Human Immunodeficiency Virus Type 1, Susceptibility To

A number sign (#) is used with this entry because variation in several different genes influences susceptibility and resistance to HIV-1 infection and the rate of progression to AIDS after infection (see PATHOGENESIS and MOLECULAR GENETICS).

The pathogenesis of HIV infection and the progression from infection to AIDS vary significantly between exposed individuals. Infection occurs after the virus, which has macrophage (M)- and T lymphocyte (T)-tropic strains and more than 12 subtypes, survives an array of nonspecific, nongenetic environmental and host factors.

Viral Entry

Entry of HIV-1 into host cells requires expression of the host cell receptor CD4 (186940) and fusion coreceptors. CCR5 (601373) and CCR2 (601267) act as fusion coreceptors for M-tropic HIV-1 strains, and CXCR4 (162643) and CX3CR1 (601470) act as fusion coreceptors for T-tropic HIV-1 strains. The HIV-1 viral envelope protein gp120 also uses DCSIGN (CD209; 604672) and syndecans (e.g., SDC2; 142460) as intermediary receptors on dendritic cells and endothelial cells, respectively. Polymorphisms in any of these receptors may confer either increased susceptibility or resistance to HIV-1 infection. In addition, ligands for the coreceptors (CCL5 (187011), CCL3 (182283), CCL3L1 (601395), and CCL4 (182284) for CCR5, and CXCL12 (600835) for CXCR4) can prevent HIV-1 entry into cells. Polymorphisms in these ligands may alter susceptibility to infection and disease progression. For further information, see MOLECULAR GENETICS and reviews by Trkola (2004), O'Brien and Nelson (2004), and Kaslow et al. (2005).

Granelli-Piperno et al. (2006) used a monoclonal antibody recognizing BDCA1 (CD1C; 188340) to directly isolate myeloid dendritic cells (DCs) from human blood. These cells expressed the HIV-1 entry receptors CD4, CCR5, and CXCR4, but not CD209. HIV-1 infected a small fraction of the blood DCs that failed to mature in culture and exhibited weak immunostimulatory functions. Granelli-Piperno et al. (2006) proposed that HIV-1 exploits myeloid DCs in blood not only for replication and transmission, but also for immune evasion.

Zhou et al. (2007) constructed stabilized gp120 molecules constrained to stay in the CD4-bound conformation, even in the absence of CD4, and determined the crystal structure of gp120 in complex with the neutralizing IgG1 antibody b12 at 2.3-angstrom resolution. Their analyses revealed the functionally conserved surface that allows for initial CD4 attachment and delineated the b12 epitope at the atomic level. Zhou et al. (2007) proposed that the b12 epitope serves as a key target for humoral neutralization of HIV-1 in long-term nonprogressors.

Hladik et al. (2007) developed an ex vivo model of intraepithelial HIV-1 infection in human vagina and found that HIV-1 rapidly penetrated both intraepithelial Langerhans cells and CD4-positive T cells. HIV-1 entered CD4-positive T cells almost exclusively through CD4 and CCR5 receptor-mediated direct fusion, without passage from Langerhans cells, and productive infection ensued. In contrast, HIV-1 entered CD1A (188370)-positive Langerhans cells through endocytosis by means of multiple receptors, and virions persisted intact within the cytoplasm for several days. Hladik et al. (2007) concluded that HIV-1 simultaneously enters CD4-positive T cells and Langerhans cells in human vaginal epithelium and that antiviral microbicides need to target both CCR5 and viral entry into Langerhans cells.

As part of a clinical trial to evaluate participants for treatment with a CCR5 inhibitor, Wilkin et al. (2007) determined coreceptor use for 391 HIV-1-infected and antiretroviral-treated patients. Half of the patients had virus that used the CCR5 coreceptor, 46% had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4, and only 4% had virus that used CXCR4. Patients with dual-tropic or mixed HIV-1 populations had a significantly lower CD4-positive T-cell count than did those whose virus used CCR5 only.

Using a large-scale small interfering RNA screen to identify host factors required by HIV-1, Brass et al. (2008) identified more than 250 HIV-dependency factors (HDFs), 79 of which showed significantly higher expression in immune tissues compared with other tissues. The HDFs RAB6A (179513) and VPS53 (615850), retrograde Golgi transport proteins, were involved in viral entry. Brass et al. (2008) proposed that targeting HDFs essential for the viral cycle but not critical for the host may avoid drug resistance due to viral diversity and escape mutation.

Using yeast 2-hybrid analysis and protein pull-down assays, Jimenez-Baranda et al. (2007) showed that CD4 and the HIV-1 coreceptors CCR5 and CXCR4 interacted with filamin A (FLNA; 300017), which regulated clustering of the HIV-1 receptors on the cell surface. Binding of HIV-1 gp120 to the receptors induced transient cofilin (see CFL1; 601442) phosphorylation inactivation through a RHOA (165390)-ROCK (see 601702)-dependent mechanism. Blockade of FLNA interaction with CD4 and/or the coreceptors inhibited gp120-induced RHOA activation and cofilin inactivation. Jimenez-Baranda et al. (2007) concluded that FLNA is an adaptor protein that links HIV-1 receptors to the actin skeleton remodeling machinery, possibly facilitating virus infection.

By incubating DARC (613665)-positive and DARC-negative red blood cells (RBCs) with HIV-1 and using flow cytometry, He et al. (2008) showed that DARC bound the virus to RBCs and, after cell washing, could mediate transfer of the virus, particularly strains using the CXCR4 coreceptor, to susceptible target cells. HIV-1 binding to DARC could be inhibited by the DARC ligands CCL5 and CXCL8 (IL8; 146930), but not by the nonligand CCL3.

KLF2 (602016) is a transcription factor that promotes T-cell quiescence and regulates T-cell migration. Richardson et al. (2012) found that CD4-positive T cells stimulated with phytohemagglutinin plus IL2 (147680) had increased expression of KLF2 and CCR5 and increased susceptibility to infection with HIV-1 compared with T cells stimulated with immobilized anti-CD3 (see 186740) and anti-CD28 (186760). Enhanced expression of KLF2 did not regulate expression of chemokine receptor ligands (e.g., CCL3) that downregulate CCR5 expression. Knockdown of KLF2 in CD4-positive T cells via small interfering RNA resulted in reduced CCR5 expression. Chromatin immunoprecipitation analysis showed that KLF2 bound to the CCR5 promoter in resting, but not CD3/CD28-activated, CD4-positive T cells. Transduction of KLF2 induced CCR5 in some, but not all, transformed T-cell lines. CCR5 upregulation after KLF2 transduction restored susceptibility to CCR5-tropic HIV-1 in the Jurkat T-cell line, which expresses little to no KLF2. Richardson et al. (2012) concluded that KLF2 is a host factor that modulates CCR5 expression in CD4-positive T cells and influences susceptibility to CCR5-tropic viruses.

Viral Replication

Transcription of HIV-1, which resides predominantly in introns of active host genes in resting CD4-positive T cells, requires CD4-positive T-cell activation, the presence of sufficient concentrations of transcription factors, such as NFKB (164011) and NFAT (600490), the HIV transcriptional activator (Tat), and Tat-associated activation-dependent host factors. Viral replication, and thereby disease progression, may be modified by intracellular factors, such as APOBEC3G (607113) and MURR1 (607238). These intracellular factors may be countered by viral factors, such as the Vif regulatory protein. For further information, see reviews by Lassen et al. (2004) and Trkola (2004).

Triboulet et al. (2007) provided evidence for a physiologic role of the miRNA silencing machinery in controlling HIV-1 replication. Type III RNAses Dicer (606241) and Drosha (608828), responsible for miRNA processing, inhibited virus replication both in peripheral blood mononuclear cells from HIV-1-infected donors and in latently infected cells. In turn, HIV-1 actively suppressed the expression of polycistronic miRNA cluster miR17-92 (see 609416). This suppression was found to be required for efficient viral replication and was dependent on the histone acetyltransferase Tat cofactor PCAF (602303). Triboulet et al. (2007) concluded that their results highlighted the involvement of the miRNA silencing pathway in HIV-1 replication and latency.

Latency of HIV-1 in resting primary CD4-positive T cells is the major barrier for eradication of the virus in patients on suppressive highly active antiretroviral treatment (HAART). Huang et al. (2007) showed that a cluster of cellular miRNAs, including miRNA28, miRNA125B (see MIRN125B1; 610104), miRNA150 (MIRN150; 611114), miRNA223, and miRNA382, were enriched in resting compared to activated CD4-positive T cells and that these miRNAs targeted the 3-prime ends of HIV-1 mRNAs. Specific inhibitors of these miRNAs, particularly when used in combination, counteracted their inhibition of HIV-1 expression, as assessed by HIV-1 protein translation in transfected CD4-positive T cells or by HIV-1 production from resting CD4-positive T cells from HIV-1-infected individuals on suppressive HAART. Huang et al. (2007) concluded that miRNAs have a pivotal role in HIV-1 latency and proposed that manipulation of miRNAs may enable purging of the latent HIV-1 reservoir.

Using a large-scale small interfering RNA screen to identify host factors required by HIV-1, Brass et al. (2008) identified more than 250 HIV-dependency factors (HDFs), 79 of which showed significantly higher expression in immune tissues compared with other tissues. Depletion of the HDF TNPO3 (610032), a karyopherin, resulted in HIV inhibition after reverse transcription, but before integration. Several components of the Mediator complex were identified as HDFs, and knockdown of MED28 (610311) inhibited viral transcription. Brass et al. (2008) proposed that targeting HDFs essential for the viral cycle but not critical for the host may avoid drug resistance due to viral diversity and escape mutation.

Manganaro et al. (2010) noted that resting peripheral blood T lymphocytes do not support efficient HIV infection and reverse transcription. They found that JNK (see 601158), which Western blot analysis showed was not expressed in resting lymphocytes, regulated permissiveness to HIV-1 infection. In activated T cells, JNK phosphorylated HIV-1 viral integrase on a highly conserved serine in its core domain. Phosphorylated integrase was a substrate for PIN1, which catalyzed a conformational modification of integrase, increasing its stability. This pathway of protein modification was required for efficient HIV-1 integration and infection and was present in activated, but not nonactivated, primary resting CD4-positive T lymphocytes.

HIV-1, produces Vif, which counteracts host antiviral defense by highjacking a ubiquitin ligase complex consisting of CUL5 (601741), ELOC (600788), ELOB (600787), and RBX1 (603814) that targets the restriction factor APOBEC3G for degradation. Using affinity tag/purification mass spectrometry, Jager et al. (2011) showed that Vif also recruited CBFB (121360) to this ubiquitin ligase complex. CBFB allowed the reconstitution of a recombinant 6-protein assembly that elicited specific polyubiquitination activity with APOBEC3G, but not with APOBEC3A (607109). RNA knockdown and genetic complementation studies demonstrated that CBFB was required for Vif-mediated degradation of APOBEC3G and the preservation of HIV-1 infectivity. Vif from the simian immunodeficiency virus also bound to and required Cbfb to degrade rhesus Apobec3g, indicating functional conservation across primate species. Jager et al. (2011) proposed that disruption of the CBFB-Vif interaction might restrict HIV-1 and be a supplemental antiviral therapy.

Independently, Zhang et al. (2012) identified the role of CBFB in Vif-mediated degradation of APOBEC3G. The N-terminal region of Vif was required for interaction with CBFB, and Vif interacted with regions of CBFB distinct from those used by CBFB to interact with RUNX. Zhang et al. (2012) suggested that the CBFB-Vif interaction is a potential target for intervention against HIV-1.

Host Immune Response

Recognition of HIV-1 by protective immune mechanisms, such as cytotoxic lymphocytes, depends largely on antigen recognition molecules encoded within the major histocompatibility complex (MHC) on chromosome 6. This region of the genome is characterized by intense polymorphism, and the inheritance of specific HLA alleles has profound effects on the outcome of infection. For example, certain allele groups (e.g., HLA-B35 and HLA-B53; see 142830) may be associated with less favorable prognosis or higher viral loads, while others (e.g., HLA-B57 and HLA-B27) may be associated with protection. HLA heterozygosity or lack of sharing of HLA antigens between the infectious donor and the recipient may also confer some protection. In addition, the adaptive immune response uses auxiliary systems of antigen recognition that are also highly polymorphic, such as the KIR gene cluster on chromosome 19 (e.g., KIR3DS1; 604946). Cytokines, such as IL10 (124092) and IFNG (147570), also inhibit HIV-1 replication. Chemokines that do not bind the primary HIV-1 coreceptors, such as CCL2 (158105), CCL7 (158106), and CCL11 (601156), may influence HIV-1 transmission by activating the immune response. For further information, see MOLECULAR GENETICS and reviews by Nolan et al. (2004), Kaslow et al. (2005) and O'Brien and Nelson (2004).

High-level immune activation and T-cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic simian immunodeficiency virus (SIV) infections in natural primate hosts. Schindler et al. (2006) found that all primate lentiviral Nef proteins downmodulated CD4, CD28 (186760), and MHC class I, but the ability to modulate surface expression of the T-cell receptor (TCR; see 186880) complex differed depending on the particular lentiviral lineage analyzed. Nef proteins from nearly all primate lentiviruses efficiently downmodulated TCR-CD3 (see 186740), thereby suppressing the responsiveness of infected T cells to activation and activation-induced cell death. In contrast, the Nef proteins of HIV-1 and its closest simian relatives failed to downmodulate TCR-CD3 and to prevent activation-induced cell death. Schindler et al. (2006) concluded that Nef exerts an important protective function that was lost during lentiviral evolution in a lineage that gave rise to HIV-1. They proposed that this Nef activity is needed to prevent chronic generalized T-cell activation typical of HIV infection and thus contributes to the nonpathogenic phenotype of natural SIV infections.

SIV does not cause progression to AIDS, loss of Cd4-positive T cells, and aberrant immune activation in its natural reservoir hosts, such as sooty mangabeys. In contrast, SIV in rhesus macaques, a non-natural reservoir host, and HIV in humans leads to CD4-positive T-cell depletion, progression to AIDS, and relentless immune system activation. Mandl et al. (2008) found that sooty mangabeys exhibited reduced innate immune system activation during acute and chronic SIV infection. Sooty mangabey plasmacytoid DCs produced markedly less Ifna (147660) in response to SIV and other Tlr7 (300365) and Tlr9 (605474) ligands compared with plasmacytoid DCs from rhesus macaques. Comparative sequence analysis of genes encoding proteins in the human, rhesus macaque, and sooty mangabey TLR7 and TLR9 signaling pathways identified 5 amino acid changes in the transactivation domain of sooty mangabey Irf7 (605047). Four of the 5 residues changed in sooty mangabey Irf7 are conserved in rhesus macaque and human IRF7, whereas 1 is different in all 3 species. The findings suggested that Irf7 is the most probable candidate responsible for the reduction in sooty mangabey Ifna production after Tlr7 and Tlr9 signaling. Mandl et al. (2008) proposed that chronic stimulation of plasmacytoid dendritic cells by SIV and HIV in non-natural hosts may drive the aberrant immune activation and dysfunction underlying AIDS progression and immunopathology.

Yan et al. (2010) observed enhanced Ifnb (147640) and Il6 (147620) expression in Trex1 (606609) -/- mouse embryonic fibroblasts (MEFs) infected with pseudotyped HIV-1 compared with uninfected Trex1 -/- MEFs or infected wildtype MEFs. Ifnb induction was mediated by reverse transcribed HIV in an Irf3 (603734)-dependent manner. HIV reverse transcripts accumulated in Trex -/- MEFs. HIV-stimulated Ifnb from Trex1 -/- MEFs inhibited HIV. Yan et al. (2010) observed an increase in cytosolic HIV DNA and reduced viral spreading, accompanied by increased IFNA (147660) and IFNB expression, in human monocyte-derived macrophages treated with small interfering RNA (siRNA) against TREX1 and subsequently infected with HIV-1. Treatment of Trex1 -/- MEFs with siRNA against genes related to innate immunity showed that HIV DNA was detected by a pathway that signaled through Sting (TMEM173; 612374), Tbk1 (604834), and Irf3 but not nucleic acid sensors. Yan et al. (2010) proposed that HIV-1 uses TREX1 to avoid triggering antiviral innate immunity.

Harman et al. (2015) had previously shown that DCs and macrophages failed to produce type I IFN in response to HIV-1, but that the failure was not mediated through HIV-1 targeting IRF3, as occurs in T cells. Harman et al. (2015) found that cells exposed to HIV-1, but not herpes simplex-2 or Sendai virus, failed to induce expression of either type I or type III IFNs, in spite of sensing the virus and inducing pathogen recognition receptor signaling. Phosphorylation of TBK1 was completely inhibited through binding of HIV-1 Vpr and Vif proteins to TBK1. HIV-1 lacking either protein induced IFNB expression. Harman et al. (2015) concluded that inhibition of TBK1 autophosphorylation due to binding of Vpr and Vif proteins is the principal mechanism by which HIV-1 blocks type I and type III IFN induction in myeloid cells.

Using a targeted RNA interference screen on primary human monocyte-derived dendritic cells (MDDCs), Yoh et al. (2015) identified PQBP1 (300463) as an immune regulator that directly interfaced with HIV-1 to initiate an innate immune response. PQBP1 bound to reverse-transcribed HIV-1 DNA and interacted with cGAS (MB21D1; 613973) to initiate an IRF3-dependent innate immune response. MDDCs from Renpenning syndrome (309500) patients, who harbor PQBP1 mutations, possessed a severely attenuated innate immune response to HIV-1 challenge, supporting the role of PQBP1 as a proximal innate sensor of HIV-1 infection. Yoh et al. (2015) concluded that PQBP1 is an essential component of the cGAS/IRF3-dependent innate response to HIV through its association with cGAS and regulation of cGAS activity.

By screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5 (614551), and to a lesser extent SERINC3 (607165), inhibited infectivity of HIV-1 and murine leukemia retrovirus (MLV). The HIV-1 Nef protein and the structurally unrelated glycosylated Gag (glycoGag) from MLV counteracted SERINC5 inhibition of infectivity. The ability of Nef to counteract SERINC5 depended on myristoylation of Nef. SERINC5 localized to plasma membrane, where it was incorporated into budding HIV-1 virions and impaired subsequent virion penetration of susceptible target cells. Nef redirected SERINC5 to a RAB7 (602298)-positive endosomal compartment and excluded it from HIV-1 particles. Ectopic expression of SERINC5 potently inhibited HIV-1, even in the presence of Nef. Rosa et al. (2015) proposed that SERINC5 might be exploited for antiretroviral therapy.

The HIV-1 Nef protein and the unrelated MLV glycoGag protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS.

Sperandio et al. (2015) found that TOE1 (613931) could inhibit HIV-1 replication. TOE1 was secreted by activated human CD8-positive T lymphocytes and could be cleaved by granzyme B (GZMB; 123910). When administered extracellularly, both full-length and cleaved TOE1 could spontaneously cross the plasma membrane, and they retained HIV-1 inhibitory activity. The antiviral and cell-penetrating functions of TOE1 were mapped to a 35-amino acid region containing the nuclear localization sequence. This region interacted directly with the HIV-1 transactivator response (TAR) element. Sperandio et al. (2015) proposed that TOE1 is a cellular mediator of HIV-1 inhibition.

Variation in Genes Involved in Viral Entry

Both Liu et al. (1996) and Samson et al. (1996) identified a molecular basis for HIV-1 resistance. In an HIV-1-infected patient with slow disease progression, Samson et al. (1996) identified a heterozygous 32-bp deletion in the CCR5 gene (601373.0001) that resulted in a frameshift and premature termination of translation of the transcript. Liu et al. (1996) identified the same homozygous 32-bp deletion with CCR5 in 2 individuals who, though multiply exposed to HIV-1 infection, remained uninfected. They showed that the severely truncated protein could not be detected at the surface of cells that normally express the protein. Through in vitro fusion assays, both Liu et al. (1996) and Samson et al. (1996) determined that the truncated receptor did not allow fusion of CD4+ cells with cells expressing env protein from either macrophage-tropic or dual-tropic viruses. Samson et al. (1996) found that coexpression of the deletion mutant with wildtype CCR5 reduced the fusion efficiency of 2 different viral envelope proteins in 3 independent experiments.

Dean et al. (1996) reported results of their CCR5 studies in 1,955 individuals included in 6 well-characterized AIDS cohort studies. They identified 17 individuals who were homozygous for the CCR5 32-bp deletion allele. Deletion homozygotes occurred exclusively among the 612 members of the HIV-1-exposed, antibody-negative group and not at all in 1,343 HIV-1 infected individuals. The frequency of the CCR5 deletion heterozygotes was significantly elevated in groups of individuals who had survived HIV-1 infection for more than 10 years. In some risk groups the frequency of CCR5 deletion heterozygotes was twice as frequent as in groups with rapid progressors to AIDS. Survival analysis clearly showed that the disease progression was slower in CCR5 deletion heterozygotes than in individuals homozygous for the normal CCR5 allele. Dean et al. (1996) postulated that the CCR5 32-bp deletion may act as 'a recessive restriction gene against HIV-1 infection' and may exert a dominant phenotype of delayed progression to AIDS among infected individuals. Dean et al. (1996) reported that in addition to the CCR5 32-bp deletion allele, they found unique single-strand conformation polymorphisms (SSCPs) in other patients, some of whom were long-term nonprogressors. They speculated that at least some of these alleles disrupt CCR5 function and inhibit the spread of HIV-1 or the progression to AIDS.

Martin et al. (1998) showed by genetic association analysis of 5 cohorts of people with AIDS that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. An estimated 10 to 17% of patients who developed AIDS within 3.5 years of HIV-1 infection did so because they were homozygous for CCR5P1/P1, and 7 to 13% of all people carry this susceptible genotype.

Smith et al. (1997) identified a val64-to-ile polymorphism (64I; 601267.0001) in the first transmembrane region of CCR2, at an allele frequency of 10 to 15% among Caucasians and African Americans. Studies of 2 cohorts of AIDS patients showed that the CCR2-64I allele exerted no influence on the incidence of HIV-1 infection, but that HIV-1 infected persons carrying the 64I allele progressed to AIDS 2 to 4 years later than persons homozygous for the more common allele. Smith et al. (1997) analyzed 2-locus genotypes and found that the 32-bp deletion at the CCR5 locus (CCR5-del32) and the 64I allele at the CCR2 locus are in strong, perhaps complete, linkage disequilibrium with each other. This means that CCR5-del32 invariably occurs on a chromosome with allele CCR2-64V, whereas CCR2-64I occurs on a chromosome that has the wildtype (undeleted) allele at the CCR5 locus. Thus, they could estimate the independent effects of the CCR2 and CCR5 polymorphisms. Rapid progression of less than 3 years from HIV-1 exposure to onset of AIDS symptoms in an estimated 38 to 45% of AIDS patients could be attributed to their wildtype status at one or the other of these loci, whereas the survival of 28 to 29% of long-term survivors, who avoided AIDS for 16 years or more, could be explained by a mutant genotype for CCR2 or CCR5.

RANTES (CCL5) is one of the natural ligands for CCR5 and potently suppresses in vitro replication of R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showing that peripheral blood mononuclear cells or CD4+ lymphocytes obtained from different individuals have wide variations in their ability to secrete RANTES prompted Liu et al. (1999) to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. They found 2 polymorphic positions, 1 of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This -28G mutation of the RANTES gene (187011.0001) occurred at an allele frequency of approximately 17% in the non-HIV-1-infected Japanese population and exerted no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the -28G mutation increases transcription of the RANTES gene. Taken together, these data suggested that the -28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.

An et al. (2002) tested the influence of 4 RANTES SNPs and their haplotypes on HIV-1 infection and AIDS progression in 5 AIDS cohorts. Three SNPs in the RANTES gene region on chromosome 17 (403A in the promoter, In1.1C in the first intron, and 3-prime 222C in the 3-prime UTR) were associated with increased frequency of HIV-1 infection. The In1.1C SNP allele is nested within an intronic regulatory sequence element (168923T/C; 187011.0002) that exhibits differential allele binding to nuclear proteins and a downregulation of gene transcription. The In1.1C allele, or haplotypes that include In1.1C, display a strong dominant association with rapid progression to AIDS among HIV-1-infected individuals in African American, European American, and combined cohorts. The principal RANTES SNP genetic influence on AIDS progression derives from the downregulating RANTES In1.1C allele, although linkage disequilibrium with adjoining RANTES SNPs, including a weaker upregulating RANTES promoter allele (-28G), can modify the observed epidemiologic patterns. The In1.1C-bearing genotypes accounted for 37% of the attributable risk for rapid progression among African Americans and may also be an important influence on AIDS progression in Africa. The diminished transcription of RANTES afforded by the In1.1C regulatory allele is consistent with increased HIV-1 spread in vivo, leading to accelerated progression to AIDS.

SDF1 (CXCL12) is the principal ligand for CXCR4, a coreceptor with CD4 for T-lymphocyte cell line-tropic HIV-1. Winkler et al. (1998) identified a common polymorphism, designated SDF1-3-prime-A (600835.0001), in an evolutionarily conserved segment of the 3-prime untranslated region of the SDF1 structural gene transcript. In homozygous state, SDF1-3-prime-A delayed the onset of AIDS, according to a genetic association analysis of 2,857 patients enrolled in 5 AIDS cohort studies. The recessive protective effect of the polymorphism was increasingly pronounced in individuals infected with HIV-1 for longer periods, was twice as strong as the dominant genetic restriction of AIDS conferred by CCR5 and CCR2 chemokine receptor variants, and was complementary with these mutations in delaying the onset of AIDS.

Gonzalez et al. (2005) examined the effect of CCL3L1 copy number, which varies due to segmental duplication on chromosome 17q, on susceptibility to HIV-1. Mean CCL3L1 copy number varied in different population groups, being generally highest in Africans, followed by East Asians, Amerindians, Central/South Asians, Middle Easterners, and Europeans. Cloning and characterization of the chimpanzee CCL3L1 gene led to the observation that this species has a substantially higher copy number than any human population. Individual susceptibility to HIV-1, however, was related not to the absolute copy number but to having a CCL3L1 copy number lower than the population-specific average. Susceptibility was even greater in individuals having disease-accelerating CCR5 genotypes, and Gonzalez et al. (2005) showed that CCR5 protein expression is, in part, influenced by CCL3L1. Gonzalez et al. (2005) concluded that CCL3L1 dose plays a central role in HIV/AIDS pathogenesis and suggested that the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.

CX3CR1 is an HIV coreceptor as well as a leukocyte chemotactic/adhesion receptor for fractalkine. Faure et al. (2000) identified 2 single nucleotide polymorphisms in the CX3CR1 gene in Caucasians and demonstrated that HIV-infected patients homozygous for I249/M280 (601470.0001) progressed to AIDS more rapidly than those with other haplotypes (relative risk = 2.13, P = 0.039). Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, Faure et al. (2000) concluded that CX3CR1-I249/M280 is a recessive genetic risk factor for HIV/AIDS.

Martin et al. (2004) found that European Americans at risk for parenteral HIV infection were more likely to carry the -336C SNP than the -336T SNP in the promoter of DCSIGN (604672.0001). This association was not observed in those at risk for mucosally acquired infection. Although the -336C SNP was common in African Americans, no significant association with risk of infection was observed in this group.

Colobran et al. (2005) identified a polymorphism in the CCL4L gene (603782), a G-to-A change at position +590 in the acceptor splice site of intron 2. They designated this allele L2 and the original allele L1. The frequency of the L2 allele was significantly higher in 175 Spanish HIV-positive patients (28.6%) compared with 220 healthy controls (16.6%).

By analysis of IL4R (147781) allele and genotype frequencies in individuals with different risk factors for HIV acquisition and different rates of progression to AIDS, Soriano et al. (2005) determined that the V50 allele of the ile50-to-val polymorphism (I50V; 147781.0002) predominated in HIV-positive long-term nonprogressors (LTNPs), whereas the I50 allele predominated in healthy controls, typical progressors, and those at risk for infection due to sexual exposure or treatment of hemophilia. Homozygosity for V50 was increased in LTNPs compared with other groups. Soriano et al. (2005) concluded that V50 homozygosity appears to be associated with slow progression to AIDS after HIV infection.

Vasilescu et al. (2007) identified a CXCR1 (IL8RA; 146929) haplotype (CXCR1-Ha; 146929.0001) carrying 2 SNPs that resulted in nonsynonymous amino acid changes: 92T-G (rs16858811), which caused a met31-to-arg change (M31R) in the N-terminal extracellular domain, and 1003C-T (rs1658808), which caused an arg335-to-cys change (R335C) in the C-terminal intracellular domain. Flow cytometric, RT-PCR, and Western blot analysis showed that expression of CXCR1-Ha in different cell lines led to reduced expression of CD4 and CXCR4 compared with cell lines transfected with the alternative haplotype. HIV-1 isolates preferentially using the CXCR4 receptor were less efficient in infecting cells expressing CXCR1-Ha than those expressing the alternative haplotype. Patients infected with HIV-1 who progressed rapidly to AIDS were significantly less likely to have CXCR1-Ha compared with patients who progressed slowly to AIDS. Vasilescu et al. (2007) concluded that the CXCR1-Ha allele protects against rapid progression to AIDS by modulating CD4 and CXCR4 expression.

Burt et al. (2008) examined a large cohort of HIV-positive European and African American subjects and found that those homozygous for the APOE4 allele (107741.0016) of APOE (107741) had an accelerated disease course and progression to death compared with those homozygous for the APOE3 allele (107741.0015). The increased risk was independent of CD4-positive T-cell count, delayed-type hypersensitivity reactivity, and CCL3L1-CCR5 type. APOE4 alleles showed a weak association with higher viral load. No association was observed with APOE4 homozygosity and HIV-associated dementia or with an increased risk of acquiring HIV infection. Expression of recombinant APOE4 or APOE3 in HeLa cells also expressing CD4 and CCR5 revealed that the presence of APOE4 enhanced HIV fusion/cell entry of both R5 (macrophage-tropic) and X4 (T lymphocyte-tropic) HIV strains in vitro. Burt et al. (2008) concluded that APOE4 is a determinant of AIDS pathogenesis.

He et al. (2008) showed that HIV-1 attached to RBCs via DARC and effected trans-infection of target cells. The -46T-C promoter SNP in DARC (110700.0002) is widely prevalent in populations of African descent, and -46CC genotype results in selective loss of DARC expression on RBCs. In the admixed African-American population, the DARC -46C allele was in Hardy-Weinberg equilibrium in HIV-negative subjects, but it was in disequilibrium in HIV-positive patients. Genotype analysis indicated that the prevalence of -46CC was greater in HIV-positive patients, and -46CC individuals had a 50% higher risk of acquiring HIV. Calculation of the population attributable fraction for excess HIV burden was estimated to be 11% for DARC -46CC in African settings. In contrast, DARC -46CC was associated with slower disease progression in terms of death or development of dementia. He et al. (2008) proposed that the interplay between DARC and chemokines may influence the amount of free versus DARC-bound virus available for eventual transfer from RBCs to target cells.

Kulkarni et al. (2009) found that ethnic leukopenia present in healthy African Americans was also present in the setting of HIV infection. The disease course among HIV+ African Americans with low WBC was slower than that of HIV+ European Americans with low WBC. DARC -46CC was present nearly exclusively in African Americans (69.1%) compared to European Americans (0.2%), and there was a trend toward a survival advantage for HIV+ African Americans with -46CC compared to HIV+ European Americans or to African Americans with DARC -46CT or -46TT. However, the survival advantage associated with -46CC was highly dependent on WBC counts, as this association was greatly magnified in subjects with low WBC and muted in those with high WBC. Overall, the observations indicated that ethnic leukopenia in HIV-infected African Americans may be associated with a more benign phenotype, despite HIV-induced immunodeficiency.

Variation in Genes Involved in Host Immune Response

Carrington et al. (1999) reported that the extended survival of 28 to 40% of HIV-1-infected Caucasian patients who avoided AIDS for 10 or more years could be attributed to their being fully heterozygous at HLA class I loci, to lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Gao et al. (2001) examined subtypes of HLA-B*35 in 5 cohorts and analyzed the relation of structural differences between subtypes to the risk of progression to AIDS. Two subtypes were identified according to peptide-binding specificity: the HLA-B*35-PY group, which consists primarily of HLA-B*3501 and binds epitopes with proline in position 2 and tyrosine in position 9; and the more broadly reactive HLA-B*35-Px group, which also binds epitopes with proline in position 2 but combines several different amino acids (not including tyrosine) in position 9. The influence of HLA-B*35 in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-Py alleles by only 1 amino acid residue. Gao et al. (2001) concluded that the previously observed association of HLA-Cw*04 with progression to AIDS was due to its linkage disequilibrium with HLA-B*35-Px alleles. The fact that the association with B*35-Px was observed in both blacks and whites supported the hypothesis that these HLA-B alleles exert an effect on the immune response to HIV-1 infection.

Gao et al. (2005) found that HLA-B alleles acted during distinct intervals after HIV infection. HLA-B35-Px and HLA-B57 were associated with rate of progression to 4 outcomes: (1) progression to CD4+ T cells less than 200 (CD4 less than 200), (2) CD4 less than 200 and/or an AIDS-defining illness, (3) an AIDS-defining illness, and (4) death. HLA-B27, on the other hand, was only associated with the last 3 outcomes. Protection mediated by HLA-B57 occurred early after infection, whereas HLA-B27-mediated protection instead delayed progression to an AIDS-defining illness after the decline in CD4 counts. HLA-B35-Px showed an early susceptibility effect associated with rapid progression from seroconversion to CD4 less than 200. Gao et al. (2005) proposed that the presence of the various HLA-B alleles may lead to different scenarios for viral escape from CTL pressure and virus subtypes with different fitnesses.

Martin et al. (2002) reported that the activating KIR allele KIR3DS1, in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in individuals infected with HIV-1 (604946.0001). In the absence of KIR3DS1, the HLA-B Bw4-80Ile allele was not associated with any of the AIDS outcomes measured. By contrast, in the absence of HLA-B Bw4-80Ile alleles, KIR3DS1 was significantly associated with more rapid progression to AIDS. These observations strongly suggested a model involving an epistatic interaction between the 2 loci. The strongest synergistic effect of these loci was on progression to depletion of CD4+ T cells, which suggested that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins soon after HIV-1 infection.

Jennes et al. (2006) genotyped HLA and KIR alleles in HIV-exposed seronegative female sex workers (FSWs), HIV-seropositive FSWs, and HIV-seronegative female blood donors from Abidjan, Cote d'Ivoire. HIV-exposed seronegative FSWs had an increased frequency of inhibitory KIR genes in the absence of their cognate HLA genes: KIR2DL2 (604937)/KIR2DL3 (604938) heterozygosity in the absence of HLA-C1 (142840), and KIR3DL1 (604936) homozygosity in the absence of HLA-Bw4. In contrast, HIV-seropositive FSWs were characterized by corresponding KIR/HLA pairings: KIR2DL3 homozygosity with HLA-C1 and a trend toward KIR3DL1/HLA-Bw4 homozygosity. Jennes et al. (2006) proposed that a lack of inhibitory KIRs may lower the threshold for NK-cell activation and that NK cells and KIR/HLA interactions may be important in antiviral immunity.

Using short tandem repeat polymorphism (i.e., microsatellite) analysis, Shin et al. (2000) identified significant genotype associations for HIV-1 infection and progression to AIDS with markers adjacent to and tracking common single nucleotide polymorphic variants in the promoter region of IL10, a powerful inhibitor of HIV-1 replication. Individuals carrying the 5-prime -592A promoter allele (124092.0001) were at increased risk for HIV-1 infection, and once infected they progressed to AIDS more rapidly than homozygotes for the alternative -592C/C genotype. Approximately 25 to 30% of long-term nonprogressors (i.e., those who avoid clinical AIDS for 10 or more years after HIV-1 infection) carried the -592C/C promoter genotype. Additional protection or susceptibility was associated with the relevant CCR5 and CCR2 alleles. EMSA analysis indicated that the -592A allele, but not the 592C/C allele, retains a binding site for ETS (see 164720) family DNA-binding proteins, whereas both alleles interact with SP1 (189906). Shin et al. (2000) noted studies (e.g., Rosenwasser and Borish (1997)) that showed that the -592A allele is associated with diminished IL10 production. They suggested that progression to AIDS might be retarded by immunotherapeutic strategies mimicking or enhancing the natural inhibitory role of IL10.

An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173G-T (147570.0003), and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF (191160). An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans, and proposed that the increased IFNG production may cause CD4 depletion by apoptosis.

Modi et al. (2003) genotyped 9 SNPs spanning the CCL2-CCL7-CCL11 gene cluster on chromosome 17q in more than 3,000 DNA samples from 5 AIDS cohorts. Extensive linkage disequilibrium was observed, particularly for 3 SNPs, -2136T in the CCL2 promoter (158105.0001), 767G in intron 1 of the CCL2 gene (158105.0002), and -1385A in the CCL11 promoter (601156.0001), that formed a 31-kb haplotype (H7) containing the 3 genes. The frequencies of these 3 SNPs and the H7 haplotype were significantly elevated in uninfected individuals repeatedly exposed to HIV-1 through high-risk sexual behavior or contaminated blood products. Since these chemokines do not bind the primary HIV-1 coreceptors CCR5 or CXCR4, Modi et al. (2003) proposed that the influence of the H7 haplotype on HIV-1 transmission may result from activation of the immune system rather than receptor blockage.

Using a whole-genome association strategy, Fellay et al. (2007) identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these lies within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B*5701 (142830.0003), whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated 2 genes, 1 of which encodes an RNA polymerase I subunit, ZNRD1 (607525). Fellay et al. (2007) noted that ZNRD1 expression significantly associated with the identified SNPs; 2 of them (rs3869068 and rs9261174) are located in a putative regulatory 5-prime region, 25 and 32 kb away from the gene, respectively.

Using genotyping for an HLA-C promoter variant, -35C-T (142840.0002), and flow cytometric analysis in 1,698 HIV-infected patients of European ancestry, Thomas et al. (2009) found that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high surface expression better control viremia and progress more slowly to AIDS. Thomas et al. (2009) concluded that high HLA-C expression results in more effective control of HIV-1, possibly through better antigen presentation to cytotoxic T lymphocytes.

Kosmrlj et al. (2010) noted that although most people infected with HIV ultimately progress to AIDS, rare individuals (elite controllers) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. The HLA-B57 class I allele is enriched in elite controllers (Migueles et al., 2000). In silico analysis showed that HLA-B57 binds to fewer self peptides than does HLA-B7, an allele associated with HIV disease progression. Binding to fewer self peptides in the thymus means that HLA-B57-restricted CD8+ T cells should be more cross-reactive to point mutants of targeted viral peptides. Analysis of 2 large HLA-typed cohorts indicated that elite controllers are more likely to be HLA-B27 or, particularly, HLA-B57 positive, whereas progressors are more likely to be HLA-B7 or HLA-B35 positive. Kosmrlj et al. (2010) noted that HLA-B57 is also protective against HCV (609532), another chronic highly mutable viral pathogen, whereas HLA-B8, which binds to a greater diversity of self peptides, is associated with faster HCV and HIV disease progression. Kosmrlj et al. (2010) concluded that HLA self-peptide analysis provides a conceptual framework, unifying diverse empirical observations, and has implications for vaccination strategies.

Human ERAP1 (606832) and ERAP2 (609497) encode 2 endoplasmic reticulum aminopeptidases. These enzymes trim peptides prior to loading onto major histocompatibility complex class I molecules and shape the antigenic repertoire presented to CD8+ T cells. Cagliani et al. (2010) resequenced 2 genic regions in ERAP1 and ERAP2 in 3 HapMap populations. They observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and reduced population genetic differentiation. The genealogy of ERAP1 and ERAP2 haplotypes was split into 2 major branches with deep coalescence times. Analysis of the lys528-to-arg (rs30187 in ERAP1) and asn392-to-lys (rs2549782 in ERAP2) variants in an Italian population of HIV-1-exposed seronegative (ESN) individuals and a larger number of Italian controls indicated that rs2549782 significantly deviated from Hardy-Weinberg equilibrium in ESN individuals but not in controls. The genotype distribution of rs2549782 was significantly different in the 2 cohorts (p = 0.004), mainly as the result of an overrepresentation of lys/lys genotypes in the ESN sample (p value for a recessive model: 0.00097). The authors concluded that genetic diversity in ERAP1 and ERAP2 has been maintained by balancing selection and that variants in ERAP2 may confer resistance to HIV-1 infection via the presentation of a distinctive peptide repertoire to CD8+ T cells.

Sironi et al. (2012) genotyped a TLR3 (603029) SNP, rs3775291, that confers a leu412-to-phe (L412F; 603029.0002) change in 102 Spanish HIV-1-exposed seronegative intravenous drug users and 131 age- and sex-matched healthy controls. They found that the frequency of individuals carrying at least 1 F412 allele was significantly higher in HIV-1-exposed seronegative individuals than in controls (odds ratio for a dominant model = 1.87; p = 0.023). They replicated this finding in 83 seronegative Italians who had been sexually exposed to HIV-1 and 238 healthy matched controls (odds ratio = 1.79; p = 0.029). The combined results for the Spanish and Italian samples suggested that the F412 allele protects from HIV-1 with a dominant effect (p = 0.003). In vitro analysis in peripheral blood mononuclear cells (PBMCs) showed significantly reduced HIV-1 replication in PBMCs carrying F412 compared with those homozygous for L412 (p = 0.025), and this reduced replication was associated with higher expression of immune activation markers, such as IL6 (147620), CCL3 (182283), and CD69 (107273). Stimulation of PBMCs with a TLR3 agonist showed that the presence of F412 resulted in significantly increased expression of CD69 and higher production of proinflammatory cytokines. Sironi et al. (2012) concluded that the F412 TLR3 allele confers immunologically mediated protection from HIV-1.

Ramsuran et al. (2018) analyzed 9,763 HIV-infected individuals from 21 cohorts and found that higher HLA-A (142800) levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A-derived signal peptide