient variant set mixed model association tests for continuous and binary traits in large-scale whole-genome sequencing studies . Am J Hum Genet 2019; 104:260–274.

Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X. Rare-variant association testing for sequencing data with the sequence kernel association test . Am J Hum Genet 2011; 89:82–93.

Bioconductor Core Team BPMMBO. Txdb.hsapiens.ucsc.hg38.knowngene. 2017.

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes . Nat Genet 2003; 34:267–273.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles . Proc Natl Acad Sci USA 2005; 102:15545–15550.

Seabold; Skipper; Perktold J. Statsmodels: econometric and statistical modeling with python . Proceedings of the 9th Python in Science Conference ; 2010.

Josefsson L, von Stockenstrom S, Faria NR, Sinclair E, Bacchetti P, Killian M, et al. The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time . Proc Natl Acad Sci USA 2013; 110:E4987–E4996.

Buzon MJ, Martin-Gayo E, Pereyra F, Ouyang Z, Sun H, Li JZ, et al. Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells . J Virol 2014; 88:10056–10065.

Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, et al. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection . Proc Natl Acad Sci USA 2012; 109:9523–9528.

Hocqueloux L, Avettand-Fenoel V, Jacquot S, Prazuck T, Legac E, Melard A, et al. Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts . J Antimicrob Chemother 2013; 68:1169–1178.

Jain V, Hartogensis W, Bacchetti P, Hunt PW, Hatano H, Sinclair E, et al. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size . J Infect Dis 2013; 208:1202–1211.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. Available at https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf [Accessed 18 December 2019]

Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies . PLoS Pathogens 2013; 9:e1003174.

Bachmann N, von Siebenthal C, Vongrad V, Turk T, Neumann K, Beerenwinkel N, et al. Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART . Nat Commun 2019; 10:3193.

Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research . Behav Brain Res 2001; 125:279–284.

Yang J, Weedon MN, Purcell S, Lettre G, Estrada K, Willer CJ, et al. Genomic inflation factors under polygenic inheritance . Eur J Hum Genet 2011; 19:807–812.

Staeheli P, Haller O. Human MX2/MxB: a potent interferon-induced postentry inhibitor of herpesviruses and HIV-1 . J Virol 2018; 92:

Haller O, Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity . J Interferon Cytokine Res 2011; 31:79–87.

Goujon C, Moncorge O, Bauby H, Doyle T, Ward CC, Schaller T, et al. Human MX2 is an interferon-induced postentry inhibitor of HIV-1 infection . Nature 2013; 502:559–562.

Liu Z, Pan Q, Ding S, Qian J, Xu F, Zhou J, et al. The interferon-inducible MxB protein inhibits HIV-1 infection . Cell Host Microbe 2013; 14:398–410.

Betancor G, Jimenez-Guardeno JM, Lynham S, Antrobus R, Khan H, Sobala A, et al. MX2-mediated innate immunity against HIV-1 is regulated by serine phosphorylation . Nat Microbiol 2021; 6:1031–1042.

Consortium GT, Laboratory DA. Coordinating Center-Analysis Working Group, Statistical Methods groups-Analysis Working Group, Enhancing Gg, Fund NIHC, et al. . Genetic effects on gene expression across human tissues . Nature 2017; 550:204–213.

Szabo PA, Levitin HM, Miron M, Snyder ME, Senda T, Yuan J, et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease . Nat Commun 2019; 10:4706.

Wang S, Zhang Q, Hui H, Agrawal K, Karris MAY, Rana TM. An atlas of immune cell exhaustion in HIV-infected individuals revealed by single-cell transcriptomics . Emerg Microbes Infect 2020; 9:2333–2347.

Ammosova T, Jerebtsova M, Beullens M, Voloshin Y, Ray PE, Kumar A, et al. Nuclear protein phosphatase-1 regulates HIV-1 transcription . J Biol Chem 2003; 278:32189–32194.

Collins KL. How HIV evades CTL recognition . Curr HIV Res 2003; 1:31–40.

Li Q, Schacker T, Carlis J, Beilman G, Nguyen P, Haase AT. Functional genomic analysis of the response of HIV-1-infected lymphatic tissue to antiretroviral therapy . J Infect Dis 2004; 189:572–582.

Vahey MT, Wang Z, Su Z, Nau ME, Krambrink A, Skiest DJ, et al. CD4+ T-cell decline after the interruption of antiretroviral therapy in ACTG A5170 is predicted by differential expression of genes in the ras signaling pathway . AIDS Res Hum Retroviruses 2008; 24:1047–1066.

Szappanos D, Tschismarov R, Perlot T, Westermayer S, Fischer K, Platanitis E, et al. The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity . PLoS Pathog 2018; 14:e1007397.

Yedavalli VS, Neuveut C, Chi YH, Kleiman L, Jeang KT. Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function . Cell 2004; 119:381–392.

Perfettini JL, Roumier T, Castedo M, Larochette N, Boya P, Raynal B, et al. NF-kappaB and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope . J Exp Med 2004; 199:629–640.

Troger J, Moutty MC, Skroblin P, Klussmann E. A-kinase anchoring proteins as potential drug targets . Br J Pharmacol 2012; 166:420–433.

Roberts BL, Severance ZC, Bensen RC, Le-McClain AT, Malinky CA, Mettenbrink EM, et al. Differing activities of oxysterol-binding protein (OSBP) targeting antiviral compounds . Antiviral Res 2019; 170:104548.

Saulle I, Ibba SV, Vittori C, Fenizia C, Mercurio V, Vichi F, et al. Sterol metabolism modulates susceptibility to HIV-1 Infection . AIDS 2020; 34:1593–1602.

Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, et al. Tetherin inhibits HIV-1 release by directly tethering virions to cells . Cell 2009; 139:499–511.

Rantakari P, Auvinen K, Jappinen N, Kapraali M, Valtonen J, Karikoski M, et al. The endothelial protein PLVAP in lymphatics controls the entry of lymphocytes and antigens into lymph nodes . Nat Immunol 2015; 16:386–396.

Hunt PW, Martin JN, Sinclair E, Bredt B, Hagos E, Lampiris H, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy . J Infect Dis 2003; 187:1534–1543.

Deeks SG, Archin N, Cannon P, Collins S, Jones RB, de Jong M, et al. Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021 . Nat Med 2021; 27:2085–2098.

Gay CL, Kuruc JD, Falcinelli SD, Warren JA, Reifeis SA, Kirchherr JL, et al. Assessing the impact of AGS-004, a dendritic cell-based immunotherapy, and vorinostat on persistent HIV-1 Infection . Sci Rep 2020; 10:5134.

Fidler S, Stohr W, Pace M, Dorrell L, Lever A, Pett S, et al. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial . Lancet 2020; 395:888–898.

Gutierrez C, Serrano-Villar S, Madrid-Elena N, Perez-Elias MJ, Martin ME, Barbas C, et al. Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy . AIDS 2016; 30:1385–1392.

Vibholm L, Schleimann MH, Hojen JF, Benfield T, Offersen R, Rasmussen K, et al. Short-course toll-like receptor 9 agonist treatment impacts innate immunity and plasma viremia in individuals with human immunodeficiency virus infection . Clin Infect Dis 2017; 64:1686–1695.

Riddler SA, Para M, Benson CA, Mills A, Ramgopal M, DeJesus E, et al. Vesatolimod, a toll-like receptor 7 agonist, induces immune activation in virally suppressed adults living with human immunodeficiency virus-1 . Clin Infect Dis 2021; 72:e815–e824.

Elliott JH, McMahon JH, Chang CC, Lee SA, Hartogensis W, Bumpus N, et al. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study . Lancet HIV 2015; 2:e520–529.

Bruner KM, Wang Z, Simonetti FR, Bender AM, Kwon KJ, Sengupta S, et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses . Nature 2019; 566:120–125.

Levy CN, Hughes SM, Roychoudhury P, Reeves DB, Amstuz C, Zhu H, et al. A highly multiplexed droplet digital PCR assay to measure the intact HIV-1 proviral reservoir . Cell Rep Med 2021; 2:100243.

Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease . Hum Genet 2013; 132:1077–1130.

Verhelst J, Hulpiau P, Saelens X. Mx proteins: antiviral gatekeepers that restrain the uninvited . Microbiol Mol Biol Rev 2013; 77:551–566.

Verhelst J, Parthoens E, Schepens B, Fiers W, Saelens X. Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly . J Virol 2012; 86:13445–13455.

Zhao G, Liu L, Su B, Zhang T, Chen P, Li W, et al. The dynamic changes of interferon lambdas related genes and proteins in JAK/STAT pathway in both acute and chronic HIV-1 infected patients . AIDS Res Ther 2017; 14:31.

Van Hecke C, Trypsteen W, Malatinkova E, De Spiegelaere W, Vervisch K, Rutsaert S, et al. Early treated HIV-1 positive individuals demonstrate similar restriction factor expression profile as long-term nonprogressors . EBioMedicine 2019; 41:443–454.

Lee SY, Choi BS, Yoon CH, Kang C, Kim K, Kim KC. Selection of biomarkers for HIV-1 latency by integrated analysis . Genomics 2019; 111:327–333.

Hormozdiari F, van de Bunt M, Segre AV, Li X, Joo JWJ, Bilow M, et al. Colocalization of GWAS and eQTL signals detects target genes . Am J Hum Genet 2016; 99:1245–1260.

Shifrut E, Carnevale J, Tobin V, Roth TL, Woo JM, Bui CT, et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function . Cell 2018; 175:1958–1971. e1915.

Peluso MJ, Bacchetti P, Ritter KD, Beg S, Lai J, Martin JN, et al. Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy . JCI Insight 2020; 5:e132997.

Falcinelli SD, Kilpatrick KW, Read J, Murtagh R, Allard B, Ghofrani S, et al. Longitudinal dynamics of intact HIV proviral DNA and outgrowth virus frequencies in a cohort of individuals receiving antiretroviral therapy . J Infect Dis 2021; 224:92–100.

Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies . Nat Genet 2006; 38:904–909.

Pantaleo G, Graziosi C, Butini L, Pizzo PA, Schnittman SM, Kotler DP, et al. Lymphoid organs function as major reservoirs for human immunodeficiency virus . Proc Natl Acad Sci USA 1991; 88:9838–9842.

Evering TH, Mehandru S, Racz P, Tenner-Racz K, Poles MA, Figueroa A, et al. Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection . PLoS Pathog 2012; 8:e1002506.

Imamichi H, Degray G, Dewar RL, Mannon P, Yao M, Chairez C, et al. Lack of compartmentalization of HIV-1 quasispecies between the gut and peripheral blood compartments . J Infect Dis 2011; 204:309–314.

Procopio FA, Fromentin R, Kulpa DA, Brehm JH, Bebin AG, Strain MC, et al. A novel assay to measure the magnitude of the inducible viral reservoir in HIV-infected individuals . EBioMedicine 2015; 2:872–881.

Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies . PLoS Pathog 2013; 9:e1003174.

Thorball CW, Borghesi A, Bachmann N, Von Siebenthal C, Vongrad V, Turk T, et al. Host genomics of the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment . J Acquir Immune Defic Syndr 2020; 85:517–524.

Zhang Z, Trypsteen W, Blaauw M, Chu X, Rutsaert S, Vandekerckhove L, et al. IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis . BMC Med 2021; 19:282.

Dolcemascolo R, Goiriz L, Montagud-Martinez R, Rodrigo G. Gene regulation by a protein translation factor at the single-cell level . PLoS Comput Biol 2022; 18:e1010087.

McLaren PJ, Carrington M. The impact of host genetic variation on infection with HIV-1 . Nat Immunol 2015; 16:577–583.

Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis . Am J Hum Genet 2011; 88:76–82.

Gondim MVP, Sherrill-Mix S, Bibollet-Ruche F, Russell RM, Trimboli S, Smith AG, et al. Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption . Sci Transl Med 2021; 13:eabd8179doi: 10.1126/scitranslmed.abd8179.

doi: 10.1126/scitranslmed.abd8179

Einkauf KB, Osborn MR, Gao C, Sun W, Sun X, Lian X, et al. Parallel analysis of transcription, integration, and sequence of single HIV-1 proviruses . Cell 2022; 185:66–282. e215.