MicrobiologyBytes

“A new vaccine can protect macaques against the monkey equivalent of HIV and could provide a fresh approach to an HIV vaccine, a study suggests. US researchers say the vaccine offered protection to 13 of 24 rhesus macaques treated in the experiment. In 12 of the monkeys, the vaccine was still effective 12 months later.”

via BBC News – Monkey HIV vaccine ‘effective’, say researchers

MicrobiologyBytes: Encouraging news but – 50% protection against the same strain of virus after 12 months? Would you trust your life to this?

Original Source: Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 11 May 2011 doi:10.1038/nature10003 (subscription required)

It is commonly accepted that the spread of most viruses occurs via the diffusion of ‘cell-free’ viral particles. In support of this, infectious viruses have been found in biological fluids and aerosols, and could be propagated in vitro using virus stocks produced from infected cell-culture supernatants. This mode of viral dissemination requires high numbers of stable viral particles released by the infected cell into the extracellular environment, such as the host bodily fluids. ‘Free’ viral particles were associated with a variety of components, such as lipids or proteins, which might reinforce virus envelop integrity and prevent envelope glycoprotein shedding. However, for other viruses, few viral particles are released, or they are poorly infectious when separated from infected cells. In such cases, virus propagation largely requires the presence of infected cells, suggesting that cell contacts mediate viral spread. This type of dissemination is mainly reported for enveloped viruses, such as some herpes viruses and some retroviruses, particularly deltaretroviruses such as the human T-cell leukemia virus type 1 (HTLV-1). Many aspects of this mode of virus dissemination are largely unknown, such as (i) the nature and the mechanism for forming cellular junctions that mediate cell–cell virus spread, and (ii) the nature of the infectious material transferred. Both of these factors depend on the virus and the type of infected cells.

Of note, the spread of two human retroviruses that infect leukocytes, HIV-1 and HTLV-1, occurs between mobile cells forming dynamic contacts with other cells. Both retroviruses cause severe chronic viral infections. Their transmission between individuals occurs through sexual contact and blood transfusion, and vertically from mother to child, including through breastfeeding. In addition to HTLV-1 dissemination through division of infected cells carrying viral genomes, transmission of HTLV-1 viral particles is known to occur mainly through cell contact in vitro and in vivo, with the exception of dendritic cells, which can be infected by cell-free viral particles. By contrast, HIV-1 spread can occur by both diffusion and direct cell–cell transfer. Nevertheless, compelling evidence indicates that direct spread through cell contact is the most efficient mode of HIV-1 dissemination in vitro, and might play a crucial role in vivo:

Can viruses form biofilms? Trends Microbiol. Mar 31 2011
The recent finding that the human T-cell leukemia virus type 1 (HTLV-1) encases itself in a carbohydrate-rich adhesive extracellular ‘cocoon’, which enables its efficient and protected transfer between cells, unveiled a new infectious entity and a novel mechanism of viral transmission. These HTLV-1 structures are observed at the surface of T cells from HTLV-1-infected patients and are reminiscent of bacterial biofilms. The virus controls the synthesis of the matrix, which surrounds the virions and attaches them to the T cell surface. We propose that, similar to bacterial biofilms, viral biofilms could represent ‘viral communities’ with enhanced infectious capacity and improved spread compared with ‘free’ viral particles, and might constitute a key reservoir for chronic infections.

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

Clinical Management of HIV Drug Resistance. Viruses 2011, 3(4), 347-378; doi:10.3390/v3040347

“New diagnoses for people infected with HIV in the UK almost doubled over the past decade, (from 1,950 in 2001 to 3,780 in 2010) according to new figures released today by the Health Protection Agency (HPA). If these 3,780 UK-acquired HIV cases in 2010 had been prevented, over £32 million annually or £1.2 billion over a lifetime in costs would have been saved. Men who have sex with men remain the group most at risk of becoming infected with HIV in the UK and new diagnoses in this group alone have increased by 70 per cent in the past 10 years rising from 1,810 in 2001 to 3,080 in 2010. Late diagnosis continues to severely affect the health outcomes of people with HIV. On average, of all those who die from HIV infection every year, three out of five are diagnosed late – that is after the point their treatment should have begun. New guidance released today by the National Institute of Clinical Excellence recommends increased testing of HIV in key risk groups. In the UK black Africans and men who have sex with men are most at risk of becoming infected with HIV. Increased testing will encourage early diagnosis in these groups.”

via HPA – UK-acquired HIV nearly doubles in ten years

“Rather than destroying HIV, a proposed treatment would embrace its infectious abilities, sending the virus into competition with a harmless, stripped-down version of itself. Dubbed therapeutic interfering particles, or TIPs, these engineered viral scraps would ride with HIV as it spreads from person to person. By out-competing HIV for cellular resources, the TIPs might slow its progression and lower infection rates. “A virus can’t replicate without a host, and similarly TIPs can’t replicate without HIV. It would piggyback on the virus,” said biophysicist and virologist Leor Weinberger of the University of California, San Diego, who modeled the epidemiology of TIPs in a study March 17 in PLoS Computational Biology. “It’s basically a virus of a virus.” Approximately 33 million people now carry HIV, or human immunodeficiency virus, which infects immune system cells that defend against disease. The virus gradually destroys them, taking away the body’s ability to protect itself. Without treatment, HIV infection leads to AIDS in about 10 years. Death follows soon after as common diseases overcome the body.”

via Piggyback Virus Could Curb HIV Pandemic | Wired.com

Source:
Autonomous Targeting of Infectious Superspreaders Using Engineered Transmissible Therapies. (2011) PLoS Comput Biol 7(3): e1002015. doi:10.1371/journal.pcbi.1002015

Background
When to initiate antiretroviral therapy in HIV infected patients is a difficult clinical decision. Actually, it is still a matter of discussion whether early highly active antiretroviral therapy (HAART) during primary HIV infection may influence the dynamics of the viral rebound, in case of therapy interruption, and overall the main disease course.
Methods
In this article we use a computational model and clinical data to identify the role of HAART timing on the residual capability to control HIV rebound after treatment suspension. Analyses of clinical data from three groups of patients initiating HAART respectively before seroconversion (very early), during the acute phase (early) and in the chronic phase (late), evidence differences arising from the very early events of the viral infection.
Results
The computational model allows a fine grain assessment of the impact of HAART timing on the disease outcome, from acute to chronic HIV-1 infection. Both patients’ data and computer simulations reveal that HAART timing may indeed affect the HIV control capability after treatment discontinuation. In particular, we find a median time to viral rebound that is significantly longer in very early than in late patients.
Conclusions
A timing threshold is identified, corresponding to approximately three weeks post-infection, after which the capability to control HIV replication is lost. Conversely, HAART initiation occurring within three weeks from the infection could allow to preserve a significant control capability. This time could be related to the global triggering of uncontrolled immune activation, affecting residual immune competence preservation and HIV reservoir establishment.

Timely HAART initiation may pave the way for a better viral control. BMC Infectious Diseases 2011, 11: 56 doi:10.1186/1471-2334-11-56

Lentiviruses owe their name (lenti means slow in latin) to the long period of time elapsing between the initial infection and the onset of the disease, that can protract over a period of months or even years. Viruses belonging to the Lentivirus genus are present in primates, ungulates (horse, cattle, sheep and goat) and felids (cat). Primates are the natural host for several lineages of closely related simian and human immunodeficiency viruses (SIV and HIV) that are the causative agents of acquired immunodeficiency syndrome (AIDS).

Lentivirus vectors bears an obvious advantage over other retrovirus vectors in that they offer the possibility to efficiently target non-dividing and differentiated cells, such as neurons. Paradoxically, the use of retrovirus vectors is hindered by the same process that makes them interesting for gene therapy, i.e., integration. This process is largely nonspecific and, as it has been shown in vivo, may either be of no consequence to the cell or lead to serious drawbacks. Although this problem may in theory be minimized in gene therapy applications targeting terminally differentiated cells, the problem of integration is serious. To this end, a number of alternative strategies have been developed, ranging from the redirection of retrovirus integration to particular chromosomal locations, to the ablation of the integration process altogether. Although in its infancy, the efforts to redirect retrovirus integration must be pursued and researchers may possibly transpose to lentiviruses a mechanism of specific integration used by other viruses.

The Inside Out of Lentiviral Vectors. (2011) Viruses 3(2): 132-159; doi:10.3390/v3020132
Lentiviruses induce a wide variety of pathologies in different animal species. A common feature of the replicative cycle of these viruses is their ability to target non-dividing cells, a property that constitutes an extremely attractive asset in gene therapy. In this review, we shall describe the main basic aspects of the virology of lentiviruses that were exploited to obtain efficient gene transfer vectors. In addition, we shall discuss some of the hurdles that oppose the efficient genetic modification mediated by lentiviral vectors and the strategies that are being developed to circumvent them.

Related:

• Retroviruses
• Genomic fossils in lemurs shed light on HIV
• Why is HIV a pathogen?

The fact that all other viruses encapsidate single copy genomes begs the question of why retroviruses co-package two genomics RNSa (gRNAs). One reason may be economy of scale: RNA dimerization allows formation of a unique structure – the dimer linkage – that distinguishes gRNAs from mRNAs. Monomeric HIV-1 RNAs are packaged when engineered with tandem dimer linkages, underscoring the importance of this RNA structure, and not gRNA counting per se, to packaging.

Co-packaging gRNAs allows retroviruses to generate intact proviruses despite pervasive gRNA nicking. Template switching during reverse transcription is probably why retroviruses maintain infectivity when their gRNAs are damaged by gamma rays, and why retroviruses are much less radiation-sensitive than RNA viruses like vescicular stomatitis virus. Researchers previously thought retroviral recombination might be mutagenic, but these notions have been dispelled. HIV-1 particles with two gRNAs generate full-length proviruses more efficiently than virions engineered to contain single gRNAs. Thus, another advantage of gRNA dimers appears to be increased replication fidelity.

Co-packaging gRNAs promotes higher recombination frequencies for retroviruses than all other viruses, allowing rapid loss of deleterious alleles and re-assortment of genome segments. With approximately three to ten crossovers occurring during the synthesis of every provirus, recombination is perhaps 10-fold more frequent than reverse transcriptase base substitution rates, and is an evolutionary driving force for retroviruses such as HIV-1 that display high levels of replication and multi-strain infection.

These observations help seal the case for likely evolutionary advantages of dimeric genome packaging. The DLS in its immature form, which results only upon association of two gRNAs, likely provides the means for selective gRNA packaging. The need to generate an intact provirus provides a strong motive for packaging redundant genetic information. And because retroviruses encapsidate gRNA dimers, recombination can provide the opportunity for almost limitless combinatorial genetic sampling.

Retroviral RNA Dimerization and Packaging: The What, How, When, Where, and Why. (2010) PLoS Pathog 6(10): e1001007. doi:10.1371/journal.ppat.1001007

Related:

• HIV-1 Genomic RNA Trafficking
• The shape of HIV RNA

“It’s hard to visualise what something as small and complex as the HIV virus actually looks like. But now Ivan Konstantinov and his team from Visual Science have created the most-detailed 3D model of the virus to date (see video above). An image of this visualisation just won first place in the 2010 International Science and Engineering Visualization Challenge, sponsored jointly by the journal Science and the National Science Foundation (NSF).  The model contains 17 different viral and cellular proteins and the membrane incorporates 160 thousand lipid molecules, of 8 different types, in the same proportions as in an actual HIV particle. It denotes the parts encoded by the virus’s own genome in orange, while grey shades indicate structures taken into the virus when it interacts with a human cell. To create the visualisation, the team consulted over 100 articles on HIV from leading science journals and talked to experts in the field. Then they reconstructed viral proteins from X-rays before assembling the structure of an entire HIV particle. The final appearance was achieved by experienced designers and 3D graphics specialists.”

Read more: New Scientist TV: HIV as you’ve never seen it before