Mitochondrial Genomics and CD4 T-Cell Count Recovery After Antiretroviral Therapy Initiation in AIDS Clinical Trials Group Study 384

Grady, Benjamin J.; Samuels, David C.; Robbins, Gregory K.; Selph, Doug; Canter, Jeffrey A.; Pollard, Richard B.; Haas, David W.; Shafer, Robert W.; Kalams, Spyros A.; Murdock, Deborah G.; Ritchie, Marylyn D.; Hulgan, Todd

doi:10.1097/qai.0b013e31822c688b

Cited by 18 publications

(24 citation statements)

References 34 publications

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“…We have also shown that except for the marginal and sole association of R0 with increased set-point VL, none of the other mtDNA lineages affected this outcome. Most importantly, the present data are consistent with those of the AIDS Clinical Trials Group (ACTG) study, which reported a decreased likelihood of CD4 + T-cell count recovery (≥100 cells per cubic millimiter CD4 + T-cell count increase) at week 48 of antiretroviral therapy (ART) among carriers of L2 [29]. …”

Section: Discussionsupporting

confidence: 89%

Mitochondrial DNA variation and virologic and immunological HIV outcomes in African Americans

Aissani¹,

Shrestha²,

Wiener³

et al. 2014

Aids

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Objective To evaluate the impact of mitochondrial DNA (mtDNA) haplogroups on virologic and immunological outcomes of HIV infection. Design HAART-naive African American adolescent participants to the Reaching for Excellence in Adolescent Care and Health study. Methods The mtDNA haplogroups were inferred from sequenced mtDNA hypervariable regions HV1 and HV2 and their predictive value on HIV outcomes were evaluated in linear mixed models, controlled for human leukocyte antigen (HLA)-B27, HLA-B57 and HLA-B35-Px alleles and other covariates. Results We report data showing that the mtDNA L2 lineage, a group composed of L2a, L2b and L2e mtDNA haplogroups in the studied population, is significantly associated (beta=−0.08; Bonferroni-adjusted P=0.004) with decline of CD4+ T cells (median loss of 8 ± 1 cells per month) in HAART-naive HIV-infected individuals of African American descent (n=133). No significant association (P<0.05) with set-point viral load was observed with any of the tested mtDNA haplogroups. The present data concur with previous findings in the AIDS Clinical Trials Group study 384, implicating the L2 lineage with slower CD4+ T-cell recovery after antiretroviral therapy in African Americans. Conclusions Whereas the L2 lineage showed an association with unfavorable immunological outcomes of HIV infection, its phylogenetic divergence from J and U5a, two lineages associated with accelerated HIV progression in European Americans, raises the possibility that interactions with common nucleus-encoded variants drive HIV progression. Disentangling the effects of mitochondrial and nuclear gene variants on the outcomes of HIV infection is an important step to be taken toward a better understanding of HIV/AIDS pathogenesis and pharmacogenomics.

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Section: Discussionsupporting

confidence: 89%

Mitochondrial DNA variation and virologic and immunological HIV outcomes in African Americans

Aissani¹,

Shrestha²,

Wiener³

et al. 2014

Aids

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“…28 However, recent studies have investigated the association of mtDNA haplogroups with human diseases and longevity. [7][8][9][10][11][12][13][14][15] We described the frequencies of the mitochondrial haplogroups in our South African cohort recruited from two Cape Town clinics, the majority of which belonged to the L0 haplogroup. There are limited data regarding the distribution of the mitochondrial haplogroups in the South African population.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in African-Americans showed associations between African mtDNA subhaplogroup L1c and peripheral neuropathy, 15 and between haplogroup L2 and CD4 T cell recovery. 7 To date, no published studies have investigated associations between African mtDNA haplogroups and important metabolic complications including lipoatrophy, dysglycemia, or dyslipidemia. In this study, we report the prevalence of mtDNA haplogroups in a South African population enrolled in an ART program, and explore associations between African mtDNA and ARTassociated complications including metabolic complications and distal sensory polyneuropathy (DSP).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Genomics and Antiretroviral Therapy-Associated Metabolic Complications in HIV-Infected Black South Africans: A Pilot Study

Sinxadi

Dave

Samuels

et al. 2013

AIDS Research and Human Retroviruses

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Studies suggest that mitochondrial DNA (mtDNA) haplogroups are associated with antiretroviral therapy (ART)-related metabolic complications and distal sensory polyneuropathy (DSP), but there have been few studies in persons of African descent. We explored such associations in South African adults. Clinical and laboratory data and DNA specimens from a cross-sectional study were used. Sequencing and Phylotree determined African mtDNA subhaplogroups. Wilcoxon and regression analyses determined associations between mtDNA subhaplogroups and ART-related complications. The 171 participants represented six major haplogroups: L0 (n=78), L1 (n=3), L2 (n=30), L3 (n=53), L4 (n=1), and L5 (n=6). Analyses were restricted to 161 participants representing L0, L2, and L3: 78% were female; the median age was 36 years. All had been exposed to thymidine analogues, 42% were on lopinavir/ritonavir (lopinavir/r), and 58% were on either efavirenz or nevirapine. Median (IQR) ART duration was 22 (14-36) months. Median fasting triglycerides were 1.60 (1.13-1.75) and 1.04 (0.83-1.45) mmol/liter among L3e1 (n=22) and other subhaplogroups, respectively (p=0.003). Subhaplogroup L3e1 [adjusted OR (aOR) 3.16 (95% CI: 1.11-8.96); p=0.03] and exposure to lopinavir/r [aOR 2.98 (95% CI: 1.02-8.96); p=0.05] were independently associated with hypertriglyceridemia, after adjusting for age, sex, and ART duration. There were no significant associations between mtDNA haplogroups and cholesterol, dysglycemia, hyperlactatemia, or lipoatrophy, or DSP. Subhaplogroup L3e1 and lopinavir/r exposure were independently associated with hypertriglyceridemia in black South Africans on ART. This is the first report to link an African mtDNA variant with hypertriglyceridemia. If replicated, these findings may provide new insights into host factors affecting metabolic complications.

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“…Previous studies have identified significant differences in mtDNA according to prior nucleoside analog exposure [43]. Differences between mtDNA haplogroups also were associated with the magnitude of CD4 restoration [44], and with differences in T-cell activation on ART (as CD38/HLA-DR expression on CD4 and CD8 cells) [45], implicating possible contributions by mitochondrial function to the association between CD4 cell restoration and immune activation.…”

Section: Discussionmentioning

confidence: 97%

Older HIV-infected patients on antiretroviral therapy have B-cell expansion and attenuated CD4 cell increases with immune activation reduction

Kalayjian

Spritzler

Matining

et al. 2013

Aids

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Background The contribution of immune activation to accelerated HIV-disease progression in older individuals has not been delineated. Methods Prospective multicenter cohort of older (≥45 years) and younger (18–30 years) HIV-infected adults initiating 192 weeks of antiretroviral therapy (ART). Longitudinal models of CD4 cell restoration examined associations with age-group, thymic volume, immune activation, and viral load. Results Forty-five older and 45 younger adults (median age 50 and 26 years, respectively) were studied. Older patients had fewer naive CD4 cells (P <0.001) and higher HLA-DR/CD38 expression on CD4 (P = 0.05) and CD8 cells (P = 0.07) than younger patients at any time on ART. The rate of naive and total CD4 cell increase was similar between age groups, but older patients had a faster mean rate of B-cell increase (by +0.7 cells/week; P = 0.01), to higher counts than healthy controls after 192 weeks (P = 0.003). Naive CD4 increases from baseline were associated with immune activation reductions (as declines from baseline of %CD8 cells expressing HLA-DR/CD38; P <0.0001), but these increases were attenuated in older patients, or in those with small thymuses. A 15% reduction in activation was associated with naive gains of 29.9 and 6.2 cells/μl in younger, versus older patients, or with gains of 25.7, 23.4, and 2.1 cells/μl in patients with the largest, intermediate, and smallest thymuses, respectively (P <0.01 for interactions between activation reduction and age-group or thymic volume). Conclusion Older patients had significant B-cell expansion, higher levels of immune activation markers, and significantly attenuated naive CD4 cell gains associated with activation reduction.

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Mitochondrial Genomics and CD4 T-Cell Count Recovery After Antiretroviral Therapy Initiation in AIDS Clinical Trials Group Study 384

Cited by 18 publications

References 34 publications

Mitochondrial DNA variation and virologic and immunological HIV outcomes in African Americans

Mitochondrial DNA variation and virologic and immunological HIV outcomes in African Americans

Mitochondrial Genomics and Antiretroviral Therapy-Associated Metabolic Complications in HIV-Infected Black South Africans: A Pilot Study

Older HIV-infected patients on antiretroviral therapy have B-cell expansion and attenuated CD4 cell increases with immune activation reduction

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