Progressive neurological dysfunction during latent HIV infection.

OBJECTIVE--To determine whether the delayed conduction through the spinal cord and peripheral nerves seen in patients with AIDS is related to infection with HIV or to the presence of an immunodeficient state. DESIGN--Two year prospective follow up study of electrophysiological measurements in subjects positive for HIV antibody but without AIDS. SETTING--HIV screening clinic and clinical departments in a university hospital in Copenhagen, Denmark. SUBJECTS--Twelve homosexual men positive for HIV antibody who had not developed AIDS. RESULTS--Eight latencies were measured: from the ankle to T12, the wrist to C7, T12 to the cerebral cortex, C7 to the cerebral cortex, the ankle to the gluteal crease (tibial nerve), the gluteal crease to T12, the wrist to Erb''s point (median nerve), and Erb''s point to C7. Spinal latencies increased in all subjects at C7 by a mean of 4.2% (SE 0.9%) and in all except one at T12 by a mean of 5.5% (1.0%). The conduction time from the gluteal crease to T12 was increased by a mean of 32.0% (5.0%) whereas that in the median and tibial nerves by only 5.6% (1.0%) and 2.2% (2.2%) respectively. CONCLUSIONS--A mild and slowly progressive peripheral neuropathy of the axonal type and a more severe progressive myelopathy or myeloradiculopathy occur concomitantly with early HIV infection, possibly as the result of a direct neurotropic action of HIV.     

T-cell induced pathogenesis in HIV: bystander effects and latent infection.

The progress of HIV is accompanied by the infection and decline of the population of CD4+ cells. This reduction in cells results from both cytolytic influences of the virus and virus-specific cytotoxic T-cell (CTL) responses. We seek to characterize the extent of CD4+ reduction caused by HIV-specific CTLs at equilibrium. Here we show that intermediate levels of cytotoxic killing of infected cells can be inferior to both strong and weak or absent immune responses. We further show that the deleterious effects of the CTL response are made worse by a slow immune response. Bystander effects in which uninfected cells are thought to be eliminated by non-specific CTL activation lead to small or negligible reductions in uninfected CD4+ cells. Latently infected cells containing pro-viral DNA and which become activated at a constant rate ensure that the immune response is more effective for a larger range of CTL activities and reduces T-cell associated pathology.     

HIV/AIDS eradication

Antiretroviral therapy can inhibit HIV replication in patients and prevent progression to AIDS. However, it is not curative. Here we provide an overview of what antiretroviral drugs do and how the virus persists during therapy in rare reservoirs, such as latently infected CD4+ T cells. We also outline several innovative methods that are currently under development to eradicate HIV from infected individuals. These strategies include gene therapy approaches intended to create an HIV-resistant immune system, and activation/elimination approaches directed towards flushing out latent virus. This latter approach could involve the use of novel chemically synthesized analogs of natural activating agents.     

TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection

TLRs trigger innate immunity by recognizing conserved motifs of microorganisms. Recently, ssRNAs from HIV and influenza virus were shown to trigger TLR7 and 8. Thus, we hypothesized that HIV ssRNA, by triggering TLR7/8, affects HIV pathogenesis. Indeed, HIV ssRNA rendered human lymphoid tissue of tonsillar origin or PBMC barely permissive to HIV replication. The synthetic compound R-848, which also triggers TLR7/8, showed similar anti-HIV activity. Loss of R-848's activity in lymphoid tissue depleted of B cells suggested a role for B cells in innate immunity. TLR7/8 triggering appears to exert antiviral effects through soluble factors: conditioned medium reduced HIV replication in indicator cells. Although a number of cytokines and chemokines were increased upon adding R-848 to lymphoid tissue, blocking those cytokines/chemokines (i.e., IFN-alpha receptor, IFN-gamma, MIP-1alpha, -1beta, RANTES, and stromal cell-derived factor-1) did not result in the reversal of R-848's anti-HIV activity. Thus, the nature of this soluble factor(s) remains unknown. Unlike lymphoid tissue acutely infected with HIV, triggering latently infected promonocytic cells induced the release of HIV virions. The anti-HIV effects of triggering TLR7/8 may inhibit rapid killing, while pro-HIV effects may guarantee a certain replication level. Compounds triggering TLR7/8 may be attractive drug candidates to purge latent HIV while preventing new infections.     

Activation of latent HIV using drug-loaded nanoparticles

Antiretroviral therapy is currently only capable of controlling HIV replication rather than completely eradicating virus from patients. This is due in part to the establishment of a latent virus reservoir in resting CD4+ T cells, which persists even in the presence of HAART. It is thought that forced activation of latently infected cells could induce virus production, allowing targeting of the cell by the immune response. A variety of molecules are able to stimulate HIV from latency. However no tested purging strategy has proven capable of eliminating the infection completely or preventing viral rebound if therapy is stopped. Hence novel latency activation approaches are required. Nanoparticles can offer several advantages over more traditional drug delivery methods, including improved drug solubility, stability, and the ability to simultaneously target multiple different molecules to particular cell or tissue types. Here we describe the development of a novel lipid nanoparticle with the protein kinase C activator bryostatin-2 incorporated (LNP-Bry). These particles can target and activate primary human CD4+ T-cells and stimulate latent virus production from human T-cell lines in vitro and from latently infected cells in a humanized mouse model ex vivo. This activation was synergistically enhanced by the HDAC inhibitor sodium butyrate. Furthermore, LNP-Bry can also be loaded with the protease inhibitor nelfinavir (LNP-Bry-Nel), producing a particle capable of both activating latent virus and inhibiting viral spread. Taken together these data demonstrate the ability of nanotechnological approaches to provide improved methods for activating latent HIV and provide key proof-of-principle experiments showing how novel delivery systems may enhance future HIV therapy.     

Vaccine strategies against latent tuberculosis infection

The leading tuberculosis (TB) vaccines currently in clinical trials are all designed as prophylactic vaccines. Although these vaccines are highly active, they will most probably not result in sterilizing immunity and, therefore, will not solve the global problem of latent TB. An attractive strategy is to target the remaining dormant bacteria with vaccines based upon antigens induced as the bacteria change from active multiplication to non-replicating dormancy (latency antigens) or during reactivation as dormant bacteria resume active metabolism (resuscitation antigens). These late-stage antigens might have potential as post-exposure vaccines or could form the basis for a multi-stage vaccine strategy, in which they are combined with prophylactic vaccines based on early antigens from replicating bacteria.     

Possible method of eradication of poliomyelitis as an infection

Problem of poliomyelitis eradication is examined in the review. After the eradication of wild poliovirus, vaccine poliomyelitis virus continues to circulate in the human population. In rare cases it can cause the development of the disease. The authors describe disadvantages of the use of oral and inactivated poliomyelitis vaccines and note that by using oral poliomyelitis vaccine and eradication only of wild poliovirus, eradication of poliomyelitis as an infection will not succeed. As one of the approaches to reach this goal the authors propose the use of various enterovirus interference. Use of live enterovirus vaccine is described and its advantages and disadvantages are examined.