Patrick Unemori

In Vivo, Nucleoside Reverse-Transcriptase Inhibitors Alter Expression of Both Mitochondrial and Lipid Metabolism Genes in the Absence of Depletion of Mitochondrial DNA

BACKGROUND Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described. METHODS We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks. RESULTS We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues. CONCLUSIONS Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase- gamma , whereas disruption of expression of lipid metabolism genes offers an explanation for NRTI-induced lipoatrophy.

Self-Portraits: Possible Selves in European-American, Chilean, Japanese and Japanese-American Cultural Contexts

Possible selves of students from European-American (EA), Chilean (CH), Japanese-American (JA), and Japanese (JN) cultural contexts were analyzed, revealing differences in the emphasis given to various content themes. EA possible selves focus on intrapersonal themes (i.e., “fear being dependent”), consistent with cultural emphases on uniqueness and independent development. In JN, JA and CH contexts, career and education themes dominate possible selves, consistent with particularly strong cultural emphasis on professional and academic accomplishments. The cultural contexts also differ in their predominant configurations of possible selves—EA and CH possible selves often show balance (expected and feared selves of similar theme but opposing valence, i.e., “expect to graduate from college” and “fear dropping out of college”) while JN and JA selves more frequently match (expected and feared selves of similar thematic content and valence, i.e., “expect to be idle” and “fear being idle”).

Effect of Rosiglitazone on Peroxisome Proliferator-Activated Receptor γ Gene Expression in Human Adipose Tissue Is Limited by Antiretroviral Drug-Induced Mitochondrial Dysfunction

BACKGROUND Treatment of human immunodeficiency virus (HIV)-1 with thymidine-analogue nucleoside reverse-transcriptase inhibitors (tNRTIs) causes lipoatrophy, mitochondrial toxicity, and lower adipose tissue expression of peroxisome proliferator-activated receptor gamma (PPARgamma [PPARG gene]). Rosiglitazone (RSG), a PPARgamma agonist, improves congenital lipoatrophy but not HIV lipoatrophy. METHODS Serial fat biopsies were taken from HIV-infected, lipoatrophic men randomized to receive RSG or placebo for 48 weeks. Adipose tissue mitochondrial and nuclear gene expression and mitochondrial DNA content were quantified by real-time polymerase chain reaction. Nonparametric analyses were applied. RESULTS Subjects receiving tNRTI-containing antiretroviral therapy had lower baseline mitochondrial RNA expression and DNA content. In subjects receiving tNRTIs, exposure to RSG did not affect PPARG expression at either week 2 or 48. At week 2, RSG increased PPARG expression only in subjects not treated with tNRTIs, whereas at week 48, increased PPARG expression was observed in subjects not treated with tNRTIs, regardless of RSG use. Similar findings were observed for the PPARG-responsive gene fatty acid-binding protein 4. Changes in PPARG expression were associated with increases in limb fat mass. CONCLUSIONS These data suggest that in HIV-infected, lipoatrophic men, adipose PPARG expression and function are dependent on intact mitochondrial function. These data support a direct link between mitochondrial toxicity and adipose tissue PPARG expression and help explain the poor clinical response to RSG observed in clinical trials.

Immunosenescence is associated with presence of Kaposi's sarcoma in antiretroviral treated HIV infection.

Objective:Some antiretroviral treated HIV-infected patients develop Kaposis sarcoma despite long-term suppression of HIV replication. These Kaposis sarcoma lesions are consistent with Kaposis sarcoma observed in the elderly uninfected population (’classical Kaposis sarcoma’). We investigated potential mechanisms for this phenomenon, focusing on measures of immune activation and T-cell senescence. Design:We compared markers of immunosenescence, naive T cells, activation, and inflammation in CD4+ and CD8+ T cells from antiretroviral-treated participants with new-onset Kaposis sarcoma (cases, n = 19) and from treated individuals without Kaposis sarcoma (controls, n = 47). Results:There was increased frequency of CD4+ and CD8+ T cells with an immunosenescence phenotype (CD57+ and CD28−) in cases vs. controls (CD4+T cells: CD57+ 7.4 vs. 3.7%, P = 0.025; CD28− 9.1 vs. 4.8%, P = 0.025; CD8+ T cells: CD57+ 41.5 vs. 27.7%, P = 0.003; CD28− 60.5 vs. 51.3%, P = 0.041). Cases had lower proportions of naïve T cells (CD27+CD28+CD45RA+) in CD4+ (23.0 vs. 32.2%, P = 0.023) and CD8+ (11.3 vs. 20.7%, P < 0.001) T-cell compartments. CCR5 was more highly expressed in CD4+ (16.3 vs. 11.0%, P = 0.025), and CD8+ (43.1 vs. 28.3%, P <0.001) T-cell compartments in cases vs. controls. There was no difference in telomere length or telomerase activity in peripheral blood mononuclear cells, or in T-cell expression of activation markers (HLADR+CD38+). Conclusion:Among antiretroviral-treated patients, increased frequencies of T cells with an immunosenescence phenotype and lower frequencies of naive T cells were associated with presence of Kaposis sarcoma among effectively treated patients. These data suggest that certain immunologic perturbations –including those associated with aging – might be causally associated with development of Kaposis sarcoma.

Skewed distribution of natural killer cells in psoriasis skin lesions

Psoriasis is a hyper‐proliferative disease of the skin in which immunological mechanisms play a direct pathogenetic role. There have been limited studies of natural killer (NK) cells in psoriasis. The aim of this study was to examine the phenotype of NK cells in skin biopsies and peripheral blood mononuclear cells from patients with psoriasis and healthy controls. CD56+CD16− and CD56+CD16+ NK cells were isolated from lesional skin, unaffected skin and PBMC of psoriasis patients, and normal skin and PBMC from healthy controls. The expression of CD57, NKG2A and NKG2C was assessed by flow cytometry. NK cells in psoriasis skin lesions were skewed in their expression of CD57, a marker of NK cell maturity, with CD57 expression significantly reduced and NKG2A expression increased on NK cells in lesional and unaffected skin compared to controls. These data suggest that in this patient cohort, NK cells could be isolated from psoriasis lesions and exhibit an immature phenotype.

CD57 expression and cytokine production by T cells in lesional and unaffected skin from patients with psoriasis.

Background The immunopathogenic mechanisms leading to psoriasis remain unresolved. CD57 is a marker of replicative inability and immunosenescence on CD8+ T cells and the proportion of CD57 expressing CD8+ T cells is increased in a number of inflammatory conditions. Methodology We examined the expression of CD57 on T cells in the skin of patients affected with psoriasis, comparing lesional and unaffected skin. We also assessed functionality of the T cells by evaluating the secretion of several inflammatory cytokines (IL-17A, IFN-gamma, IL-2, IL-33, TNF-alpha, IL-21, IL-22, and IL-27), from cell-sorted purified CD4+ and CD8+ T cells isolated from lesional and unaffected skin biopsies of psoriasis patients. Principal Findings We observed that the frequency of CD57+CD4+ and CD57+CD8+ T cells was significantly higher in unaffected skin of psoriasis patients compared to lesional skin. Sorted CD4+ T cells from psoriatic lesional skin produced higher levels of IL-17A, IL-22, and IFN-gamma compared to unaffected skin, while sorted CD8+ T cells from lesional skin produced higher levels of IL-17, IL-22, IFN-gamma, TNF-alpha, and IL-2 compared to unaffected skin. Conclusions/Significance These findings suggest that T cells in unaffected skin from psoriasis patients exhibit a phenotype compatible with replicative inability. As they have a lower replicative capacity, CD57+ T cells are less frequent in lesional tissue due to the high cellular turnover.

Disseminated herpes zoster with increased CD4 counts in 3 HIV-infected patients

It has been reported that the diagnosis of multidermatomal herpes zoster in HIV-infected patients occurs at a lower CD4 level than zoster involving a single dermatome. Herein, we describe 3 cases of HIV-infected patients presenting with disseminated zoster at high CD4 counts and low HIV viral loads.

Persistent Prurigo Nodularis Responsive to Initiation of Combination Therapy With Raltegravir

Prurigo nodularis (PN) presents with excoriated nodules on the extensor surfaces of limbs and trunk. It is commonly seen in persons infected with human immunodeficiency virus (HIV) and with low CD4 counts.1 The pathogenesis of PN is not well understood, but it may be related to inflammatory mediators.2–4 Interestingly, combination therapy that includes raltegravir, an integrase inhibitor that prevents viral DNA insertion into host cell DNA, has been noted to rapidly reduce viral load to levels comparable to or lower than other HIV antiretroviral therapies (ARTs).5,6 We report 2 cases of PN that dramatically improved within 2 weeks of initiating twice daily oral dosing with raltegravir, 400 mg.

Response to: A Retrospective Analysis of AIDS-Associated Kaposi’s Sarcoma in Patients With Undetectable HIV Viral Loads and CD4 Counts Greater Than 300 cells/mm3

We read with interest a report from Mani et al characterizing demographic, immunologic, and clinical characteristics of a retrospectively collected cohort of patients with Kaposi’s sarcoma (KS), most of whom were entered into the AIDS Malignancy Consortium studies. In a previous letter, we prospectively identified 9 individuals who developed KS with at least 2 years of good immunologic control (CD4 counts >300 cells/mm and undetectable viral load [VL]). Their KS has been persistent and indolent throughout follow-up. In Mani’s group, 20 (22%) of 91 had KS despite CD4 >300 cells/mm and undetectable VL; however only 7 (7%) of 90 had CD4 counts >300 cells/mm and undetectable VL at the time of KS diagnosis. The duration of immunologic control before the diagnosis of KS is not clear from this description. In our description, we are drawing attention to that group similar to the 7 patients in Mani’s report, who developed KS in the setting of concurrent, well-controlled HIV infection. While we and others agree that this is not a new phenomenon, it is perhaps more unusual than the prototypic patient who develops KS with lower CD4 counts and detectable VL only to resolve their KS with better immunologic control or develop persistent KS in spite of this. Making a distinction among these different groups may be important as they may be clinically and immunologically distinct. It is yet to be determined whether the characteristics that we described still persist in larger prospective studies. These characteristics include longer duration of HIV infection, older age at diagnosis of KS with higher CD4 counts, and higher CD4 nadir. Finally, it should be noted that we are in agreement with Mani et al in that in our letter we state that patients were on both protease inhibitor (PI) and non-PI antiretroviral (ARV) regimens and that there did not seem to be an association of persistent KS with either regimen.

Cutis verticis gyrata in men affected by HIV-related lipodystrophy

We report the occurrence of cutis verticis gyrata (CVG), a disfiguring dermatological condition, in four patients with HIV-related lipodystrophy (HIVLD). These four patients had abnormal metabolic and hormonal lab values which we compare with metabolic and hormonal perturbations cited in previous HIVLD cohorts. In addition, we describe the sole use of poly-L-lactic acid as a potential treatment for decreasing the appearance of CVG-associated ridges.