Cerebrospinal fluid CD14++CD16+ monocytes in HIV-1 subtype C compared with subtype B.

CD14++CD16+ monocytes are susceptible to HIV-1 infection, and cross the blood-brain barrier. HIV-1 subtype C (HIV-1C) shows reduced Tat protein chemoattractant activity compared to HIV-1B, which might influence monocyte trafficking into the CNS. We hypothesized that the proportion of monocytes in CSF in HIV-1C is lower than HIV-1B group. We sought to assess differences in monocyte proportions in cerebrospinal fluid (CSF) and peripheral blood (PB) between people with HIV (PWH) and without HIV (PWoH), and by HIV-1B and -C subtypes. Immunophenotyping was performed by flow cytometry, monocytes were analyzed within CD45 + and CD64 + gated regions and classified in classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14lowCD16+). Among PWH, the median [IQR] CD4 nadir was 219 [32-531] cell/mm3; plasma HIV RNA (log10) was 1.60 [1.60-3.21], and 68% were on antiretroviral therapy (ART). Participants with HIV-1C and -B were comparable in terms of age, duration of infection, CD4 nadir, plasma HIV RNA, and ART. The proportion of CSF CD14++CD16+ monocytes was higher in participants with HIV-1C than those with HIV-1B [2.00(0.00-2.80) vs. 0.00(0.00-0.60) respectively, p = 0.03 after BH correction p = 0.10]. Despite viral suppression, the proportion of total monocytes in PB increased in PWH, due to the increase in CD14++CD16+ and CD14lowCD16+ monocytes. The HIV-1C Tat substitution (C30S31) did not interfere with the migration of CD14++CD16+ monocytes to the CNS. This is the first study to evaluate these monocytes in the CSF and PB and compare their proportions according to HIV subtype.

CD3+CD56+ and CD3-CD56+ lymphocytes in the cerebrospinal fluid of persons with HIV-1 subtypes B and C.

The transactivator of transcription (Tat) is a HIV regulatory protein which promotes viral replication and chemotaxis. HIV-1 shows extensive genetic diversity, HIV-1 subtype C being the most dominant subtype in the world. Our hypothesis is the frequency of CSF CD3+CD56+ and CD3-CD56dim is reduced in HIV-1C compared to HIV-1B due to the Tat C30S31 substitution in HIV-1C. 34 CSF and paired blood samples (PWH, n = 20; PWoH, n = 14) were studied. In PWH, the percentage of CD3+CD56+ was higher in CSF than in blood (p < 0.001), comparable in both compartments in PWoH (p = 0.20). The proportion of CD3-CD56dim in CSF in PWH was higher than PWoH (p = 0.008). There was no subtype differences. These results showed CNS compartmentalization of NKT cell response in PWH.

Main lymphocyte subpopulations in cerebrospinal fluid and peripheral blood in HIV-1 subtypes C and B.

HIV-1 subtype C (HIV-1C) shows reduced Tat protein chemoattractant activity compared with HIV-1B. The impact of HIV-1C Tat on the chemotaxis of the main lymphocyte subpopulations in the cerebrospinal fluid (CSF) and the peripheral blood (PB) is unclear. We hypothesized that there would be a lower frequency of specific lymphocyte subpopulations CD3+ or CD19+ in CSF in HIV-1C than in HIV-1B. The objectives were to detect the differences in the proportions of main lymphocyte subpopulations in CSF and PB, between people with HIV (PWH) and HIV-1-uninfected volunteers (PWoH) and in HIV-1B and HIV-1C. Lymphocyte immunophenotyping was studied in CSF and paired PB samples of PWH (n = 22) and PWoH (n = 14). Lymphocytes were analyzed within the CD45+ gated region. The proportions of CSF CD3+CD4+, CD3+CD8+, and CD3-CD19+ lymphocytes in CSF were comparable in HIV-1B and C. There was an increase in the proportion of CD3+CD8+ cells and a decrease in CD3+CD4+ T cells (ps = 0.016) in the CSF samples of the PWH compared with the PWoH group. In the PWH group, both CD3+CD4+ and CD3+CD8+ lymphocytes were significantly higher in the CSF than in the PB (p = 0.047 and 0.005). The proportion of CD3+CD4+ was lower and that of CD3+CD8+ was higher in the CSF samples of the aviremic group than that of HIV-negative control (p = 0.0008 and < 0.0001, respectively). HIV-1C Tat substitution (C30S) did not interfere with the CNS migration of the main lymphocyte subpopulations. This is the first study to evaluate these lymphocytes in CSF and PB of HIV-1C compared with HIV-1B.

Social Determinants and COVID-19 in a Community Health Center Cohort.

Associations between social determinants of health (SDOH), demographic factors including preferred language, and SARS-CoV-2 detection are not clear. We conducted a retrospective cohort study among those seeking testing for SARS-CoV-2 at a multi-site, urban community health center. Logistic regression and exact matching methods were used to identify independent predictors of SARS-CoV-2 detection among demographic, SDOH, and neighborhood-level variables. Of 1,361 included individuals, SARS-CoV-2 was detected among 266 (19.5%). Logistic regression demonstrated that SARS-CoV-2 detection was less likely in White participants relative to Hispanic participants (adjusted odds ratio [aOR] 0.18, 95% confidence interval [CI] 0.05-0.46). and more likely in patients who prefer Spanish relative to those that prefer English (aOR 2.04, 95% CI 1.43-2.96). No observed SDOH predicted SARS-CoV-2 detection in adjusted models. A robustness analysis using a matched subset of the study sample produced findings similar to those in the main analysis. Preferring to receive care in Spanish is an independent predictor of SARS-CoV-2 detection in a community health center cohort.

Race and ethnicity do not impact eligibility for remdesivir: A single-center experience.

As the Coronavirus-2019 (COVID-19) pandemic continues, multiple therapies are rapidly being evaluated for efficacy in clinical trials. Clinical trials should be racially and ethnically representative of the population that will eventually benefit from these medications. There are multiple potential barriers to racial and ethnic minority enrollment in clinical trials, one of which could be that inclusion and exclusion criteria select for certain racial or ethnic groups disproportionately. In this observational cohort study at a single health care system, we examined if there were differences in eligibility for treatment with remdesivir based on clinical trial criteria for racial and ethnic minorities compared to non-Hispanic Whites. 201 electronic medical record charts were reviewed manually. Self-identified Whites were older than other racial or ethnic groups. At the time of presentation, Black, Latinx, and White participants met inclusion criteria for remdesivir at similar rates (72%, 80%, and 73% respectively), and exclusion criteria at similar rates (43%, 38% and 49% for Black, Latinx and White participants respectively). In this study, there was no difference in eligibility for remdesivir based on race or ethnicity alone.

Beneficial Effects of Cannabis on Blood-Brain Barrier Function in Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to blood-brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy (ART) and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity. METHODS: We studied persons with HIV (PWH) and HIV-negative (HIV-) individuals who had used cannabis recently. We assessed 2 biomarkers of BBB permeability: the cerebrospinal fluid (CSF) to serum albumin ratio (CSAR) and CSF levels of soluble urokinase plasminogen activator receptor (suPAR), a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay. RESULTS: Participants were 45 PWH and 30 HIV- individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r = 0.47, P < .001). PWH had higher (more abnormal) BBB index values than HIV- individuals (mean ± SD, 0.361 ± 1.20 vs -0.501 ± 1.11; P = .0214). HIV serostatus interacted with cannabis use frequency, such that more frequent use of cannabis was associated with lower BBB index values in PWH but not in HIV- individuals. Worse BBB index values were associated with higher NFL in CSF (r = 0.380, P = .0169). CONCLUSIONS: Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity.

Recent cannabis use in HIV is associated with reduced inflammatory markers in CSF and blood.

OBJECTIVE: To determine whether cannabis may reduce HIV-related persistent inflammation, we evaluated the relationship of cannabis use in people with HIV (PWH) to inflammatory cytokines in CSF and blood plasma. METHODS: We measured a panel of proinflammatory cytokines (interleukin [IL]-16, C-reactive protein [CRP], IL-6, interferon gamma-induced protein [IP]-10, soluble CD14, and soluble tumor necrosis factor receptor type II [sTNFRII]) in CSF and blood plasma in PWH and HIV- individuals who did or did not use cannabis at various levels of exposure. Participants in this observational cohort were recruited from community sources and underwent lumbar puncture and phlebotomy. Cannabis use parameters were characterized by self-report based on a semistructured timeline follow-back interview. Cytokines were measured using commercially available immunoassays. Data were analyzed using factor analysis. RESULTS: Participants were 35 PWH and 21 HIV- individuals, mean (SD) age 45.4 (14.5) years, 41 cannabis ever users, and 15 never users. PWH and HIV- were not different in recency, cumulative months, grams, or density of cannabis use. A factor analysis using CSF biomarkers yielded a factor loading on CRP, IL-16, and sTNFRII that was significantly associated with recency of cannabis use (more recent use associated with lower factor 1 values, reflecting less inflammation; r = 0.331 [95% CI 0.0175, 0.586]). In particular, more recent cannabis use was related to lower IL-16 levels (r = 0.549 [0.282, 0.737]). Plasma biomarkers yielded a factor loading on sTNFRII and IP-10 that was associated with more recent cannabis use (more recent use related to less inflammation; r = 0.374 [0.0660, 0.617]). CONCLUSIONS: Recent cannabis use was associated with lower levels of inflammatory biomarkers, both in CSF and blood, but in different patterns. These results are consistent with compartmentalization of immune effects of cannabis. The principal active components of cannabis are highly lipid soluble and sequestered in brain tissue; thus, our findings are consistent with specific anti-neuroinflammatory effects that may benefit HIV neurologic dysfunction.

Subclinical Cytomegalovirus DNA Is Associated with CD4 T Cell Activation and Impaired CD8 T Cell CD107a Expression in People Living with HIV despite Early Antiretroviral Therapy.

Most people living with HIV (PLWH) are coinfected with cytomegalovirus (CMV). Subclinical CMV replication is associated with immune dysfunction and with increased HIV DNA in antiretroviral therapy (ART)-naive and -suppressed PLWH. To identify immunological mechanisms by which CMV could favor HIV persistence, we analyzed 181 peripheral blood mononuclear cell (PBMC) samples from 64 PLWH starting ART during early HIV infection with subsequent virologic suppression up to 58 months. In each sample, we measured levels of CMV and Epstein-Barr virus (EBV) DNA by droplet digital PCR (ddPCR). We also measured expression of immunological markers for activation (HLA-DR+ CD38+), cycling (Ki-67+), degranulation (CD107a+), and the immune checkpoint protein PD-1 on CD4+ and CD8+ T cell memory subsets. Significant differences in percentages of lymphocyte markers by CMV/EBV shedding were identified using generalized linear mixed-effects models. Overall, CMV DNA was detected at 60/181 time points. At the time of ART initiation, the presence of detectable CMV DNA was associated with increased CD4+ T cell activation and CD107a expression and with increased CD8+ T cellular cycling and reduced CD107a expression on CD8+ T cells. While some effects disappeared during ART, greater CD4+ T cell activation and reduced CD107a expression on CD8+ T cells persisted when CMV was present (P < 0.01). In contrast, EBV was not associated with any immunological differences. Among the covariates, peak HIV RNA and CD4/CD8 ratio had the most significant effect on the immune system. In conclusion, our study identified immune differences in PLWH with detectable CMV starting early ART, which may represent an additional hurdle for HIV cure efforts.IMPORTANCE Chronic viral infections such as with HIV and CMV last a lifetime and can continually antagonize the immune system. Both viruses are associated with higher expression of inflammation markers, and recent evidence suggests that CMV may complicate efforts to deplete HIV reservoirs. Our group and others have shown that CMV shedding is associated with a larger HIV reservoir. Subclinical CMV replication could favor HIV persistence via bystander effects on our immune system. In this study, we collected longitudinal PBMC samples from people starting ART and measured immune changes associated with detectable CMV. We found that when CMV was detectable, CD4+ T cell activation was higher and CD8+ T cell degranulation was lower. Both results may contribute to the slower decay of the size of the reservoir during CMV replication, since activated CD4+ T cells are more vulnerable to HIV infection, while the loss of CD8+ T cell degranulation may impede the proper killing of infected cells.

Brief Report: Effect of CMV and HIV Transcription on CD57 and PD-1 T-Cell Expression During Suppressive ART.

HIV-infected men who have sex with men are nearly universally coinfected with cytomegalovirus (CMV). In this study of 45 HIV-infected men who have sex with men virologically suppressed on ART, we found that presence of seminal CMV DNA shedding and higher levels of systemic cellular HIV RNA transcription were both independently associated with increased PD-1 expression on circulating CD4 T cells, but not with higher levels of senescent (CD57) T cells. In addition, greater HIV RNA transcription was associated with lower CD57 expression on CD8 T cells. Although causality cannot be inferred from this retrospective study, these results suggest that asymptomatic CMV replication and residual cellular HIV transcription may contribute to persistent immune dysregulation during suppressive ART.

Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection.

Cell-free mitochondiral DNA (mtDNA) is an immunogenic molecule associated with many inflammatory conditions. We evaluated the relationship between cell-free mtDNA in cerebrospinal fluid (CSF) and neurocognitive performance and inflammation during HIV infection. In a cross-sectional analysis, we evaluated the association of mtDNA levels with clinical assessments, inflammatory markers, and neurocognitive performance in 28 HIV-infected individuals. In CSF, we measured mtDNA levels by droplet digital PCR, and soluble CD14 and CD163, neurofilament light, and neopterin by ELISA. In blood and CSF, we measured soluble IP-10, MCP-1, TNF-α, and IL-6 by ELISA, and intracellular expression of IL-2, IFN-γ, and TNF-α in CD4(+) and CD8(+) T cells by flow cytometry. We also evaluated the relationship between CSF pleocytosis and mtDNA longitudinally in another set of five individuals participating in an antiretroviral treatment (ART) interruption study. Cell-free CSF mtDNA levels strongly correlated with neurocognitive performance among individuals with neurocognitive impairment (NCI) (r = 0.77, p = 0.001). CSF mtDNA also correlated with levels of IP-10 in CSF (r = 0.70, p = 0.007) and MCP-1 in blood plasma (r = 0.66, p = 0.01) in individuals with NCI. There were no significant associations between inflammatory markers and mtDNA in subjects without NCI, and levels of mtDNA did not differ between subjects with and without NCI. MtDNA levels preceded pleocytosis and HIV RNA following ART interruption. Cell-free mtDNA in CSF was strongly associated with the severity of neurocognitive dysfunction and inflammation only in individuals with NCI. Our findings suggest that within a subset of subjects cell-free CSF mtDNA is associated with inflammation and degree of NCI.

Methamphetamine Use in HIV-infected Individuals Affects T-cell Function and Viral Outcome during Suppressive Antiretroviral Therapy.

We investigated the associations between methamphetamine (meth) use, immune function, and the dynamics of HIV and cytomegalovirus [CMV] in the blood and genital tract of HIV-infected ART-suppressed subjects. Self-reported meth use was associated with increased CD4(+) and CD8(+) T-cell proliferation (Ki67(+), p < 0.005), CD4(+) T-cell activation (CD45RA(-)CD38(+), p = 0.005) and exhaustion (PD-1(+), p = 0.0004) in blood, compared to non-meth users. Meth use was also associated with a trend towards higher blood HIV DNA levels (p = 0.09) and more frequent shedding of CMV in seminal plasma (p = 0.002). To explore possible mechanisms, we compared ex vivo spontaneous and antigen-specific proliferation in PBMC collected from subjects with and without positive meth detection in urine (Utox+ vs. Utox-). Despite higher levels of spontaneous proliferation, lymphocytes from Utox+ meth users had a significantly lower proliferative capacity after stimulation with a number of pathogens (CMV, candida, mycobacterium, toxoplasma, HIV, p < 0.04 in all cases), compared to Utox- participants. Our findings suggest that meth users have greater proliferation and exhaustion of the immune system. Meth use is also associated with a loss of control of CMV replication, which could be related to loss of immune response to pathogens. Future studies should consider meth use as a potential modulator of T-cell responses.

Cerebrospinal fluid (CSF) CD8+ T-cells that express interferon-gamma contribute to HIV associated neurocognitive disorders (HAND).

BACKGROUND: HIV associated neurocognitive disorders (HAND) continue to affect cognition and everyday functioning despite anti-retroviral treatment (ART). Previous studies focused on mechanisms related to monocyte/macrophage mediated inflammation. However, in the ART era, there is increasing evidence for the involvement of CD8+ T-cells in CNS pathogenesis. METHODS: To investigate the relationship between T-cell responses and neurocognitive impairment (NCI), cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T-cell intracellular cytokine (IFNγ, IL-2, TNFα) and lytic marker (CD107a) expression were assessed in HIV infected subjects who underwent comprehensive neurocognitive (NC) evaluation and either initiated or changed ART. RESULTS: Data were collected from 31 participants at 70 visits. The frequency of cytokine expressing T-cells in CSF was significantly higher than in peripheral blood for CD4+T-cells: TNFα, IL-2, IFNγ and CD8+T-cells: IL-2 and IFNγ. Analysis of T-cell activity and NCI as a function of CSF HIV RNA levels suggested a general association between NCI, high CSF CD8+ (but not CD4+T-cell) cytokine expression and CSF HIV RNA <103 copies/ml (p<0.0001). Specifically, CSF CD8+ T-cell IFNγ expression correlated with severity of NCI (r = 0.57, p = 0.004). Multivariable analyses indicated that CSF CD8+T-cell IFNγ and myeloid activation (CD163) contributed equally and independently to cognitive status and a composite variable produced the strongest correlation with NCI (r = 0.83, p = 0.0001). In contrast, CD8+ cytolytic activity (CD107a expression) was negatively correlated with NCI (p = 0.05) but was dependent on CD4 levels >400/µl and low CSF HIV RNA levels (<103 copies/ml). In our longitudinal analysis of 16 subjects, higher CSF CD8+IFNγ expression at baseline predicted NC decline at follow-up (p = 0.02). Severity of NCI at follow-up correlated with level of residual HIV RNA in CSF. CONCLUSIONS: Presence of IFNγ expressing CD8+ T-cells, absence of cytolytic CD8+ T-cells, high myeloid activation, and failure of ART to suppress HIV replication in CSF contribute to increased risk of HAND.

The impact of stent graft evolution on the results of endovascular abdominal aortic aneurysm repair.

OBJECTIVE: There have been four eras in the development of endovascular aneurysm repair (EVAR): physician-made grafts, early industry devices, intermediary commercial endografts, and modern stent grafts. This study analyzes differences in outcomes between these four groups and the impact of device evolution and increased physician experience. METHODS: From 1992 to 2012, 1380 patients underwent elective EVAR. Fourteen different devices were used during this time. The four generations were defined as follows: era 1, all physician-made devices; era 2, June 1994 to June 2003; era 3, June 2003 to January 2008; and era 4, January 2008 to July 2012. Grafts used in each era were the following: era 1, physician made; era 2, early industry, such as EVT, Talent, AneuRx, Excluder, Quantum LP, Vanguard, Ancure, and Teramed; era 3, Talent, Endologix, Excluder, AAAdvantage, Zenith, and Aptus; and era 4, Zenith, Endurant, and Excluder. RESULTS: Mean age was 75.2 years, and 84.5% were men. Adjunctive procedures decreased from era 1 to era 2 (P < .001) but rose again in eras 3 and 4 (P < .001). Procedure times (P < .001), blood loss (P < .001), and length of stay (P < .001) have decreased in eras 2, 3, and 4 compared with era 1. Major perioperative complications (era 1, 23%; era 2, 5.9%; era 3, 4.9%; and era 4, 4.7%; P < .001), abdominal aortic aneurysm-related perioperative mortality (era 1, 4.3%; era 2, 0.2%; era 3, 0.06%; and era 4, 0.5%; P < .001), and all-cause perioperative mortality (era 1, 7.7%; era 2, 1.9%; era 3, 1.5%; and era 4, 0.47%; P < .001) have also decreased in eras 2, 3, and 4 compared with era 1. Type I and type III endoleaks (P < .001) and the need for reintervention (P < .001) have decreased. Freedom from aneurysm-related mortality has significantly improved. CONCLUSIONS: EVAR has evolved during the last 20 years, resulting in an improvement in efficiency, outcomes, and procedural success. The most significant advance is seen in the transition from era 1 to the later eras.

The influence of HLA on HIV-associated neurocognitive impairment in Anhui, China.

BACKGROUND: HLA-DR*04 was identified as a predictor of HIV-Associated neurocognitive disorder (HAND), low CD4 T-cell responses to HIV, and low plasma HIV RNA levels in a U.S. cohort. We hypothesized that low CD4 T-cell activation leads to poor immune control of HIV in the CNS, predisposing to HAND, but also provided fewer target (activated CD4 T-cells) for HIV replication. To assess the consistency of these HLA Class II associations in a new cohort and extend analysis to HLA Class I, HLA types, neurocognitive, and virologic status were examined in a cohort of former plasma donors in China. METHODS: 178 HIV infected individuals in Anhui China, were HLA typed and underwent neurocognitive evaluations (using locally standardized norms), neuromedical, treatment and virologic assessments at baseline and at 12 months. RESULTS: HLA DR*04 was associated with a higher rate of baseline neurocognitive impairment (p = 0.04), neurocognitive decline (p = 0.04), and lower levels of HIV RNA in plasma (p = 0.05). HLA Class I alleles (B*27,57,58,A*03,33) that specify a CD8 T-cell response to conserved HIV sequences were neuroprotective, associated with less impairment at baseline (p = 0.037), at month 012 (p = 0.013) and less neurocognitive decline (p = 0.023) in the interval. Consistent with the theory that effective CD8 T-cell responses require CD4 T-cell support, the HLA DR*04 allele reduced the neuroprotective effect of the Class I alleles. The presence of HLA-DR*04 and the Alzheimer associated allele ApoE4 in the same individual had a synergistic negative effect on cognition (p = 0.003). CONCLUSIONS: Despite major background differences between U.S. and Anhui China cohorts, HLA DR*04 predicted neurocognitive impairment and lower plasma HIV RNA levels in both populations. HLA Class I alleles associated with CD8 T-cell control of HIV were associated with protection from HAND, but protection was reduced in the presence of HLA-DR*04.

APOE epsilon4 and MBL-2 O/O genotypes are associated with neurocognitive impairment in HIV-infected plasma donors.

BACKGROUND: Host genetic factors are important determinants for risk of HIV-1 infection and disease progression. This study examined associations of host genetic variants and neurocognitive impairment in Chinese individuals infected through contaminated blood products. METHODS: Two hundred and one HIV-infected patients from Anhui, China, had neuropsychological tests at baseline and 12 months. DNA was genotyped for APOE epsilon2, epsilon3 and epsilon4 alleles; MBL2-A/O; CCR5-wt/Delta32; CCR5-59029-G/A; CCR2-180-G/A; SDF-1-G/A; IL4-589-C/T; MCP-1-2518-A/G; CX3CR1-745-G/A; -849-C/T polymorphisms and CCL3L1 copy number variants using real-time PCR. Univariate and multivariate analyses were performed. RESULTS: The cohort included 61% men, with mean education 5.5 years, AIDS diagnosis 113 (55%), on antiretrovirals 114 (56%), mean baseline CD4(+) cell count 349 cells/microl and mean log10 RNA 4.09. At baseline, 37% had global neuropsychological impairment increasing to 44% after 12 months. Of 43 patients with the APOE epsilon4 allele, 58% were cognitively impaired compared with 31% without the epsilon4 allele (P = 0.001, odds ratio 3.09, 95% confidence interval 1.54-6.18). The mean global deficit score (GDS) for epsilon4-positive participants on antiretrovirals for 12 months was 0.88 (0.55) compared with 0.63 (0.54) for epsilon4-negative participants (P = 0.053, 95% confidence interval -0.004 to 0.51). For MBL2, 52% of patients with the O/O genotype declined in cognitive function over 12 months compared with 23% with A/A (odds ratio 3.62, 95% confidence interval 1.46-9.03, P = 0.004). No associations were observed for the other genetic variants. CONCLUSION: The APOE epsilon4 allele was associated with increased risk for cognitive deficits, whereas the MBL2 O/O genotype was associated with increased risk for progressive cognitive decline in Chinese individuals infected with HIV through contaminated blood products.

Characterization of cytokine gene expression associated with noninfectious human immunodeficiency virus retinopathy in human autopsy eyes.

PURPOSE: The purpose of this study was to determine the cytokine-related pathogenesis of human immunodeficiency virus retinopathy in human autopsy eyes. METHODS: Fresh autopsy eyes were procured from clinically diagnosed patients with acquired immunodeficiency syndrome who had died as a result of disease-related complications; eyes were immediately immersed in RNAlater. Clean 2-mm trephines were used to punch individual pathologic retina in areas of cotton-wool spots and control punches. Total RNA was extracted using the TRIzol extraction protocol, and the optimal density of the RNA was measured at an optical density of 260 nm. [Delta]Ct (cytokine) values were calculated using the comparative cytokine analysis method. The results are expressed as a mean fold modulation and as a statistical comparison of Ct values controlling for retinal areas without a lesion in the same eye. RESULTS: The fold modulations and the statistical comparisons of the cytokines studied in tissues from cotton-wool spots and control retina, respectively, regulated on activation normal T cell expressed and secreted (RANTES), macrophage inflammatory protein 1beta, macrophage inflammatory protein 1alpha (5.32x, P = 0.04), and Bcl-2-associated X protein (1.24x, P = 0.05) had a marked elevation of fold modulation and were statistically significant compared with control tissue. Interleukin-8 (1.09x, P = 0.18), interleukin-4, and interleukin-10 (2.7x, P = 0.30) were not significantly expressed in cotton-wool spots. CONCLUSION: Certain inflammatory human immunodeficiency virus-associated and apoptotic cytokines are expressed in cotton-wool spots in eyes with human immunodeficiency virus retinopathy.

Intraocular viral and immune pathogenesis of immune recovery uveitis in patients with healed cytomegalovirus retinitis.

PURPOSE: To investigate immune and viral contributions to the pathogenesis of immune recovery uveitis (IRU), which presents as vitritis, macular edema, or formation of epiretinal membranes, and develops in patients with acquired immunodeficiency syndrome (AIDS) who experienced cytomegalovirus (CMV) retinitis before antiretroviral treatment (ART) induced immune reconstitution. METHODS: Aqueous and vitreous fluids from patients with IRU, active CMV retinitis, and control human immunodeficiency virus (HIV)-negative, noninflamed eyes were compared for presence of cytokines IL-6, IL12, interferon gamma using enzyme-linked immunosorbent assay techniques, and CMV DNA (by polymerase chain reaction). RESULTS: IRU eyes (11 patients, 18 samples) had the highest levels of IL-12 (median 48 pg/mL), moderate levels of IL-6 (median 146 pg/mL), and low but significant interferon gamma (median 15 pg/mL), compared to controls (P < 0.01). All uveitis eyes tested (9/9) were CMV DNA negative. In contrast, active CMV retinitis eyes were CMV DNA positive, had higher levels of IL-6 (median 349 pg/mL) (25 patients, 41 samples) than both control (P = 0.0001) and uveitis eyes (P = 0.048), similar levels of interferon gamma (median 27 pg/mL) to uveitis eyes, but less IL-12 (median 0 pg/mL) than uveitis eyes. CONCLUSIONS: Inflammatory IRU can be differentiated from active CMV retinitis by the presence of IL-12, less IL-6, and absence of detectable CMV replication.

Valganciclovir therapy for immune recovery uveitis complicated by macular edema.

PURPOSE: To determine whether treatment with valganciclovir will improve visual acuity in eyes with immune recovery uveitis complicated by macular edema. DESIGN: Prospective open label controlled Phase II drug study. METHODS: Five patients with chronic macular edema as a result of immune recovery uveitis were studied. Baseline fluorescein angiograms, best-corrected ETDRS visions, and cytomegalovirus (CMV) lymphoproliferative T-cell function assays were obtained and repeated after three months of valganciclovir therapy (900 mg daily) and again three months after withdrawal of therapy. RESULTS: Vision improved by a mean of 11 letters in the treatment phase (P =.05). Graded angiograms showed three patients had treatment reduction of macular edema. One patient had rebound increase in macular edema after the withdrawal phase. The CMV lymphoproliferative response was not affected by the valganciclovir. CONCLUSION: Results suggest valganciclovir treatment may benefit visual acuity in patients with macular edema from immune recovery uveitis.