AIDS and its virus]

An etiological agent of AIDS is a human retrovirus called HIV. The genomic structure of HIV features regulatory genes in which tat and rev genes control the viral replication and affect cellular functions. Understanding their molecular mechanism may provide a clue to prevent the onset of AIDS from the viral carriers and to direct drug designing of AIDS.     

Proliferative and cytotoxic T cells to AIDS virus glycoproteins in chimpanzees immunized with a recombinant vaccinia virus expressing AIDS virus envelope glycoproteins

PBL from chimpanzees immunized with a recombinant vaccinia virus that expresses HIV envelope glycoproteins ("env"), were found to proliferate after stimulation with HIV or with "env". Furthermore, CTL clones lytic for autologous target cells expressing HIV envelope glycoproteins were generated after stimulation of the chimpanzees' PBL with "env", indicating that immunization of these primates with a recombinant vaccinia virus primes HIV-specific CTL and also that HIV envelope glycoproteins serve as target antigens for CTL.     

Immunopathogenesis and immunotherapy in AIDS virus infections

The heterogeneity of HIV and the different human leukocyte antigen (HLA) backgrounds of infected individuals have posed challenges to understanding the pathogenesis of HIV infection. But continuing advances in our knowledge of the role of immune responses in controlling HIV viremia should help to define goals for immune-based therapies and vaccine strategies against AIDS.     

HIV-2: the forgotten AIDS virus

HIV type 2 (HIV-2), a closely related retrovirus discovered a few years after HIV type 1, causes AIDS in only a minority of infected individuals. Determining why HIV-2 causes asymptomatic infection in most patients could further our understanding of HIV immunopathogenesis. Studies to date have suggested that both enhanced immune responses and lower viral replication could play a role. We summarize the important findings to date and highlight areas that warrant further exploration.     

Nucleotide sequence of the AIDS virus, LAV

The complete 9193-nucleotide sequence of the probable causative agent of AIDS, lymphadenopathy-associated virus (LAV), has been determined. The deduced genetic structure is unique: it shows, in addition to the retroviral gag, pol, and env genes, two novel open reading frames we call Q and F. Remarkably, Q is located between pol and env and F is half-encoded by the U3 element of the LTR. These data place LAV apart from the previously characterized family of human T cell leukemia/lymphoma viruses.     

Functional contributions of carbohydrate on AIDS virus glycoprotein

Envelope glycoprotein spikes on the surface of the human immunodeficiency virus (HIV) are used by the virus to bind to cellular receptors to gain entry into target cells. As such, the envelope spikes are the targets of antibodies that can neutralize viral infectivity. Fifty percent or more of the mass of the viral-encoded surface glycoprotein of HIV, and of its close monkey relative simian immunodeficiency virus (SIV), is actually carbohydrate; it is one of the most heavily glycosylated proteins that can be found in mammals. It has been clearly demonstrated that one of the functions of this carbohydrate is to shield viral epitopes that would otherwise be the direct target of antibodies that could neutralize viral infection. In addition, it is now generally accepted that the carbohydrate on the viral envelope glycoprotein is recognized by multiple cellular lectins of the host lymphoreticular system, and these interactions play a role in the dissemination of virus within the host as well as the release of modulatory cytokines. Our work recently demonstrated fundamental differences in the composition of the carbohydrate on HIV type 1, the cause of the AIDS pandemic, versus the SIV in the sooty mangabey monkey, a natural host that does not develop disease from its infection. We now speculate that this fundamental difference in carbohydrate composition reflects evolutionary pressures on both virus and host. Furthermore, carbohydrate composition on the virus and genetic differences in carbohydrate-sensing proteins of the host could be critically important for the generalized lymphoid activation that characterizes the acquired immunodeficiency syndrome (AIDS).     

Neurology of AIDS virus infection: a clinical classification

Infection with the AIDS virus itself (HIV, HTLV-III, LAV, ARV) is associated with a full spectrum of neurological disorders. The application of diagnostic studies for HTLV-III infection has demonstrated that these neurologic disorders can be the first manifestation of AIDS or occur in the absence of AIDS. The most common conditions associated with HTLV-III infection alone are a subacute encephalopathy (AIDS dementia) and peripheral neuropathy; however, vacuolar myelopathy and both acute and chronic aseptic meningitis are also common. Congenital (or neonatal) transmission of the virus can result in a mental retardation syndrome of delayed onset. The AIDS virus is neurotropic as well as targeting T-helper lymphocytes. The virus has been readily identified in neural tissues and cerebrospinal fluid, including instances in which other central nervous system infections, such as toxoplasmosis, coexist. Hence, recognition of an appropriate syndrome, neurodiagnostic studies, and exclusion (or treatment) of other infections, as well as evidence for HTLV-III infection are required for diagnosis. The development of successful therapy will require agents which cross the blood-brain barrier.     

Assessing genetic-based therapies for AIDS using the simian immunodeficiency virus

Abstract: A plasmid encoding the full-length infectious molecular proviral clone of SIV_mac239 was generated. Virus derived from cells transfected with this clone replicated to high levels and was cytopathic for some transformed human CD4⁺ cell lines and primary rhesus macaque peripheral blood mononuclear cells. Since replication of SIV requires the functional expression of the viral encoded rev protein, transient co-transfection studies were initiated with the infectious proviral clone and a well-characterized trans-dominant negative HIV-1 rev mutant.     

Morphine suppresses IFN signaling pathway and enhances AIDS virus infection

Background

Opioids exert a profound influence on immunomodulation and enhance HIV infection and replication. However, the mechanism(s) of their action remains to be determined. We thus investigated the impact of morphine on the intracellular innate antiviral immunity.

Methodology/Principal Findings

Seven-day-cultured macrophages were infected with equal amounts of cell-free HIV Bal or SIV Delta_B670 for 2 h at 37°C after 24 h of treatment with or without morphine. Effect of morphine on HIV/SIV infection and replication was evaluated by HIV/SIV RT activity assay and indirect immunofluorescence for HIV p24 or SIV p28 antigen. The mRNA expression of cellular factors suppressed or induced by morphine treatment was analyzed by the real-time RT-PCR. We demonstrated that morphine treatment of human blood monocyte-derived macrophages significantly inhibited the expression of interferons (IFN-α, IFN-β and IFN-λ) and IFN-inducible genes (APOBEC3C/3F/3G and 3H). The further experiments showed that morphine suppressed the expression of several key elements (RIG-I and IRF-7) in IFN signaling pathway. In addition, morphine treatment induced the expression of suppressor of cytokine signaling protein-1, 2, 3 (SOCS-1, 2, 3) and protein inhibitors of activated STAT-1, 3, X, Y (PIAS-1, 3, X, Y), the key negative regulators of IFN signaling pathway.

Conclusions

These findings indicate that morphine impairs intracellular innate antiviral mechanism(s) in macrophages, contributing to cell susceptibility to AIDS virus infection.     

Inhibition of AIDS virus replication by acemannan in vitro.

Acemannan (ACE-M), a beta-(1,4)-linked acetylated mannan, was evaluated for in vitro activity against human immunodeficiency virus type 1 (HIV-1). Castanospermine (CAS), deoxymannojirimycin (DMN), swainsonine (SWS), azidothymidine (AZT), and dideoxythymidine (DDC) were tested in parallel as control compounds. In vitro antiviral efficacy of ACE-M was evaluated in a variety of cell lines including human peripheral mononuclear, CEM-SS1 and MT-2(2) cells. The virus strain, number of infectious units per cell, and target cell line were important factors in determining the degree of inhibition of viral cytopathic effect in the presence of ACE-M and other control compounds tested. Maximum inhibitory effect was observed in CEM-SS cells infected with the RFII strain of HIV-1. This inhibitory effect was determined to be concentration-dependent. Assay design included primary screening to measure cell viabilities of infected target cells in the presence and absence of test compounds. When tested on HIV-1/RFII-infected CEM-SS cells, the 50% inhibitory effect of CAS (IC50 = 28), an inhibitor of alpha-glucosidase I, was determined to be similar to that observed for ACE-M (IC50 = 45). However, DMN and SWS, inhibitors of mannosidase I and II, tested in parallel to CAS and ACE-M, exhibited no IC50 values. Antiviral potential of ACE-M as an inhibitor of syncytia formation was also explored using CEM-SS cells. Suppression of syncytia formation was observed at an ACE-M concentration of 31.25 micrograms/ml, and complete inhibition was observed at 62.5 micrograms/ml. In addition, HIV-1 RNA levels were studied to establish the antiviral potential of ACE-M in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)