New Algorithm for detection of viral sequence fragments of HIV-1 subfamilies

Background

Methods of determining whether or not any particular HIV-1 sequence stems - completely or in part - from some unknown HIV-1 subtype are important for the design of vaccines and molecular detection systems, as well as for epidemiological monitoring. Nevertheless, a single algorithm only, the Branching Index (BI), has been developed for this task so far. Moving along the genome of a query sequence in a sliding window, the BI computes a ratio quantifying how closely the query sequence clusters with a subtype clade. In its current version, however, the BI does not provide predicted boundaries of unknown fragments.

Results

We have developed Unknown Subtype Finder (USF), an algorithm based on a probabilistic model, which automatically determines which parts of an input sequence originate from a subtype yet unknown. The underlying model is based on a simple profile hidden Markov model (pHMM) for each known subtype and an additional pHMM for an unknown subtype. The emission probabilities of the latter are estimated using the emission frequencies of the known subtypes by means of a (position-wise) probabilistic model for the emergence of new subtypes. We have applied USF to SIV and HIV-1 sequences formerly classified as having emerged from an unknown subtype. Moreover, we have evaluated its performance on artificial HIV-1 recombinants and non-recombinant HIV-1 sequences. The results have been compared with the corresponding results of the BI.

Conclusions

Our results demonstrate that USF is suitable for detecting segments in HIV-1 sequences stemming from yet unknown subtypes. Comparing USF with the BI shows that our algorithm performs as good as the BI or better.

Figure 1. Method outline. Outline of the steps of the method, assuming 2 subtypes composed each of 2 sequences. The following color code for columns and nucleotides, respectively, is used in the topmost part: green - completely conserved columns (with respect to all subtype sequences and the query sequence), red - columns removed due to insertion by the query sequence or too much gaps in the alignment, yellow - minority nucleotides in the column. The part of the sequence coloured in gray (at the bottom) indicates a subtype yet unknown. The last row gives the classification of the query sequence into known and unknown positions.

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HIV Experts Propose New Approach to Eradicate HIV in Latest Issue of Science

A group of leading HIV experts call for the exploration of a new approach to treating HIV – one that could ultimately help eradicate the virus– through a collaboration involving academia, industry, government and patient advocates. This new approach to HIV treatment is discussed in a perspective article published in the March 6, 2009 issue of Science.

The article, provocatively titled, “The Challenge of a Cure for HIV Infection,” is authored by three academics, Doug Richman, UCSD; David Margolis, UNC; Warner Greene, UCSF; one community advocate, the late Martin Delaney, Project Inform; and two industry scientist leaders Daria Hazuda, Merck; Roger Pomerantz, Tibotec.

This diverse group came together to set a goal for the next era in HIV therapeutics – drug free remission – and assemble a coordinated initiative to identify potential interventions and a clinical assessment to reach this goal. The initiative, which the authors coined a “collaboratory,” aims to accelerate the progress of individual research groups, harness the drug discovery capabilities of industry and utilize the government to coordinate regulatory approaches and mobilize funding.

“A successful vaccine or microbicide still remains a significant challenge in spite of billions of dollars and years of research, and having millions of people on lifelong highly active antiretroviral therapy (HAART) may not be sustainable,” said Roger Pomerantz, M.D., FACP, President of Tibotec R&D. “At Tibotec, we have a heritage of partnership and collaboration, and we are committed to forging new approaches with others to develop HIV therapeutics that could finally eradicate the disease.”

Envisioning the Post-HAART Era

Since the arrival of HAART more than a decade ago, people diagnosed with HIV have gained a lengthened life expectancy and improved quality of life. Today, patients newly infected with HIV can expect to live 40-50 years as a result of HAART. However, HAART is not the optimal solution for HIV – it requires lifelong therapy, the medication can cause various side effects and the effects of long-term HAART are not yet known. And, if HAART is interrupted, the virus rapidly replicates and the patients’ immune system is attacked once more. HAART suppresses the virus, but it is unable to eradicate it completely. As a result, the virus persists in latently infected cells (HIV latency) and other reservoirs. The authors conclude that eradicating the virus from these cells and reservoirs is a crucial approach in the pursuit for therapies that could provide drug free remission and potentially, a cure.

The three academics and two industry scientists who authored the Science article have individually been involved in independent studies of HIV latency and reservoirs, and there has been significant progress in understanding these conditions. However, the authors point out, such discrete studies may be duplicative and slow to build up a complete picture.

“A flexible, collaborative private-public joint venture has the possibility to catalyze progress in the search for therapeutic interventions that can eradicate HIV and result in drug-free remission for HIV patients,” said Paul Stoffels, M.D., Company Group Chairman, Johnson & Johnson. “This new approach of ‘open innovation’ is critical if we are to meet the really big challenges that remain today in the HIV field, such as eradication.”

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Certain HIV treatment less effective when used with anti-TB therapy

Combination antiretroviral therapy (ART) is frequently initiated in resource-limited countries when patients are being treated for tuberculosis. Co-administration of ART and anti-tubercular therapy may be complicated by shared toxicity or adverse drug interactions, according to background information in the article. Rifampicin-based anti-tubercular therapy reduces the plasma concentrations of the antiretroviral agents efavirenz and nevirapine. The virological consequences of these interactions are not well known.

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Controlling HIV Evolution

Dr. Ronald Collman talks about exciting new discoveries on HIV, the virus that has taken 25 million lives. Dr. Ronald Collman, professor of medicine in microbiology, virus/cell/molecular core director, Penn Center for AIDS Research, University of Pennsylvania.He describes the molecular structure, pathology, and with great insight, the incredible discoveries that might just help us conquer HIV.
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Protein Linked To Alzheimer's Disease Also Has Role In HIV Progression

A protein related to heart disease and Alzheimer's is found to be a factor in HIV. The apolipoprotein (apo) E4 isoform has been implicated in neurodegeneration in Alzheimer's disease, cardiovascular disease, and stroke. Now, investigators at the Gladstone Institutes, the University of California, San Francisco, the University of Texas Health Science Center at San Antonio, and the Infectious Disease Clinical Research Program, Uniformed Services University, Bethesda, Maryland have shown that this troubling protein is a risk factor for AIDS progression rates and promotes entry of HIV into cells.

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