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IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection. - The Journal of clinical investigation
In HIV-1-infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1-infected patients. Compared with healthy controls, untreated HIV-1-infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. VÎ² expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1-infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1-infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients.
Duration of Viral Suppression and Risk of Rebound Viremia with First-Line Antiretroviral Therapy in Rural Uganda. - AIDS and behavior
Little is known about associations between viral suppression, adherence, and duration of prior viral suppression in sub-Saharan Africa. Study participants were from the UARTO study in Mbarara, Uganda. We fit regression models to characterize relationships between average adherence, treatment interruptions, and rebound viremia (>400 copies/mL) following a previously undetectable result. Our goal was to understand the impact of prior viral suppression on these relationships. 396 participants contributed 2864 quarterly visits. Restricted to periods with average adherence <50Â %, each 10Â % increase in adherence reduced the odds of rebound viremia by 74Â % [adjusted odds ratio (AOR)Â =Â 0.26, PÂ =Â 0.002] and 29Â % (AORÂ =Â 0.71, PÂ =Â 0.057) during the first 12Â months of suppression and beyond 12Â months respectively, interaction term PÂ =Â 0.018. Among periods with adherence â‰¥50Â %, the risk of rebound viremia decreased with increasing adherence during the first 12Â months of viral suppression (AORÂ =Â 0.73 for each 10Â % increase, PÂ =Â 0.001), but not thereafter (AORÂ =Â 1.09, PÂ =Â 0.67), interaction term PÂ =Â 0.027. In contrast, 72-h interruptions, were associated with increased rebound viremia during the first 12Â months (AORÂ =Â 1.30, PÂ =Â 0.009) and after (AORÂ =Â 1.39, PÂ =Â 0.005), interaction term PÂ =Â 0.69. Completing 12Â months of viral suppression decreases the impact of average adherence, but not prolonged treatment interruptions, on risk of rebound viremia.
D-dimer levels and traditional risk factors are associated with incident hypertension among HIV-infected individuals initiating antiretroviral therapy in Uganda. - Journal of acquired immune deficiency syndromes (1999)
We sought to describe blood pressure changes after antiretroviral therapy (ART) initiation and evaluate the association of markers of inflammation with incident hypertension in a cohort of HIV-individuals in Uganda.We used mixed effects linear regression to model changes in systolic blood pressure (BP) over time among a cohort of HIV-infected individuals initiating ART in Uganda. After exclusion of participants with pre-existing hypertension, we identified participants with normal BP throughout follow-up (controls) and those with elevated BP on â‰¥3 consecutive visits (cases). Prior to ART initiation, participants had testing for lnterleukin-6, kynurenine/tryptophan ratio, lipopolysaccharide, soluble CD14, soluble CD163, and D-dimer and those with viral suppression at six months during ART had repeat tests. We fit logistic regression models to estimate associations between biomarkers and risk of incident hypertension.In the entire cohort, systolic BP increased by 9.6 mmHg/year (95% CI 7.3 - 11.8) in the first six months of ART, then plateaued. Traditional factors: male gender (AOR 2.76, 95% CI 1.34-5.68), age (AOR 1.09, 95% CI 1.04-1.13), overweight (AOR 4.48, 95%CI 1.83-10.97), and a CD4 count < 100 cells (AOR 3.08, 95% CI 1.07-8.89) were associated with incident hypertension. After adjusting for these, D-dimer levels at month 6 were inversely associated with incident hypertension (AOR 0.61, 95% CI 0.37-0.99). Although not significant, similar associations were seen with sCD14 and Kynurenine/Tryptophan (K/T) ratio.Blood pressure increases early after ART initiation in Ugandans. Traditional risk factors, rather than immune activation were associated with incident hypertension in this population.
Non-R5-tropic HIV-1 in subtype A1 and D infections were associated with lower pretherapy CD4+ cell count but not with PI/(N)NRTI therapy outcomes in Mbarara, Uganda. - AIDS (London, England)
Previous studies suggest that infection with non-R5-tropic subtype B HIV-1, compared with R5, is associated with a more rapid decline in CD4 cell count, but does not affect PI/(N)NRTI therapy outcome. Here, we explored clinical correlates associated with viral tropism in subtype A1 and D infections.HIV-1 subtype A1 (nâ€Š=â€Š196) and D (nâ€Š=â€Š143) pretherapy plasma samples and up to 7.5 years of posttherapy virologic and CD4 data were collected from a cross-sectional cohort in Mbarara, Uganda. Tropism and subtype were inferred using env V3 (geno2pheno) and gp41 (RIP) Sanger sequences. For each subtype, R5 infection was compared with non-R5 in terms of: pretherapy viral load and CD4 cell count (Mann-Whitney tests), and therapy outcomes, including time to virologic suppression, postsuppression virologic rebound, CD4 decline and CD4 recovery (log-rank tests).A 94% of all patients in this study achieved virologic suppression within median 3 months posttherapy. In both subtypes, non-R5 infection was associated with lower pretherapy CD4 cell count (non-R5 vs. R5; A: median 57 vs. 147â€Šcells/Î¼l Pâ€Š=â€Š0.005; D: 80 vs. 128â€Šcells/Î¼l Pâ€Š=â€Š0.006). Multivariable linear regression confirmed that tropism, not subtype nor the interaction between subtype and tropism, was a significant predictor of pretherapy CD4 cell count (Pâ€Š<â€Š0.0001). None of pretherapy viral load, time to virologic suppression, virologic rebound, CD4 decline nor CD4 recovery was significantly different (all Pâ€Š>â€Š0.09).Regardless of HIV-1 subtype or tropism, the majority of patients in this Ugandan cohort responded to therapy, even though non-R5 infection was associated with lower pretherapy CD4 cell count.
Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans. - AIDS (London, England)
Plasma kynurenine/tryptophan ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of kynurenine/tryptophan ratio in HIV-infected ART-suppressed Ugandans.We performed genome-wide and exome array genotyping and measured plasma kynurenine/tryptophan ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated more than 16 million single nucleotide polymorphisms in association with log10 kynurenine/tryptophan ratio using linear mixed models adjusted for cohort, sex, pregnancy, and ancestry.Among 597 Ugandans, 62% were woman, median age was 35, median baseline CD4 cell count was 135 cells/Î¼l, and median baseline HIV-1 RNA was 5.1â€Šlog10â€Šcopies/ml. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log10 kynurenine/tryptophan ratio (Pâ€Š<â€Š5.0â€ŠÃ—â€Š10). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (Pâ€Š<â€Š5.0â€ŠÃ—â€Š10), including genes encoding protein tyrosine phosphatases (PTPRM and PTPRN2) and the vitamin D metabolism gene, CYP24A1. Several of these single nucleotide polymorphisms were associated with markers of inflammation, coagulation, and monocyte activation, but did not replicate in a small US cohort (Nâ€Š=â€Š262; 33% African-American).Our findings highlight a potentially important role of IFN-Î³, TNF-Î±, and Toll-like receptor signaling in determining IDO activity and subsequent mortality risk in HIV-infected ART-suppressed Ugandans. These results also identify potential novel pathways involved in IDO immunoregulation. Further studies are needed to confirm these findings in treated HIV-infected populations.
Relationship Power and Sexual Violence Among HIV-Positive Women in Rural Uganda. - AIDS and behavior
Gender-based power imbalances place women at significant risk for sexual violence, however, little research has examined this association among women living with HIV/AIDS. We performed a cross-sectional analysis of relationship power and sexual violence among HIV-positive women on anti-retroviral therapy in rural Uganda. Relationship power was measured using the Sexual Relationship Power Scale (SRPS), a validated measure consisting of two subscales: relationship control (RC) and decision-making dominance. We used multivariable logistic regression to test for associations between the SRPS and two dependent variables: recent forced sex and transactional sex. Higher relationship power (full SRPS) was associated with reduced odds of forced sex (AORÂ =Â 0.24; 95Â % CI 0.07-0.80; pÂ =Â 0.020). The association between higher relationship power and transactional sex was strong and in the expected direction, but not statistically significant (AORÂ =Â 0.47; 95Â % CI 0.18-1.22; pÂ =Â 0.119). Higher RC was associated with reduced odds of both forced sex (AORÂ =Â 0.18; 95Â % CI 0.06-0.59; pÂ <Â 0.01) and transactional sex (AORÂ =Â 0.38; 95Â % CI 0.15-0.99; pÂ =Â 0.048). Violence prevention interventions with HIV-positive women should consider approaches that increase women's power in their relationships.
Immune Activation and HIV-Specific CD8(+) T Cells in Cerebrospinal Fluid of HIV Controllers and Noncontrollers. - AIDS research and human retroviruses
The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIV-specific CD8(+) T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4(+) and CD8(+) T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8(+) T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8(+) T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/Î¼l. The majority of HIV-specific CD8(+) T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy.
Larval development assays reveal the presence of sub-populations showing high- and low-level resistance in a monepantel (Zolvix(Â®))-resistant isolate of Haemonchus contortus. - Veterinary parasitology
Resistance to the amino-acetonitrile derivative monepantel has been reported in several species of gastrointestinal nematodes over recent years. We were interested in the use of in vitro assays with free-living worm life-stages to detect resistance to this drug. We therefore used larval development and larval migration assays to examine dose response relationships for the drug against two susceptible and one resistant isolate of Haemonchus contortus. The resistant isolate was established by laboratory propagation of the survivors of a field treatment with Zolvix(Â®) that had originally resulted in a drug efficacy of over 99%. Drug efficacy against this field-derived laboratory-propagated resistant isolate in vivo was approximately 15%. The larval development assay proved able to discriminate between the susceptible and resistant isolates, with larvae of the resistant isolate showing an ability to develop at higher drug concentrations than the two susceptible isolates. The resistant isolate showed the presence of two distinct subpopulations, separated by a plateau in the dose-response curve. Sub-population 1 (approximately 40% of the total population) showed a low level of resistance with an IC50 increased approximately 7-fold compared to the baseline susceptible isolate, while sub-population 2 (the remaining 60% of the total population) showed an IC50 increased over 1000-fold compared to the baseline susceptible isolate. This level of resistance is unusually high for any gastrointestinal nematode species in drug dose-response in vitro assays. In contrast, the migration assay could not discriminate between the three isolates, with migration not reduced to zero at any of the drug concentrations tested. This study demonstrates that a larval development assay is able to detect resistance to monepantel in H. contortus, and that resistance can exist in two distinct forms. This suggests that at least two separate monepantel resistance mechanisms are acting within the worm isolate studied here, with one or more mechanisms conferring a much higher level of resistance than the other(s).Crown Copyright Â© 2016. Published by Elsevier B.V. All rights reserved.
Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus-Associated Acquired Immunodeficiency Syndrome. - Cell host & microbe
Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation ofÂ microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 TÂ cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4Â T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.Copyright Â© 2016 Elsevier Inc. All rights reserved.
Immunologic profiles distinguish aviremic HIV-infected adults. - AIDS (London, England)
Prior hypothesis-driven studies identified immunophenotypic characteristics associated with the control of HIV replication without antiretroviral therapy (HIV controllers) as well as with the degree of CD4 T-cell recovery during ART. We hypothesized that an unbiased 'discovery-based' approach might identify novel immunologic characteristics of these phenotypes.We performed immunophenotyping on four 'aviremic' patient groups: HIV controllers (nâ€Š=â€Š98), antiretroviral-treated immunologic nonresponders (CD4â€Š<â€Š350; nâ€Š=â€Š59), antiretroviral-treated immunologic responders (CD4â€Š>â€Š350, nâ€Š=â€Š142), and as a control group HIV-negative adults (nâ€Š=â€Š43). We measured levels of T-cell maturation, activation, dysfunction, senescence, functionality, and proliferation.Supervised learning assessed the relative importance of immune parameters in predicting clinical phenotypes (controller, immunologic responder, or immunologic nonresponder). Unsupervised learning clustered immune parameters and examined if these clusters corresponded to clinical phenotypes.HIV controllers were characterized by high percentages of HIV-specific T-cell responses and decreased percentages of cells expressing human leukocytic antigen-antigen D related in naive, central memory, and effector T-cell subsets. Immunologic nonresponders were characterized by higher percentages of CD4 T cells that were TNFÎ±+ or INFÎ³+, higher percentages of activated naive and central memory T cells, and higher percentages of cells expressing programmed cell death protein 1. Unsupervised learning found two distinct clusters of controllers and two distinct clusters of immunologic nonresponders, perhaps suggesting different mechanisms for the clinical outcomes.Our discovery-based approach confirmed previously reported characteristics that distinguish aviremic individuals, but also identified novel immunologic phenotypes and distinct clinical subpopulations that should lead to more focused pathogenesis studies that might identify targets for novel therapeutic interventions.
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