Biomarkers of HIV Susceptibility and Disease Progression

Both host and viral factors are associated with HIV-1 susceptibilityand disease progression. Host factors can typically be divided intothree categories (Chatterjee, 2010): 1) genes encoding cell-surface re-ceptors or ligands for these proteins, including the classic CCR5 32-bpdeletion;2)geneswithinthehumanleukocyteantigens(HLA)thatreg-ulatehostresponsestoinfection;and3)othercytokineandimmunere-sponsegenes,includingthehomozygosityatposition−308intheTNF-alpha promoter. More recently genome-wide association studies(GWAS)havedetectednewgeneticfactorsassociatedwithHIV-1infec-tion (van Manen et al., 2012). In addition, an extensive array of hostphysiological responses have been assessed, including MCP-1 (CCL2)(Price et al., 2007).InrelationtoHIV-1susceptibility,theco-receptorsCXCR4andCCR5are classically linked to infection of T cells and cells of the monocyte–macrophage lineage (MML), respectively. CCR5-utilizing viruses arethe major type of virus transmitted therefore MML cells have beenthought to contribute to early disease progression. More recently ithasbeendemonstratedthatTlymphocytesmayalsobeamajorvehicleforHIV-1transmission.TransmittedvirusespreferentiallyuseCCR5asaco-receptor, require high levels of CD4, and are able to replicate efﬁ-ciently in primary CD4+ T-cells, suggesting a CCR5-utilizing T-tropicviral phenotype (Ochsenbauer et al., 2012). Subsequently, these foun-der viruses can infect MML cells, resulting in the development of awider target cell population that expresses higher levels of CCR5 thanT cells (Ochsenbauer et al., 2012). Although in the classical sense, co-receptorutilizationremainsthemost importantfactorinHIV-1suscep-tibility,anumberofotherhostfactorsare currentlyunderinvestigationthat also appear to playa role in cellularsusceptibility. Often thesehostfactors interact with viral proteins thereby affecting the efﬁciency ofviral infection.HIV-1viralproteinR (Vpr)isamultifunctionalvirion-associatedac-cessoryprotein(Cohenetal.,1990).Vprfunctionsbothearlyafterentryinto cells and also following integration of the proviral genome(Hrimech et al., 1999). Vpr is a component of the preintegration com-plex, and following nuclear import Vpr likely plays a major role in reg-ulating the expression of immediate-early HIV-1 genes from the nowintegrated proviral genome. This mechanism is utilized prior to thetransitiontoTat-drivengeneexpression.Vpriscriticalintheviralrepli-cation cycle in non-dividing cells, such as monocytes (Connor et al.,1995), whereas it has been shown to be dispensable in T-lymphocytes(Eckstein et al., 2001).InthemanuscriptbyChiangetal.withinthisissueofEBioMedicine,anew host factor is described as playing a role in HIV-1 susceptibility(Chiang et al., 2014). This host factor, MRJ-L, is the large splice isoformof DNAJB6 (a homolog of heat shock protein 40) and the authors statethat it has been shown to interact with Vpr, however this data, to datehasnotbeenpublishedandthereforethispointisinneedoffurtherde-tailed exploration. The authors, studying cohorts of “men who had sexwith men” (MSM), found that macrophage expression of MRJ-L variedamong healthy subjects but was signiﬁcantly and substantially higherinHIV-1-infectedsubjects.ThemacrophageMRJ-Lexpressionlevelpre-dicted the risk of HIV-1 infection with similar power as whether or notsubjects engaged in unprotected sexual contact. To demonstrate acause-and-effectrelationshipbetweenMRJ-LexpressionandHIV-1sus-ceptibility,monocytesfromhealthysubjectswereisolatedandthendif-ferentiatedandinfectedexvivo.Interestingly,thisexperimentrevealedthatmacrophageswithhighMRJ-LexpressionweremoresusceptibletoHIV-1 infection than those with low MRJ-L expression. Furthermore,RNAi knockdown of MRJ-L in high-expressing cells decreased suscepti-bility to infection, while lentiviral over-expression of MRJ-L in low-expressingcells increased their susceptibility to infection. These resultsclearly implicate high expression of MRJ-L with macrophage suscepti-bility to HIV infection. The authors were able to identify a plausiblemechanism, showing that MRJ-L colocalizes with Vpr and is requiredfor localizingVprto thenucleus. Although thelocalization experimentswereperformedinHeLacells,becauseoftheimportanceofVprinmac-rophages, the extension can be made that MRJ-L plays a major role inthe nuclear transport of this important viral protein (and possibly thewhole pre-integration complex) in other cell types. The stochastic ex-pression of MRJ-L in uninfected subjects raises the possibility that ge-netic factors controlling this variability are also responsible forvariability in susceptibility to infection.Numerous studies have demonstrated the role of host proteins inHIV-1 susceptibility, and the strong evidence provided by Chiang et al.thatMRJ-Llevelsimpactsusceptibilitytoinfectionmakesitanattractive