Mitochondria are critical for energy production and control of apoptosis in the cell. Through oxidative phosphorylation, mitochondria convert calories to ATP, release heat to maintain body temperature, and generate reactive oxygen species (ROS). Mitochondrial energetics is accomplished by cooperation of 37 genes encoded by the mitochondrial genome with an estimated 1500 nuclear genes . Although mitochondrial DNA (mtDNA) encodes only 13 proteins directly involved in ATP production, their roles are central to mitochondrial function. MtDNA variation in these genes from indigenous populations correlates with latitude and climate, suggesting that these differences are adaptive [2–4]. Genotypes differ in coupling efficiency such that there is a trade-off between highly efficient ATP production and increased heat release in colder temperatures. Because mitochondrial gene function is critical, mtDNA variation has also been directly associated with propensity for metabolic disease, neurodegenerative disease, cancer, and microbial infections [1,5–9].
Interactions between viral infection and mitochondrial energetics suggest that mtDNA variation could also play a role in viral disease progression. Mitochondria are the key regulators of apoptosis, an important host immune response to viral infection . Many viruses have evolved strategies to prevent viral suppression through apoptosis or even exploit mitochondrial pathways to destroy cells involved in the host immune response. HIV-1 uses both antiapoptotic and apoptotic strategies during infection and AIDS progression. Early in infection, HIV-1-encoded viral protein R (Vpr) impedes apoptosis to prevent eradication of virus . As HIV-1 infection progresses, higher concentrations of Vpr [12,13] and other viral-encoded proteins, including Tat  and the gp120-gp41 envelope complex [15,16], elicit apoptosis of cells in the immune system. Loss of CD4+ T cells, in particular, correlates well to stage of HIV-1 disease . Compared with HIV-1+ long-term non-progressors, patients with AIDS have a higher frequency of peripheral blood lymphocytes exhibiting mitochondrial membrane permeabilization (MMP), the point of no-return in apoptosis . AIDS progression is also associated with mtDNA depletion , disruption of energy production through oxidative phosphorylation, increased ROS production , antioxidant enzyme deficiency , and increased oxidative damage that accelerates AIDS progression . In addition, mitochondrial toxicity to drugs used in HAART for HIV-1 has been linked to severe side effects including lipodystrophy, peripheral neuropathy, hepatic steatosis, myopathy, cardiomyopathy, pancreatitis, bone marrow suppression, and lactic acidosis [23–27]. Nearly all of these side effects resemble clinical symptoms seen in inherited mitochondrial diseases , and mtDNA haplogroup T has been associated with peripheral neuropathy .
Because AIDS progression is associated with changes in mitochondrial oxidative phosphorylation, ROS production, and apoptosis, which can be influenced by functional mtDNA variants, herein, we survey the mtDNA haplotypes of 1833 HIV-1 infected European American patients to determine whether host mtDNA haplogroup correlates with AIDS progression rate. We examined mtDNA haplotypes in the context of our recent global mutational phylogeny  and describe five associations with AIDS progression that can be interpreted in light of the physiological influences known for the mitochondrial genotypes.
The study group consisted of 1833 HIV-1 infected European American patients including 633 seroconvertors (infected after study enrollment) and 1200 seropositives (infected prior to enrollment) from five longitudinal cohorts: the Multicenter AIDS Cohort Study (MACS), the San Francisco City Clinic Study (SFCC), Hemophilia Growth and Development Study (HGDS) , the Multicenter Hemophilia Cohort Study (MHCS) , and the AIDS Linked to Intravenous Experiences (ALIVE) cohort. Informed consent was obtained from all patients. Ninety-seven percent of patients were men. Cohorts can be divided into mode of infection (intravenous versus sexual transmission). There are two cohorts of people with hemophilia who would have likely contacted AIDS through exposure to contaminated blood products: the MHCS is a multicenter longitudinal cohort study enrolling patients from 17 American or European treatment centers beginning in September 1982 , and the HGDS is a US-based multicenter cohort of participants from 14 US treatment centers who became infected between 1982 and 1983 . Sexual transmission is the most likely mode of infection for the MACS and SFCC. MACS is a US-based ongoing prospective study of HIV-1 infection in adult (ages 18–70) men who have sex with men (MSM) in Baltimore, Chicago, Pittsburgh, and Los Angeles enrolled between 1984 and 1991 . The SFCC is a prospective study of the natural history of HIV and AIDS conducted in adult MSM and bisexual men enrolled in 1978–1980 for studies of hepatitis B (HBV), followed by a HBV vaccine trial in 1980–1983. Recruitment into the SFCC for follow-up studies of HIV and AIDS began in 1983–1992 . SFCC contains more long-term survivors than the other cohorts . ALIVE is a community-based cohort of injecting drug users in Baltimore, Maryland established in 1988 and followed until 2000 . ALIVE patients were included in the analyses of all European Americans but were not analyzed separately due to limited sample size. Clinical data used here were collected from 1978 to 1996 (or censored), before widespread use of HAART.
DNA was extracted from immortal lymphoblastoid B cell lines for each patient. Initially six haplotype-tagging single-nucleotide polymorphisms (SNP) were used to put individuals into major mitochondrial N, M, and L groups. Individuals within the Western European (N) subset were further parsed into haplogroups using the Mitochondrial Haplogrouping using Candidate Functional Variants, a multistep haplotyping strategy that interrogates key European mtDNA polymorphisms located at internal branch points of the global human mitochondrial phylogenetic tree. On the basis of the hierarchical nature of the tree, we devised a strategy for identifying haplotypes by subdividing the samples using highly conserved polymorphic sites located at key haplogroup branch points. In this way, samples were defined to a high degree using the minimal number of SNP. In total, the study used 32 sequential SNP [Supplemental Online Material (SOM): http://home.ncifcrf.gov/ccr/lgd/publications.asp?PY=2008] to define haplogroups. Genotyping was performed using TaqMan assays-by-design (SM). Thermocycling conditions were an initial 95°C hold for 3 min, followed by 30 cycles of 92°C for 15 s, and 56°–62°C annealing for 1 min depending on primer specificity.
Because mtDNA is inherited maternally as a single haplotype, a ‘dominant’ genetic model was tested. Analyses were performed in each successive level of the phylogenetic tree of N haplogroups. All analyses were performed with SAS version 8.1 (SAS Institute, Inc., Cary, North Carolina, USA). SAS analyses were visualized with the AIDS restriction gene (ARG) ARRAY and ARG Highway software created at National Cancer Institute and ABCC, Frederick, Maryland, USA . Statistical significance in these figures was declared at the P value of 0.05 or less.
Four separate end points reflecting advancing AIDS morbidity were considered: CD4 cell count less than 200 cells/μl; AIDS-1993, the Centers for Disease Control and Prevention 1993 definition  (HIV-1 infected and AIDS-defining illness, decline of CD4 T lymphocytes to less than 200 cells/μl or death); the more stringent AIDS-1987 definition  (HIV-1 infection plus AIDS-defining illness) or death; and death during follow-up from AIDS of an HIV-1-infected patient.
Tests for association were performed using both categorical case–control and Cox proportional hazards models . For survivorship models, only known seroconvertors (n = 633) were used for analysis. Therefore, we also performed categorical analyses using time categories (<8 years and ≥8 years for dichotomous, and <3.5, 3.5 to ≤7, 7 to ≤10, 10 to ≤13, 13 to ≤16, and >16 years for multipoint models)  in order to capture the information available from the additional 1200 seropositives with estimated seroconversion dates in our study. A Fisher's exact test was used for dichotomous categorical analyses, and a Mantel–Hanzel χ2 test (degrees of freedom = 1) was used for multipoint models. Cox proportional hazard models were stratified by age at seroconversion (0–20, 20–40, and >40 years). Survival analyses were performed on all European American seroconvertors in the study, on subgroups separated by mode of transmission, and on individual cohorts in the case of the MACS and SFCC, which had larger samples of seroconvertors than the other cohorts. Significance was based on the log-likelihood χ2 test (P < 0.05).
For seroconvertors, we used data for 304 SNP from previous studies [35,42–44] (for which the missing genotype information was less than 5%) and applied the EIGENSOFT  program to examine and adjust for potential population stratification. Analysis of variation (ANOVA) F-statistic was performed on the recovered eigenvectors given the mitochondrial haplogroups.
Despite that we found no significant geographic substructure among the mitochondrial haplogroups based on the nuclear markers, we did adjust for known European ARGs including CCR5-Δ32, CCR2-64I, CCR5 P1 haplotype, HLA class I B27, B57, B35-Px alleles, and HLA class I homozygosity [46,47], some of which are known to have geographic substructure.
Our study included 1833 European Americans within the N haplogroup that is ancestral to almost all European and many Eurasian haplogroups . The N subgroup frequencies (‘f’ in Fig. 1) in our study were consistent with an independent population dataset (D.C.W., unpublished observation). Genetic association tests were performed on major haplogroups and then on haplotypes from successively more definitive phylogenetic nodes (Fig. 1a). Minor haplogroups with frequencies less than 0.01 were collapsed into more inclusive haplogroups to minimize type I errors. Statistical tests were non-independent for two reasons: the phylogenetic overlap of haplogroups and subgroup haplotypes; and the nonindependence of varying AIDS endpoint association tests. As non-independence precludes Bonferoni corrections for multiple tests, we focused on signals that were repeated within successive nested haplogroups; replicated in cohorts tested separately in survivorship analyses; and/or had strong P values in related hypotheses. We are also aware that the European American combined and MSM combined analyses had more power due to a larger sample size. This is important given the relative rarity of some of the haplogroups . Figure 1 presents a visual heat plot display of P values for genetic association for each of the 34 mtDNA genotypes. On the basis of ARG ARRAY visualization routine , different colors represent different levels of statistical significance. MtDNA haplotypes related by a phylogenetic tree can be inspected individually or as a group for each AIDS progression test. Figure 1b presents the same ARG ARRAY display for candidate SNP variants included within the mtDNA haplotypes that showed association signals in Fig. 1a. The significant tests, P values, relative hazard (RH), and confidence interval (CI) values are tabulated in Tables 1 and 2 (unabridged test results are provided in SOM: http://home.ncifcrf.gov/ccr/lgd/publications.asp?PY=2008). The association tests revealed five mtDNA haplogroups that showed consistent, significant associations: IWX, U5a, Uk, J, and H3 (Fig. 1; Tables 1 and 2). Each haplogroup will be described separately.
The J haplogroup was associated with accelerated progression to AIDS'87 (RH = 1.55, 95% CI = 1.08–2.23, P = 0.024) and AIDS-related death (RH = 1.53, 95% CI = 1.03–2.26, P = 0.043) in all European Americans. This association appears to be primarily driven by the cohorts who were infected through sexual transmission (RH = 1.84, 95% CI = 1.22–2.76, P = 0.006) (Figs. 1a and 2a, Table 1); however, the signal is observed in AIDS'87 and not in AIDS'93. Perhaps the J haplogroup specifically increases the risk of Kaposi's sarcoma, an AIDS-defining condition that occurred at high rates in MSM cohorts but that was seldom seen in injecting drug use and hemophilia cohorts. Additional research will be needed to examine this hypothesis. When we consider the MSM cohorts individually, there is a significant acceleration of AIDS'87 with J haplotypes in the MACS cohort (RH = 1.69, 95% CI = 1.08–2.66, P = 0.03) and a non-significant trend for acceleration in the SFCC (RH = 2.74, 95% CI = 0.97–7.70, P = 0.08). Within haplogroup J, both subhaplogroups J1and J2 are associated with accelerated disease progression. J1 is associated with accelerated AIDS'87 in European Americans (RH = 1.57, 95% CI = 1.03–2.38, P = 0.046) and in MSM cohorts (RH = 1.80, 95% CI = 1.12–2.87, P = 0.023). The J1 association signal for accelerated AIDS progression is driven largely by the J1c-14798* haplotype (f = 0.057), which is consistently highly significant in all patients, MSM, and individual MSM cohorts (MACS and SFCC; Fig. 1a; Table 1). J1c was significant for AIDS'87 (all RH = 1.67, CI = 1.07–2.61, P = 0.034; MSM RH = 1.94, 95% CI = 1.18–3.17, P = 0.016; MACS RH = 2.25, 95% CI = 1.27–3.98, P = 0.012), AIDS'93 (MSM RH = 1.64, 95% CI = 1.05–2.55, P = 0.041; MACS RH = 1.82, 95% CI = 1.08–3.09, P = 0.038), and death (all RH = 1.72, 95% CI = 1.07–2.78, P = 0.038). J2 shows an association with accelerated AIDS progress in the SFCC (CD4 cell count < 200 cells/μl: RH = 23.13, 95% CI = 2.33–229.65, P = 0.044; AIDS'87: RH = 63.69, 95% CI = 3.61–1124.28, P = 0.019; AIDS'93: RH = 44.26, 95% CI = 3.71–528.15, P = 0.024). As this cohort is biased towards long-term survivors , this signal may represent a moderate, late-term effect.
The U5a haplogroup is associated with accelerated AIDS progression to CD4 cell count less than 200 cells/μl in European Americans (RH = 1.78, 95% CI = 1.11–2.85, P = 0.028) and in MSM pooled cohorts (RH = 2.06, 95% CI = 1.17–3.63, P = 0.024). The signal is largely driven by the U5a1-15218 haplotype, which comprises 79% of the U5a haplotype (Fig. 1a; Table 1).
The Uk haplotype was associated with a decrease in the rate of AIDS progression to CD4 cells less than 200 cells/μl in both dichotomous and multipoint categorical models (OR = 0.47, 95% CI = 0.24–0.85, P = 0.008; common OR = 0.60, 95% CI = 0.37–0.97, P = 0.038, respectively) as shown in Table 2 and Fig. 3. Uk was also protective against AIDS'93 (Fig. 3c,d) (OR = 0.50, 95% CI = 0.27–0.87, P = 0.012; common OR = 0.61, 95% CI = 0.40–0.95, P = 0.022, dichotomous and multipoint models, respectively). In survivorship analyses (Fig. 1a, Table 1), only one signal was observed indicating Uk is protective against AIDS'87 in the MSM cohorts (relative hazard = 0.53, 95% CI = 0.29–1.00, P = 0.031).
A strong association signal suggests H3 was protective for hemophiliacs against progression to AIDS'93 (relative hazard = 0.21, 95% CI = 0.06–0.72, P = 0.003), AIDS'87 (relative hazard = 0.12, 95% CI = 0.02–0.94, P = 0.006), and death (relative hazard = undefined, P = 0.0004) (Fig. 1a, Table 1). However, this result is based on few individuals as only seven of the hemophiliacs analyzed in the survival model are in haplogroup H3, and, of those, one patient developed AIDS and no patients died. Protection, albeit relatively weak and inconsistent, was also observed in H4, H5, and H6 (Fig. 1a; Table 1).
IWX haplogroup was associated with delayed progression to CD4 cell count less than 200 cells/μl in MSM cohorts, driven largely by the MACS cohort (relative hazard = 0.56, 95% CI = 0.33–0.96, P = 0.022; relative hazard = 0.52, 95% CI = 0.29–0.94, P = 0.017); however, we did not see an association when we look at all European Americans combined. Within the IWX group, The W (W8994) haplotype showed the strongest protective association among MSM cohorts pooled or individually (Fig. 1a; Table 1).
Haplogroups U and J contain a number of functional variants that we analyzed separately (Fig. 1b). Strong disease accelerating associations consistent with parent haplotypes were observed for SNP 3010 G > A (included in J1 and H1 haplotypes) and SNP 13708G > A (found at the root of the J haplogroup). The 13708G > A SNP is a amino acid-altering variant in the ND5 protein coding gene. As both associated SNP variants, 3010G > A and 13708G > A, are carried together on the J1 haplogroups, it was not possible to resolve their independent contributions to the J1 association with rapid AIDS progression among MSM. However, the 3010G > A association may explain the accelerating association seen in H1, which is counter to the protective associations observed for H3 and other H subhaplogroups. The Uk haplotype protecting against AIDS progression was recapitulated by non-synonymous CYTB-14798T > C SNP. SNP 14798T > C is present on J1 and Uk haplotypes, but the protective influence was only apparent in Uk.
We determined the mitochondrial haplogroups of 1833 HIV-infected patients from five AIDS cohort studies in the United States and found certain haplogroups associated with progression to AIDS and death. For these analyses, we used a nested phylogenetic approach that allowed us to look for consistent signals between related clades at different levels of the mitochondrial tree and to pinpoint associations within specific haplogroups. The strongest signals for AIDS survival indicate haplogroups U5a and J are associated with accelerated AIDS progression, whereas haplogroups IWX and H3 are associated with a delay in AIDS onset (Figs 1 and 2; Table 1). In categorical analyses, Uk was found to lower AIDS risk (Fig. 3).
There are at least two potential explanations consistent with the results. First, because of the strong phylo-geographic structure of mitochondrial haplogroups, it is possible that the associations observed in our study are correlated with background nuclear genetic effects that are distinctive between geographically separated populations. However, population stratification analysis using 304 autosomal markers did not find significant difference between the major haplogroups, and we adjusted for known ARGs as an additional control against population substructure. However, replicating these haplotype associations in additional cohorts from different ethnic backgrounds would be informative. Second, an interesting trend was observed that uncoupled haplogroups with lower ATP and ROS production (U5 and J) are associated with accelerated disease, whereas more tightly coupled groups (H3 and H4, H5, and H6) are associated with protection, suggesting mitochondrial functional variation plays a role in AIDS progression. Combined data on longevity [50–52], neurodegenerative disease susceptibility [5,6,52,53], sperm motility [54,55], sprint performance , and climate adaptation [1,2] suggest functional mtDNA variation in different haplogroups influences ATP production efficiency and correlated ROS and heat generation. Less efficient ATP production in partially uncoupled mitochondria (haplogroups J and U5) would accelerate AIDS because it would exacerbate the energetic effects of the mtDNA depletion , disruption of oxidative phosphorylation, antioxidant enzyme deficiency , apoptosis [12,13,15], and increased oxidative damage observed during AIDS progression [22,57]. In contrast, in tightly coupled haplogroups (H3, H4, H5, H6), increased ATP production would allow HIV-infected patients to remain healthy for longer, and increased ROS production may enhance innate immunity and thus retard AIDS progression. Perhaps relevant is the report that haplogroup H has also been found to increase the survival rate of individuals with sepsis . It may also be important that the H signal was observed only in the transfusion patients and not in MSM groups, even though the MSM sample is much larger, and mitochondria genetic studies with small samples size and rare haplogroups have been found to be less reliable . Haplogroup Uk lowers AIDS risk in categorical analyses (Fig. 1a). The most common subhaplogroup of Uk, Uk1, harbors functional variants ND3 A10398G (T114A) and cytb T14798C (F18L), which it shares with J1c, and variants tRNALeu(CUN) A12308G and 16S rRNA A1811G which it shares with U4. HIV-1 relies on mitochondrial ATP production for replication and productive infection, yet inhibits mitochondrial ATP production . One possibility is that, the large number of uncoupling SNP in Uk causes ATP production to fall below the threshold level needed for productive viral replication. Further, as AIDS viral transcription is driven by NFkappaB , and NFkappaB is activated by ROS , the low ROS production of Uk would be protective. The IWX association with slow progression is intriguing but cannot be interpreted in the context of uncoupling/AIDS acceleration as coupling status of IWX is unknown.
Further functional studies and replication in other cohorts are needed for a better understanding of whether and how functional differences between haplogroups influence AIDS progression. Nonetheless, the associations here observed, interpreted in the limited functional inferences about mtDNA phylogeography and function, offer important genetic insight in the complex interaction of HIV and host physiology in AIDS pathogenesis.
We thank the all the participants in the AIDS cohorts, Susan Buchbinder for clinical data from the San Francisco City Cohort, Michael Malasky and Mary McNally of the LGD-CORE Genotyping Facility, Bailey Kessing and Shawn Palmer for technical assistance, and George Nelson and Randall Johnson for statistical advice.
Contribution: All authors contributed to critical revision of the article. S.L.H. haplogrouped patients, designed statistical tests, created all visuals, and wrote the paper draft. S.L.H. and J.L. organized clinical data and performed analyses. H.B.H. developed genotyping assays. E.S. performed the analysis of geographic structure. D.C.W., E.R.-P., and J.C.P. designed the SNP algorithm to define haplogroups. Contributions to study conception and design, and analysis and interpretation of data were made by D.C.W. and S.J.O., and L.K., J.J.G., D.V., and S.D. were responsible for clinical and epidemiological data.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
Sources of support: This project has been funded whole or in part with federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under contract N01-CO-12400, the Intramural Research of the NCI, the Center for Cancer Research and Division of Cancer Epidemiology and Genetics, Spanish Fondo de Investigacion Sanitaria grant # FIS-PI05-0647, NIH postdoctoral fellowship AG25638 and NIH R01 AG24373 and DK73691. The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the NCI. The MHCS is supported by NCI contract N02-CP-55504 with RTI International. The HGDS is funded by the NIH, National Institute of Child Health and Human Development, 1 R01 HD41224. NCI contracts include UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041.
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