- Detection of Neutralizing Antibodies in HIV-1 Patients on Antiretroviral Treatment for Over Ten Years. [Journal Article]
- CLClin Lab 2019 Jul 01; 65(7)
- CONCLUSIONS: We thus confirm the possibility of production of neutralizing antibodies in patients infected for over ten years on ART, and it is possible over time of the improvement of HIV-1 potent neutralizing activity associated with viremia and immune reconstruction.
- Conserved Residue Asn-145 in the C-Terminal Heptad Repeat Region of HIV-1 gp41 is Critical for Viral Fusion and Regulates the Antiviral Activity of Fusion Inhibitors. [Journal Article]
- VViruses 2019 Jul 03; 11(7)
- Entry of HIV-1 into target cells is mediated by its envelope (Env) glycoprotein composed of the receptor binding subunit gp120 and the fusion protein gp41. Refolding of the gp41 N- and C-terminal hep…
Entry of HIV-1 into target cells is mediated by its envelope (Env) glycoprotein composed of the receptor binding subunit gp120 and the fusion protein gp41. Refolding of the gp41 N- and C-terminal heptad repeats (NHR and CHR) into a six-helix bundle (6-HB) conformation drives the viral and cellular membranes in close apposition and generates huge amounts of energy to overcome the kinetic barrier leading to membrane fusion. In this study, we focused on characterizing the structural and functional properties of a single Asn-145 residue, which locates at the middle CHR site of gp41 and is extremely conserved among all the HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates. By mutational analysis, we found that Asn-145 plays critical roles for Env-mediated cell-cell fusion and HIV-1 entry. As determined by circular dichroism (CD) spectroscopy and isothermal titration calorimetry (ITC), the substitution of Asn-145 with alanine (N145A) severely impaired the interactions between the NHR and CHR helices. Asn-145 was also verified to be important for the antiviral activity of CHR-derived peptide fusion inhibitors and served as a turn-point for the inhibitory potency. Intriguingly, Asn-145 could regulate the functionality of the M-T hook structure at the N-terminus of the inhibitors and displayed comparable activities with the C-terminal IDL anchor. Crystallographic studies further demonstrated the importance of Asn-145-mediated interhelical and intrahelical interactions in the 6-HB structure. Combined, the present results have provided valuable information for the structure-function relationship of HIV-1 gp41 and the structure-activity relationship of gp41-dependent fusion inhibitors.
- Novel prime-boost vaccine strategies against HIV-1. [Journal Article]
- ERExpert Rev Vaccines 2019 Jul 09; :1-15
- Introduction: Given the complexities of HIV infection and the HIV genetic heterogeneity, a successful HIV vaccine should elicit broad adaptive and innate immune responses. Vaccine prime-boost platfor…
Introduction: Given the complexities of HIV infection and the HIV genetic heterogeneity, a successful HIV vaccine should elicit broad adaptive and innate immune responses. Vaccine prime-boost platforms may achieve this goal. Several factors including selection of antigen, type of vector, delivery route, dose, adjuvant, boosting regimen, order of vector injection, and intervals between vaccinations influence the outcome. Areas covered: We reviewed the literature on the latest findings of the various prime-boost HIV vaccine clinical trials, with particular emphasis on the most advanced and promising strategies. Expert opinion: Data suggest that heterologous may be better than homologous prime-boost regimens for protection. The most advanced strategies to have reached efficacy trials use either canarypox vector (ALVAC) boosted by adjuvanted gp120 protein or adenovirus (Ad26) vector expressing mosaic antigens boosted by gp140 protein. DNA prime and vectors and/or protein boost regimens are at less advanced development stage. These regimens, while imperfect (efficacy ≥50%), could contribute substantially to the control of HIV epidemics as a part of a comprehensive HIV prevention program. To ensure prompt vaccine access in populations with the greatest need, attention should be given to post-efficacy activities necessary to achieve appropriate uptake and implementation of effective vaccines.
- HIV infection stabilizes macrophage:T cell interactions to promote cell-cell HIV spread. [Journal Article]
- JVJ Virol 2019 Jul 03
- Macrophages are susceptible to HIV infection and play an important role in viral dissemination through cell-cell contacts with T cells. However, our current understanding of macrophage-to-T cell HIV …
Macrophages are susceptible to HIV infection and play an important role in viral dissemination through cell-cell contacts with T cells. However, our current understanding of macrophage-to-T cell HIV transmission are derived from studies that do not consider the robust migration and cell-cell interaction dynamics between these cells. Here, we performed live-cell imaging studies in 3-dimensional (3D) collagen that allows CD4+ T cells to migrate, locate and engage HIV-infected macrophages, modeling the dynamic aspects of the in situ environment in which these contacts frequently occur. We show that HIV+ macrophages form stable contacts with CD4+ T cells that are facilitated by both gp120:CD4 and LFA-1:ICAM-1 interactions, and that prolonged contacts are a pre-requisite for efficient viral spread. LFA-1:ICAM-1 adhesive contacts function to restrain highly motile T cells, since their blockade substantially de-stabilized macrophage:T cell contacts, resulting in abnormal tethering events that reduced cell-cell viral spread. HIV-infected macrophages displayed strikingly elongated podosomal extensions that were dependent on Nef expression, but were dispensable for stable, cell-cell contact formations. Finally, we observed persistent T cell infection during dynamic MDM:T cell co-cultures in the presence of single high antiretroviral drug concentrations, but achieved complete inhibition with combination therapy. Together, our data implicate macrophages as drivers of T cell infection by altering physiological MDM:T cell contact dynamics to access and restrain large numbers of susceptible, motile T cells within lymphoid tissues.Importance:Once HIV enters the lymphoid organs, exponential viral replication in T cells ensues. Given the densely-packed nature of these tissues, where infected and uninfected cells are in near-constant contact with one another, efficient HIV spread is thought to occur through cell-cell contacts in vivo However, this has not been formally demonstrated. In this study, we performed live-cell imaging studies within a 3-dimensional space to recapitulate the dynamic aspects of the lymphoid microenvironment, and asked whether HIV can alter the morphology, migration capacity and cell-cell contact behaviors between macrophages and T cells. We show that HIV-infected macrophages can engage T cells into stable contacts through binding of virus- and host-derived adhesive molecules, and that stable macrophage:T cell contacts were required for high viral spread. Thus, HIV alters physiological macrophage:T cell interactions in order to access and restrain large numbers of susceptible, motile T cells, thereby playing an important role in HIV progression.
- Molecular Mechanism of HIV-1 Entry. [Review]
- TMTrends Microbiol 2019 Jun 28
- HIV-1 envelope glycoprotein [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3] attaches the virion to a susceptible cell and induces fusion of viral and cell membranes to initiate infection. It intera…
HIV-1 envelope glycoprotein [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3] attaches the virion to a susceptible cell and induces fusion of viral and cell membranes to initiate infection. It interacts with the primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4) to allow viral entry by triggering large structural rearrangements and unleashing the fusogenic potential of gp41 to induce membrane fusion. Recent advances in structural biology of HIV-1 Env and its complexes with the cellular receptors have revealed molecular details of HIV-1 entry and yielded new mechanistic insights. In this review, I summarize our latest understanding of the HIV-1 membrane fusion process and discuss possible pathways for productive viral entry.
- Enhancement of Immune Responses by Guanosine-Based Particles in DNA Plasmid Formulations against Infectious Diseases. [Journal Article]
- JIJ Immunol Res 2019; 2019:3409371
- Immunogenicity of DNA vaccines can be efficiently improved by adding adjuvants into their formulations. In this regard, the application of nano- and microparticles as vaccines adjuvants, or delivery …
Immunogenicity of DNA vaccines can be efficiently improved by adding adjuvants into their formulations. In this regard, the application of nano- and microparticles as vaccines adjuvants, or delivery systems, provides a powerful tool in designing modern vaccines. In the present study, we examined the role of "Supramolecular Hacky Sacks" (SHS) particles, made via the hierarchical self-assembly of a guanosine derivative, as a novel immunomodulator for DNA plasmid preparations. These plasmids code for the proteins HIV-1 Gag (pGag), the wild-type vaccinia virus Western Reserve A27 (pA27L), or a codon-optimized version of the latter (pOD1A27Lopt), which is also linked to the sequence of the outer domain-1 (OD1) from HIV-1 gp120 protein. We evaluated the enhancement of the immune responses generated by our DNA plasmid formulations in a murine model through ELISpot and ELISA assays. The SHS particles increased the frequencies of IFN-γ-producing cells in mice independently immunized with pGag and pA27L plasmids. Moreover, the addition of SHS to pGag and pA27L DNA plasmid formulations enhanced the production of IFN-γ (Th1-type) over IL-4 (Th2-type) cellular immune responses. Furthermore, pGag and pA27L plasmids formulated with SHS, triggered the production of antigen-specific IgG in mice, especially the IgG2a isotype. However, no improvement of either of those adaptive immune responses was observed in mice receiving pOD1A27Lopt+SHS. Here, we demonstrated that SHS particles have the ability to improve both arms of adaptive immunity of plasmid coding "wild-type" antigens without additional strategies to boost their immunogenicity. To the best of our knowledge, this is the first report of SHS guanosine-based particles as DNA plasmid adjuvants.
- Helix-A peptide prevents gp120-mediated neuronal loss. [Journal Article]
- MBMol Brain 2019 Jun 25; 12(1):61
- The human-immunodeficiency virus (HIV) envelope protein gp120 promotes synaptic damage similar to that observed in people living with HIV who have neurocognitive disorders. The neurotoxic effect of g…
The human-immunodeficiency virus (HIV) envelope protein gp120 promotes synaptic damage similar to that observed in people living with HIV who have neurocognitive disorders. The neurotoxic effect of gp120 appears to occur through the α-helix motif that binds to neuronal microtubules (MTs). In this study, we examined the ability of short peptide derivatives from Helix-A, a peptide synthesized based on α-helix structure of gp120, to displace gp120 from binding to MTs and prevent its neurotoxic effects.
- Mitochondrial dysfunction in HIV-induced peripheral neuropathy. [Journal Article]
- IRInt Rev Neurobiol 2019; 145:67-82
- Mitochondria play an essential role in cellular energy production and calcium homeostasis. Abnormalities in mitochondrial homeostasis and function are seen in several acquired as well as genetic neur…
Mitochondria play an essential role in cellular energy production and calcium homeostasis. Abnormalities in mitochondrial homeostasis and function are seen in several acquired as well as genetic neuropathies, emphasizing their prominent role in neuronal cell activities. Chronic infection with HIV, even when appropriately treated, is a risk factor for developing peripheral neuropathy. In this chapter, we discuss the way in which HIV infection, the resultant toxic viral products that are generated, and some of the viral inhibitors used in its treatment may lead to abnormal mitochondrial function. Of importance are the effects on mitochondrial DNA replication and the neurotoxic effects of the viral gp120 protein. One aspect of mitochondrial dysfunction that remains unexplored is the role of the interaction between mitochondria and the endoplasmic reticulum as a possible target of disruption in HIV neuropathy.
- HIV in the cART era and the mitochondrial: immune interface in the CNS. [Journal Article]
- IRInt Rev Neurobiol 2019; 145:29-65
- HIV-associated neurocognitive disorders (HAND) persist in the era of effective combined antiretroviral therapy (cART). A large body of literature suggests that mitochondrial dysfunction is a prospect…
HIV-associated neurocognitive disorders (HAND) persist in the era of effective combined antiretroviral therapy (cART). A large body of literature suggests that mitochondrial dysfunction is a prospective etiology of HAND in the cART era. While viral load is often suppressed and the immune system remains intact in HIV+ patients on cART, evidence suggests that the central nervous system (CNS) acts as a reservoir for virus and low-level expression of viral proteins, which interact with mitochondria. In particular, the HIV proteins glycoprotein 120, transactivator of transcription, viral protein R, and negative factor have each been linked to mitochondrial dysfunction in the brain. Moreover, cART drugs have also been shown to have detrimental effects on mitochondrial function. Here, we review the evidence generated from human studies, animal models, and in vitro models that support a role for HIV proteins and/or cART drugs in altered production of adenosine triphosphate, mitochondrial dynamics, mitophagy, calcium signaling and apoptosis, oxidative stress, mitochondrial biogenesis, and immunometabolism in the CNS. When insightful, evidence of HIV or cART-induced mitochondrial dysfunction in the peripheral nervous system or other cell types is discussed. Lastly, therapeutic approaches to targeting mitochondrial dysfunction have been summarized with the aim of guiding new investigations and providing hope that mitochondrial-based drugs may provide relief for those suffering with HAND.
New Search Next
- Conformational Plasticity in the HIV-1 Fusion Peptide Facilitates Recognition by Broadly Neutralizing Antibodies. [Journal Article]
- CHCell Host Microbe 2019 06 12; 25(6):873-883.e5
- The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as …
The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a "β strand" interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.