Search

Human immunodeficiency virus (HIV) is a retrovirus that infects and destroys CD4 T cells. In the United States, HIV infection affects an estimated 1,189,700 individuals 13 years and older. (1) [...]

Byline: Divya. Nagabushana, Thavasimuthu. Nishamol, Kajari. Bhattacharya, Jitender. Saini, Ravindranadh. Chowdary, Anita. Mahadevan, Kiran. Polavarapu, Nalini. Atchayaram Anti-N-methyl-D-aspartate-receptor (A-NMDAR) encephalitis is the most common type of autoimmune encephalitis in the [...]

Chronic HIV-1 infection is generally characterized by progressive [CD4.sup.+] T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of [CD4.sup.+] T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating [CD4.sup.+] T cells, which revealed that pyroptotic and apoptotic [CD4.sup.+] T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in [CD4.sup.+] T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1-infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in [CD4.sup.+] T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in [CD4.sup.+] T cell loss in HIV-1-infected patients and implicate pyroptosis signaling as a target for anti-HIV-1 treatment., Introduction Human immunodeficiency virus type 1 (HIV-1) infection leads to a progressive loss of [CD4.sup.+] T cells, which has long been recognized as central to HIV-1 pathogenesis but remains to [...]

Clonal expansion of infected CD[4.sup.+] T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor [beta]-chain (TCR[beta]) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD[4.sup.+] T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCR[beta] repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCR[beta] and integration site analysis showed that infection could occur early or late in the course of a clone's response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts., Introduction Latently infected CD[4.sup.+] T cells represent the main barrier to an HIV-1 cure (1-3). Decay of the latent reservoir, defined as the pool of cells containing inducible and replication-competent [...]

The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human [CD4.sup.+] cells that are shed into cervicovaginal secretions (CVS). A high percentage of the [CD4.sup.+] T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of [CD4.sup.+] and [CD8.sup.+] T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA* cells in both the FRT and CVS., Introduction Most clinical trials of HIV prevention have aimed at preventing HIV acquisition by topical or systemic administration of preventative antiretroviral drugs to uninfected individuals (1-10). Results from these clinical [...]

Background: Mycobacterium tuberculosis has been shown to enhance antibody responses against diverse viruses, potentially via the impact of lipid antigens or trained immunity. We hypothesized that active tuberculosis (TB) enhances the development of HIV-1 neutralizing antibodies in HIV-1 co-infection. Methods: We compared anti-HIV-1 antibody responses among treatment-naive plasma samples from 15 HIV-1 participants with TB (HIV-1/TB) and 16 HIV-1 participants without TB. Ability to inhibit 12 different tier 1 and 2 HIV-1 variants of diverse subtypes in the TZM-bl neutralization assay was used to estimate a neutralization breadth and potency (BP) score. ELISA was used to compare antibody titers against other latent infections. Results: HIV-1/TB and HIV-1 infected participants had similar baseine plasma virus levels (p = 0.33) and CD4 counts (p = 0.40). HIV-1/TB individuals had a significantly higher BP score (0.57 [+ or -] 0.05, range 0.32 to 0.97) than HIV-1 group (0.41 [+ or -] 0.05, range 0.24 to 0.57, p = 0.02). The plasma activity of 6 HIV-1/TB individuals with high baseline BP scores clustered with CD4 binding site and membrane-proximal external region targeting broadly neutralizing antibodies (bnAbs). After completing TB treatment and/or starting HIV-1 therapy for 6 months, HIV-1/TB (0.64 [+ or -] 0.09, n = 6, range 0.22 to 0.99) as compared to HIV-1 participants (0.48 [+ or -] 0.09, n = 8, range 0.26 to 0.78) still had higher neutralizing capacity, but the difference was not statistically significant (p = 0.11). Neutralization BP score did not correlate with the total plasma IgG, baseline viral load, CD4 count, IL-6, sCD163, and MCP-1 concentrations. HIV-1/TB (0.02 [+ or -] 0.01) as compared to HIV-1 (0.03 [+ or -] 0.01; p = 0.68) group had similar level of HIV-1 envelope diversity. The HIV-1/TB and HIV-1 only participants had similar anti-tetanus (p = 0.44) and anti-HSV (p = 0.25) antibody titers. Conclusions: Our results suggest that active TB enhances the neutralizing capacity of anti-HIV-1 antibodies, possibly leading to the emergence of bnAbs that target conserved envelope domains. TB neither potentiates pre-existing antibody responses against latent infections nor correlates with other factors previously shown to be important for bnAb emergence. Mechanisms that account for the enhanced HIV-1 neutralization in HIV-1 individuals with active TB could be leveraged in the generation of a more effective humora response in HIV-1 vaccination and treatment., OA08.04 B. Adeoye (1); A.J. Olson (2); L. Nakiyingi (3); Y.C. Manabe (4); K.R. Jacobson (5); J. Ellner (6) and M. Sagar (7) (1) Boston University School of Medicine, Microbiology, [...]

Chronic immune activation is a key factor in HIV-1 disease progression. The translocation of microbial products from the intestinal lumen into the systemic circulation occurs during HIV-1 infection and is associated closely with immune activation; however, it has not been determined conclusively whether microbial translocation drives immune activation or occurs as a consequence of HIV-1 infection. In an important study in this issue of the JCI, Kristoff and colleagues describe the role of microbial translocation in producing immune activation in an animal model of HIV-1 infection, SIV infection of pigtailed macaques. Blocking translocation of intestinal bacterial LPS into the circulation dramatically reduced T cell activation and proliferation, production of proinflammatory cytokines, and plasma SIV RNA levels. This study directly demonstrates that microbial translocation promotes the systemic immune activation associated with HIV-1/SIV infection., Immune activation and disease progression in HIV-1 infection In humans, the gut-associated lymphoid tissue (GALT) contains a large number of activated [CD4.sup.+][CCR5.sup.+] T cells, thus serving as a major site [...]

HIV infection is a global disease that disproportionately burdens populations with nutritional vulnerabilities. Laboratory experiments have shown that selenium has an inhibitory effect on HIV in vitro through antioxidant effects of glutathione peroxidase and other selenoproteins. Numerous studies have reported low selenium status in HIV-infected individuals, and serum selenium concentration declines with disease progression. Some cohort studies have shown an association between selenium deficiency and progression to AIDS or mortality. In several randomized controlled trials, selenium supplementation has reduced hospitalizations and diarrheal morbidity, and improved [CD4.sup.+] cell counts, but the evidence remains mixed. Additional trials are recommended to study the effect of selenium supplementation on opportunistic infections, and other HIV disease-related comorbidities in the context of highly active antiretroviral therapy in both developing and developed countries. doi: 10.1111/j.1753-4887.2010.00337.x

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.socscimed.2010.07.025 Byline: Jane P. Messina (a), Michael Emch (a), Jeremie Muwonga (b), Kashamuka Mwandagalirwa (b), Samuel B. Edidi (b), Nicaise Mama (b), Augustin Okenge (b), Steven R. Meshnick (c) Abstract: This study uses a 2007 population-based household survey to examine the individual and community-level factors that increase an individual's risk for HIV infection in the Democratic Republic of Congo (DRC). Using the 2007 DRC Demographic Health Surveillance (DHS) Survey, we use spatial analytical methods to explore sub-regional patterns of HIV infection in the DRC. Geographic coordinates of survey communities are used to map prevalence of HIV infection and explore geographic variables related to HIV risk. Spatial cluster techniques are used to identify hotspots of infection. HIV prevalence is related to individual demographic characteristics and sexual behaviors and community-level factors. We found that the prevalence of HIV within 25 km of an individual's community is an important positive indicator of HIV infection. Distance from a city is negatively associated with HIV infection overall and for women in particular. This study highlights the importance of improved surveillance systems in the DRC and other African countries along with the use of spatial analytical methods to enhance understanding of the determinants of HIV infection and geographic patterns of prevalence, thereby contributing to improved allocation of public health resources in the future. Author Affiliation: (a) University of North Carolina, Department of Geography and Carolina Population Center, Chapel Hill, NC, United States (b) Ministry of Health, Democratic Republic of Congo (c) Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC, United States Article Note: (footnote) [star] Funding for this paper and the Center for Accurate Data on Endemic and Emerging Infectious Diseases in Developing Countries was provided through the Gillings Innovation Labs program. JM was funded by the NSF IGERT program at the Carolina Population Center.

In the absence of treatment, most HIV-1-infected humans develop AIDS. However, a minority are long-term nonprogressors, and resistance is associated with the presence of particular HLA-[B.sup.*]27/ [B.sup.*]57 molecules. In contrast, most HIV-1-infected chimpanzees do not contract AIDS. In comparison with humans, chimpanzees experienced an ancient selective sweep affecting the MHC class I repertoire. We have determined the peptide-binding properties of frequent chimpanzee MHC class I molecules, and show that, like HLA-[B.sup.*]27/[B.sup.*]57, they target similar conserved areas of HIV-1/[SIV.sub.cpz]. In addition, many animals appear to possess multiple molecules targeting various conserved areas of the HIV-1/[SIV.sub.cpz] Gag protein, a quantitative aspect of the immune response that may further minimize the chance of viral escape. The functional characteristics of the contemporary chimpanzee MHC repertoire suggest that the selective sweep was caused by a lentiviral pandemic. HIV/SIV | peptide-binding | selection | selective sweep doi/ 10.1073/pnas.1009136107

HIV infection can persist in spite of efficacious antiretroviral therapies. Although incomplete inhibition of viral replication may contribute to this phenomenon, this is largely due to the early establishment of a stable reservoir of latently infected cells. Thus, life-long antiviral therapy may be needed to control HIV. Such therapy is prone to drug resistance and cumulative side effects and is an unbearable financial burden for regions of the world hit hardest by the epidemic. This review discusses our current understanding of HIV persistence and the limitations of potential approaches to eradicate the virus and accordingly pleads for a joint multidisciplinary effort toward two highly related goals: the development of an HIV prophylactic vaccine and the achievement of long-term drug-free remissions in HIV-infected individuals. 10.1126/science.1191047

We conducted a retrospective cohort study to determine the 3-year reincarceration rate of all HIV-infected inmates (n = 1917) released from the Texas prison system between January 2004 and March 2006. We also analyzed postrelease changes in HIV clinical status in the subgroup of inrnates who were subsequently re- incarcerated and had either CD4 lymphocyte counts (n = 119) or plasma HIV RNA levels (n = 122) recorded in their electronic medical record at both release and reincarceration. Multivariable analyses were performed to assess predictors of reincarceration and clinical changes in HIV status. Only 20% of all HIV-infected inmates were reincarcerated within 3 years of release. Female inmates (hazard ratio [HR] 0.63; 95% confidence interval [CI], 0.47, 0.84) and inmates taking antiretroviral therapy at the time of release (HR 0.31; 95% CI, 0.25, 0.39) were at decreased risk of reincarceration. African Americans (HR 1.58; 95% CI, 1.22, 2.05), inmates with a major psychiatric disorder (HR 1.82; 95% CI, 1.41, 2.34), and inmates released on parole (HR 2.86; 95% CI, 2.31, 3.55) were at increased risk of reincarceration. A subgroup of reincarcerated inmates had a mean decrease in CD4 cell count of 79.4 lymphocytes per microliter (p < 0.0003) and a mean increase in viral load of 1.5 log10 copies per milliliter (p < 0.0001) in the period between release and reincarceration. Our findings, although substantially limited by selection bias, highlight the importance of developing discharge planning programs to improve linkage to community-based HIV care and reduce recidivism among released HIV-infected inmates. DOI: 10.1089/apc.2009.0303

Problem statement: HIV infected and neonatal candidaemia is a serious condition where proper selection of the antifungal agent is the key factor in the prognosis of the disease. Thus in this study susceptibility of Candida species to Amphotericin B was explored in such patients. Approach: Forty different Candida isolates obtained from blood culture of such candidaemia cases were tested for Amphotericin B susceptibility by disc diffusion method and by microdilution method. Results: There was a good correlation between low MIC values and large inhibition zones among most isolates as expected, particularly with 24 h reading. Several outlier data were also observed during the study. After analysis it was found that 24 h microdilution method results were better for interpretation of susceptibility results. Conclusion: Microdilution method is the reliable method for susceptibility testing of Candida isolates from HIV infected and neonatal candidaemia patients to Amphotericin B. Key words: Candidaemia, disc diffusion, microdilution, INTRODUCTION Candidiasis is a common opportunistic infection in immunocompromised hosts and candidaemia causes significant morbidity and mortality in this group of patients (Richards et al., 1999). In recent past, life-threatening [...]

Human immunodeficiency virus (HIV)-1-associated nephropathy (HIVAN) is characterized by proliferation of glomerular and tubular epithelial cells. We studied the role of epithelial mesenchymal transdifferentiation (EMT) in the development of HIVAN phenotype. Renal cortical sections from six FVB/N (control) and six Tg26 (HIVAN) mice were immunolabeled for PCNA, [alpha]-smooth muscle actin ([alpha]-SMA), fibroblast-specific protein-1 (FSP1), CD3, and F4/80. Since periglomerular cells (PGCs) and peritubular cells (PTCs) did not show any labeling for CD3 and F4/80 but showed labeling for [alpha]-SMA or FSP1, it appears that these were myofibroblasts that migrated from either glomerular or tubular sites, respectively. Occurrence of EMT was also supported by diminished expression of E-cadherin by renal epithelial cells in Tg26 mice. Interestingly, Tg26 mice also showed enhanced renal tissue expression of ZEB2; henceforth, it appears that transcription of molecules required for maintenance of de novo renal epithelial cell phenotype was suppressed. To evaluate the role of ANG II, Tg26 mice in groups of three were administered either normal saline or telmisartan (an [AT.sub.1] receptor blocker) for 2 wk, followed by evaluation for renal cell EMT. Renal cortical section of Tg26 mice showed a sevenfold increase (P < 0.001) in parietal epithelial cell (PEC)-PGC and a threefold increase (P < 0.01) in tubular cell (TC)-PTC proliferation (PCNA-positive cells). Similarly, both PECs-PGCs and TCs-PTCs in Tg26 mice showed enhanced expression of [alpha]-SMA and FSP1. Both PECs and podocytes contributed to the glomerular proliferative phenotype, but the contribution of PECs was much greater. Telmisartan-receiving Tg26 mice (TRM) showed attenuated number of proliferating PECs-PGCs and TCs-PTCs compared with saline-receiving Tg26 mice (SRM). Similarly, TRM showed diminished expression of [alpha]-SMA and FSP1 by both PECs-PGCs and TCs-PTCs compared with SRM. We conclude that EMT contributes to the manifestation of the proliferative phenotype in HIVAN mice. human immunodeficiency virus-1-associated nephropathy; renal epithelial cells; smooth muscle actin doi:10.1152/ajprenal.00415.2009

Lens epithelium-derived growth factor (LEDGF) fusion proteins can direct HIV-1 DNA integration to novel sites in the host genome. The C terminus of LEDGF contains an integrase binding domain (IBD), and the N terminus binds chromatin. LEDGF normally directs integrations to the bodies of expressed genes. Replacing the N terminus of LEDGF with chromatin binding domains (CBDs) from other proteins changes the specificity of HIV-1 DNA integration. We chose two well-characterized CBDs: the plant homeodomain (PHD) finger from ING2 and the chromodomain from heterochromatin binding protein 1[alpha] (HP1[alpha]). The lNG2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1[alpha] chromodomain binds H3K9me2,3, histone marks that are widely distributed throughout the genome. A fusion protein in which the ING2 PHD finger was linked to the LEDGF IBD directed integrations near the start sites of expressed genes. A similar fusion protein in which the HP1[alpha] chromodomain was linked to the LEDGF IBD directed integrations to sites that differed from both the PHD finger fusion-directed and LEDGF-directed integration sites. The ability to redirect HIV-1 DNA integration may help solve the problems associated with the activation of oncogenes when retroviruses are used in gene therapy. chromatin | histone marks | lentiviral vectors www.pnas.org/cgi/doi/10.1073/pnas.0914142107

Both activated and resting [CD4.sup.+] T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin [[alpha].sub.4][[beta].sub.7] ([[alpha].sub.4][[beta].sub.7]), the gut mucosal homing receptor. We find that [[alpha].sub.4][[beta].sub.7.sup.high] [CD4.sup.+] T cells are more susceptible to productive infection than are [[alpha].sub.4][[beta].sub.7.sup.low-neg] [CD4.sup.+]T cells in part because this cellular subset is enriched with metabolically active [CD4.sup.+]T cells, [[alpha].sub.4][[beta].sub.7.sup.high] [CD4.sup.+]T cells are [CCR5.sup.high] and [CXCR4.sup.low]; on these cells, [[alpha].sub.4][[beta].sub.7]appears in a complex with CD4. The specific affinity of gp120 for [[alpha].sub.4][[beta].sub.7] provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission. integrin receptor | transmission | gut-associated lymphoid tissues (GALT) doi/10.1073/pnas.0911796106

Integration of HIV-1 linear DNA into the host chromatin is an essential step in the viral life cycle. However, the majority of reverse-transcribed, nuclear-imported viral genomes remain episomal, either as linear or circular DNA. To date, these nonintegrated viral genomes are largely considered 'dead-end products' of reverse transcription. Indeed, limited gene expression from nonintegrated HIV-1 has been reported, although the mechanism that renders nonintegrating HIV-1 genomes incapable of supporting efficient viral replication has not been fully elucidated. Here, we demonstrate that nonintegrating HIV-1 and HIV-l-based vector genomes are organized into chromatin structures and enriched with histone modifications typical of transcriptionally silenced chromatin. Gene expression and replication of nonintegrating HIV-1 was notably increased in vitro upon exposure to histone deacetylase inhibitors (HDACi) in the form of various short-chain fatty acids (SCFAs) known to be endogenously produced by normal microbial-gut flora. Furthermore, we demonstrated genetic and functional crosstalk between episomal and integrated vector/viral genomes, resulting in recombination between integrated and nonintegrated HIV-1, as well as mobilization of episomal vector genomes by productive viral particles encoded by integrated viral genomes. Finally, we propose a mechanism describing the role of episomal HIV-1 forms in the viral life cycle in a SCFA-rich gut environment. episomal expression | HDAC inhibitors | histone modifications www.pnas.org/cgi/doi/10.1073/pnas.0905859106

One third of the world's population is infected with Mycobacterium tuberculosis, and [approximately equal to]9 million tuberculosis (TB) cases were diagnosed worldwide in 2006 (1). Introduced in the early 1990s, [...]

Fusion between the membrane of HIV and the membrane of a host cell is a crucial step in HIV infection and is catalyzed by the binding of the fusion peptide domain (HFP) of the HIV gp41 protein to the host cell membrane. The HFP by itself induces vesicle fusion and is a useful model system to understand the fusion peptide/host cell membrane interaction. This article reports an experimental correlation between the membrane locations of different HFP constructs and their fusogenicities. The constructs were the HFP monomer with Val-2 to Glu-2 mutation (HFPmn_mut), wild type HFP monomer (HFPmn), and wild type HFP trimer (HFPtr). All constructs have predominant [beta] sheet structure in membranes with physiologically relevant cholesterol content. HFPmn_mut does not fuse vesicles, HFPmn has moderate fusion rate, and HFPtr has the putative oligomerization state of HIV gp41 and a very rapid fusion rate. The HFP membrane locations were probed with solid-state NMR measurements of distances between labeled carbonyl ([sup.13]CO) nuclei in the HFP backbone and lipid nuclei in the surface or interior regions of the membrane bilayer. HFPmn_mut is located at the membrane surface, HFPmn is inserted into a single membrane leaflet, and HFPtr is the most deeply inserted construct with contact with the center of the membrane. These results show a clear positive correlation between the insertion depths and the fusion activities of the HFP constructs. Other disease-causing enveloped viruses contain fusion peptides and this correlation may be a general structure-function model for these peptides. NMR | enveloped virus | AIDS | trimer | location