Purpose: To evaluate relationships among retinal vascular caliber and biomarkers of systemic inflammation in patients with AIDS. Methods: A total of 454 participants with AIDS had retinal vascular caliber (central retinal artery equivalent and central retinal vein equivalent) determined from enrollment retinal photographs by reading center graders masked to clinical and biomarker information. Cryopreserved plasma specimens were assayed for inflammatory biomarkers, including C-reactive protein (CRP), IL-6, interferon-γ inducible protein (IP)-10, kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP). Results: In the simple linear regression of retinal vascular caliber on plasma biomarkers, elevated CRP, IL-6, and IP-10 were associated with retinal venular dilation, and elevated KT ratio with retinal arteriolar narrowing. In the multiple linear regression, including baseline characteristics and plasma biomarkers, AMD was associated with dilation of retinal arterioles (mean difference: 9.1 μm; 95% confidence interval [CI] 5.2, 12.9; P < 0.001) and venules (mean difference, 10.9 μm; 95% CI, 5.3, 16.6; P < 0.001), as was black race (P < 0.001). Hyperlipidemia was associated with retinal venular narrowing (mean difference, −7.5 μm; 95% CI, −13.7, −1.2; P = 0.02); cardiovascular disease with arteriolar narrowing (mean difference, −5.2 μm; 95% CI, −10.3, −0.1; P = 0.05); age with arteriolar narrowing (slope, −0.26 μm/year; 95% CI, −0.46, −0.06; P = 0.009); and IL-6 with venular dilation (slope, 5.3 μm/standard deviation log10[plasma IL-6 concentration]; 95% CI, 2.7, 8.0; P < 0.001). Conclusions: These data suggest that retinal vascular caliber is associated with age, race, AMD, hyperlipidemia, cardiovascular disease, and selected biomarkers of systemic inflammation.
Despite detailed analysis of the HIV-1-specific cytotoxic T lymphocyte response by various groups, its relation to viral load and viral sequence variation remains controversial. We analyzed HLA-A*0201 restricted cytotoxic T lymphocyte responses in 17 HIV-1-infected individuals with viral loads ranging from < 400 to 221,000 HIV RNA molecules per milliliter of plasma. In 13 out of 17 infected subjects, CTL responses against the SLYNTVATL epitope (p17 Gag; aa 77-85) were detectable, whereas two other HLA-A*0201 restricted epitopes (ILKEPVHGV, IV9; and VIYQYMDDL, VL9) were only recognized by six and five individuals out of 17 individuals tested, respectively. Naturally occurring variants of the SL9 epitope were tested for binding to HLA-A*0201 and for recognition by specific T cell clones generated from five individuals. Although these variants were widely recognized, they differed by up to 10,000-fold in terms of variant peptide concentrations required for lysis of target cells. A comparison of viral sequences derived from 10 HLA-A*0201-positive individuals to sequences obtained from 11 HLA-A*0201-negative individuals demonstrated only weak evidence for immune selective pressure and thus question the in vivo efficacy of immunodominant CTL responses present during chronic HIV-1 infection.
Immune dysregulation in HIV-1 infection is associated with increased expression of inhibitory molecules such as CTLA-4, TGF-β, and IL-10. In this study we examined one potential mechanism for regulating TGF-β and IL-10 expression by HIV-specific suppressor CD8+ T cells. No overlap between TGF-β, IL-10, and IFN-γ cytokine production by HIV-specific CD8+ T cells was observed. TGF-β positive and IL-10 positive cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. TGF-β and IL-10 positive CD8+ T cells did not express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-β positive and IL-10 positive CD8+ T cell responses, and a concomitant increase in HIV-specific IFN-γ positive CD8+ T cell responses. Depletion of CD4+ T cells abrogated the impact of CTLA-4 on HIV-specific TGF-β positive and IL-10 positive CD8+ T cells. Our study suggests that CTLA-4 Signaling on CD4+ T cells regulates the inhibitory functions of the HIV-specific suppressor CD8+ T cells.
Abstract : The objective of the microwave data transmission test program - Quaternary baseband modem was to design, construct and conduct system tests on a quaternary baseband modulator/demodulator (Modem). The modem is designed to permit the passage of digital data traffic over conventional frequency division multiplex radios with baseband interface. Data rates from 1.536 Mbps to 12.95 Mbps, in 1 Kbps increments, can be accommodated by the QPSK Modem. This program was performed concurrently with a program to develop a modem with an IF interface (QPSK Modem). Of particular interest are the system test results, including bit error rate as a function of received signal level and transmitted spectral occupancy.
The mechanism for the lower rate of disease progression in HIV-2 infection remains undefined. We evaluated T cell activation in a cohort of HIV-infected commercial sex workers in Dakar, Senegal. CD8+ T cell activation was significantly lower in HIV-2- compared to HIV-1-infected volunteers and both groups displayed higher activation levels compared to seronegative individuals. In contrast, CD4+ T cell activation was similar between the HIV-1 and HIV-2 groups and significantly higher compared to the seronegative group. Interestingly, HIV-2-positive volunteers with evidence of Gag-specific CD8+ T cell responses displayed lower CD4+ T cell activation. Our data suggest that the distinct T cell activation profile in HIV-2-positive individuals may reflect on the presence of effective host immune responses in HIV-2 infection.
Rab monomeric GTPases regulate specific aspects of vesicle transport in eukaryotes including coat recruitment, uncoating, fission, motility, target selection and fusion. Moreover, individual Rab proteins function at specific sites within the cell, for example the ER, golgi and early endosome. Importantly, the localization and function of individual Rab subfamily members are often conserved underscoring the significant contributions that model organisms such as Caenorhabditis elegans can make towards a better understanding of human disease caused by Rab and vesicle trafficking malfunction. With this in mind, a bioinformatics approach was first taken to identify and classify the complete C. elegans Rab family placing individual Rabs into specific subfamilies based on molecular phylogenetics. For genes that were difficult to classify by sequence similarity alone, we did a comparative analysis of intron position among specific subfamilies from yeast to humans. This two-pronged approach allowed the classification of 30 out of 31 C. elegans Rab proteins identified here including Rab31/Rab50, a likely member of the last eukaryotic common ancestor (LECA). Second, a molecular toolset was created to facilitate research on biological processes that involve Rab proteins. Specifically, we used Gateway-compatible C. elegans ORFeome clones as starting material to create 44 full-length, sequence-verified, dominant-negative (DN) and constitutive active (CA) rab open reading frames (ORFs). Development of this toolset provided independent research projects for students enrolled in a research-based molecular techniques course at California State University, East Bay (CSUEB).
Whereas the human fetal immune system is poised to generate immune tolerance and suppress inflammation in utero, an adult-like immune system emerges to orchestrate anti-pathogen immune responses in post-natal life. It has been posited that cells of the adult immune system arise as a discrete ontological “layer” of hematopoietic stem-progenitor cells (HSPCs) and their progeny; evidence supporting this model in humans has, however, been inconclusive. Here, we combine bulk and single-cell transcriptional profiling of lymphoid, myeloid, and HSPCs from fetal, perinatal, and adult developmental stages to demonstrate that the fetal-to-adult transition occurs progressively along a continuum of maturity — with a substantial degree of interindividual variation at the time of birth — rather than via a transition between discrete waves. These findings have important implications in the design of strategies for prophylaxis against infection in the newborn, and for the use of umbilical cord blood (UCB) in the setting of transplantation.
HIV infection is characterized by a decrease in total CD4 cell count, rising viral load, as well as an increase in immune activation levels. Increased activation can lead to an increase in apoptosis and contribute to CD4 depletion. We evaluated the clinical and immunologic responses of 23 HIV-positive Ugandan volunteers following initiation of antiretroviral therapy (ART). All volunteers achieved and maintained complete viral suppression within the first 3 months of therapy (p > 0.05). CD4+ and CD8+ T cell activation also decreased significantly, although it never reached the level of HIV negative Ugandan volunteers. Viral suppression and CD4 cell recovery were also associated with an improved profile in CD8+ T cell functional markers, but had no effect on HIV-specific proliferation. We conclude that ART in a cohort of therapy-naive Ugandans with AIDS partially restores but does not fully reverse the immune dysfunction observed in chronic HIV infection.
The entire population of Graciosa Bay, Santa Cruz, Solomon Islands, was tested for hepatitis B surface antigen (HB5Ag) by reverse passive hemagglutination and antibody to HBsAg (anti-HBs) sby passive hemagglutination. Analysis of the distribution of HBsAg in relatives of HBsAg carriers and non-carriers showed clustering only in children of carrier mothers. Similarly, there was no clustering of total exposure as measured by serologic tests except in children of carrier parents primarily due to the antibody and antigen of children of carrier mothers. This distribution pattern is probably due to cultural and environmental factors which increase exposure between HBsAg carriers and people who are not related to them and also reduce the amount of contact between siblings.
Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1-infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound was analyzed using the Kaplan-Meier method. Vesatolimod was associated with induction of immune cell activation, decreases in intact proviral DNA during ART, and a modest increase in time to rebound after ART was interrupted. The delayed viral rebound was predicted by the lower intact proviral DNA at the end of vesatolimod treatment (13 days after the final dose). Inferred pathway analysis suggested increased dendritic cell and natural killer cell cross-talk and an increase in cytotoxicity potential after vesatolimod dosing. Larger clinical studies will be necessary to assess the efficacy of vesatolimod-based combination therapies aimed at long-term control of HIV infection.
