HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels

Abstract

Studies in humans and in experimental models of HIV-1 infection indicate an important role for monocyte chemoattractant protein-1 (MCP-1; also known as CC chemokine ligand 2), a potent chemoattractant and activator of mononuclear phagocytes (MP) in the pathogenesis of HIV-associated dementia (HAD). We determined the influence of genetic variation in MCP-1 on HIV-1 pathogenesis in large cohorts of HIV-1-infected adults and children. In adults, homozygosity for the MCP-1 -2578G allele was associated with a 50% reduction in the risk of acquiring HIV-1. However, once HIV-1 infection was established, this same MCP-1 genotype was associated with accelerated disease progression and a 4.5-fold increased risk of HAD. We examined the molecular and cellular basis for these genotype-phenotype associations and found that the mutant MCP-1 -2578G allele conferred greater transcriptional activity via differential DNA-protein interactions, enhanced protein production in vitro, increased serum MCP-1 levels, as well as MP infiltration into tissues. Thus, MCP-1 expression had a two-edged role in HIV-1 infection: it afforded partial protection from viral infection, but during infection, its proinflammatory properties and ability to up-regulate HIV-1 replication collectively may contribute to accelerated disease progression and increased risk of dementia. Our findings suggest that MCP-1 antagonists may be useful in HIV-1 infection, especially for HAD, and that HIV+ individuals possessing the MCP-1 -2578G allele may benefit from early initiation of antiretroviral drugs that effectively cross the blood-brain barrier. In a broader context, the MCP-1 -2578G allele may serve as a genetic determinant of outcome of other disease states in which MP-mediated tissue injury is central to disease pathogenesis.

Figure 1

MCP-1 SNPs, haplotypes and haplotype pairs. (a) Schematic illustration of the genomic organization and SNPs (*) in human MCP-1. Open boxes represent the three exons. The sequence at the position corresponding to the human SNPs in chimpanzees (AA is the ancestral state) is also shown. The designation of each haplotype is based on the 5′→3′ arrangement of the SNPs. Thus, for example, the haplotype that contains MCP-1 –2578G and MCP-1 –2136A is designated as the MCP-1 GA haplotype. (b) Frequencies of the MCP-1 haplotypes in control blood donors (–) and infected (+) European- (EA), African- (AA), and Hispanic-Americans (HA) as well as Argentinean (Arg) children exposed perinatally to HIV-1 (+, HIV+; −, HIV-). (c) The frequency (%) of the MCP-1 haplotype pairs in the different study groups is shown (Upper) [control blood donors or HIV-1 (–) and HIV-1 infected (+)]. The total number of individuals with a given haplotype pair is shown (Lower). The color codes shown adjacent to each haplotype pair listed (Lower) correspond to the colored histograms shown (Upper). The codes shown for the HIV status in b are also applicable for the data shown in c. AA/AA is the ancestral haplotype pair.

Figure 2

Disease-modifying effects of MCP-1 alleles in a cohort of infected European- and African-American adults or in a cohort of Argentinean children with perinatally acquired HIV-1. (a and b) KM curves of the development of AIDS or death in the entire European-American portion of the adult cohort that are wild type (blue), heterozygous (black), or homozygous (red) for the MCP-1 –2578G allele. P and relative hazard (RH) (95% CI) indicate the significance value by log-rank test and the relative hazard with respect to the reference group (−2578A/A), respectively. (c) KM curves of the development of AIDS in infected Argentinean children that are wild type (blue), heterozygous (black), or homozygous (red) for the –2578G allele. P and RH (95% CI) indicate the significance value by log-rank test and the RH with respect to the reference group (−2578A/A), respectively. (d and e) KM curves of the development of AIDS or death in the entire European-American portion of the adult cohort that possess (blue) or lack (red) the ancestral MCP-1 AA haplotype. The reference group consists of individuals who possess the ancestral AA haplotype. (f and g) KM curves comparing the clinical course in European-Americans with the following haplotype pairs: AA/AA, the reference group (blue) and GA/GA (red). Compared with the reference group, there was no difference in progression to AIDS or death for individuals who had the AA/GA, GA/AT, AA/AT or AT/AT haplotype pairs. For illustrative purposes, we therefore combined the data for AA/GA and AT/GA (black), and AA/AT and AT/AT (green). (h and i) KM curves comparing the clinical course of infected African-Americans who possess the following haplotype pairs: AA/AA, the reference group (blue); AA/AT (green); and AA/GA (red). The reference groups for the survival analyses in f–i consist of individuals of the indicated population that are homozygous for MCP-1 haplotype AA (blue). Note that the red- and green-colored KM curves in f, g and h, i are for individuals with different haplotype pairs. (j) Risk of developing HAD in individuals who possess the MCP-1 GA/GA haplotype pair compared with those who have the ancestral haplotype pair AA/AA. (k) Risk of developing HAD, MAC infection, PCP, cytomegalovirus (CMV) infection, or Kaposi's sarcoma (KS) in individuals who possess the GA/GA haplotype pair. Closed circles and crosses denote the OR and boundaries of the 95% CI limits, respectively. NS, not significant. (l) The KM curves of the development of HAD, MAC, and PCP in European-Americans that possess the following haplotype pairs: AA/AA, the reference group (blue); GA/GA (red); and combined analyses for the other four MCP-1 haplotype pairs (green). The rate per 1,000 person-years of HAD was 9.0; of MAC infection, 15.4; of PCP, 32.8; of CMV infection, 16.7; and of Kaposi's sarcoma, 12.4.

Figure 3

MCP-1 genotype and renal leukocyte infiltration in SLE. (a–d) Renal biopsy tissue from patients with class IV SLE nephritis was stained for macrophages (CD68+ cells) and T lymphocytes (CD3+ cells) by immunoperoxidase labeling (see Methods). Representative sections (digital photomicrographs; ×40 objective) demonstrate macrophages in glomeruli and the tubulointerstitial space, whereas lymphocytes are mainly found in the tubulointerstitium. Leukocyte infiltration is more intense in kidneys from individuals who have a MCP-1 −2578G allele (c and d) compared with those who lack this allele (a and b).