TWiV Special: Gary Nabel on World AIDS Day 2016

For World AIDS Day 2016, Vincent speaks with Gary Nabel, Chief Scientific Officer at Sanofi and former Director of the Vaccine Research Institute of NIAID, about his career and his work on HIV vaccines.

You can find this TWiV Special at microbe.tv/twiv, or listen and watch here.

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TWiV 417: O is the loneliest letter

The Fellowship of the Virus trace the early history of HIV in North America, based on genome sequences obtained from late 1970s archival sera, which also reveal that Gaetan Dugas was not Patient Zero.

You can find TWiV #417 at microbe.tv/twiv, or listen below.

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Dugas was not AIDS Patient Zero

aids_index_case_graphThe popular history of HIV/AIDS describes a man known as Patient Zero, a sexually active flight attendant who traveled the globe and initiated the AIDS epidemic in North America. A new analysis of the viral genome recovered from his serum and that of other patients in the 1970s proves beyond a doubt that he was not Patient Zero (link to paper).

In a heroic effort, thousands of archived serum samples originally collected from cohorts of men who have sex with men in the 1970s in New York and San Francisco, were examined for the presence of HIV by western blot analysis. A total of 83 samples were found to be HIV positive and subjected to deep sequencing, but the viral RNA was degraded and present only in short pieces. To overcome this problem, many DNA primers were used to amplify short RNA fragments by PCR in a procedure colorfully called ‘jackhammering’. The impressive result is that complete HIV-1 coding sequences were obtained from 8 samples: 3 from San Francisco and 5 from New York City.

Analysis of the HIV genome sequences, and comparison with earlier and later data revealed that the virus likely traveled from Africa to the Caribbean around 1967, and from there to New York City in 1971. These results disprove previous ideas that HIV arrived in the Caribbean from the US.

Sequence analysis also reveals that New York City was a hub of early diversification of HIV, and that the epidemic was already mature and genetically diverse by the late 1970s. There appears to have been a single introduction of HIV into San Francisco from New York City in 1976. From those two cities the virus spread elsewhere in the US and overseas.

It has been suggested that a sexually active flight attendant, identified as Gaetan Dugas by Randy Shilts in his book And the Band Played On, was the source of the North American AIDS epidemic. Although at least one study years ago concluded that he was not the first case, this belief persists. Sequencing of HIV from this patient’s serum revealed that he was certainly not the first person in North America infected with this line of HIV-1 (Group M, subtype B) .

A historical reconstruction of the early days of AIDS in the US reveals how Dugas earned the label ‘Patient Zero’. CDC investigators who were studying a sexual network of 40 gay men placed one man at its center, whom they called ‘Patient O’, standing for ‘outside of California’ because he was Canadian (pictured; image credit). Upon publication of this work, the ‘O’ was misinterpreted as a zero and so began the belief that he was the origin of the AIDS outbreak in North America.

TWiV 409: A Nef is enough

Jeremy joins the TWiVeroids to tell the amazing story of how the function of the HIV-1 protein called Nef was discovered and found to promote infection by excluding the host protein SERINC from virus particles.

You can find TWiV #409 at microbe.tv/twiv, or listen below.

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TWiV 408: Boston Quammens

Four years after filming ‘Threading the NEIDL’, Vincent and Alan return to the National Emerging Infectious Diseases Laboratory BSL4 facility at Boston University where they speak with science writer David Quammen.

You can find TWiV #408 at microbe.tv/twiv, or watch/listen here.

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TWiV 320: Retroviruses and cranberries

On episode #320 of the science show This Week in Virology, Vincent speaks with John Coffin about his career studying retroviruses, including working with Howard Temin, endogenous retroviruses, XMRV, chronic fatigue syndrome and prostate cancer, HIV/AIDS, and his interest in growing cranberries.

You can find TWiV #320 at www.microbe.tv/twiv.

Combination antiviral therapy for hepatitis C

Ledipasvir and SofosbuvirThe Food and Drug Administration has approved the use of a single pill containing two different antiviral drugs for the treatment for hepatitis C. It is the first combination pill approved for the disease, and also the first treatment that does not contain interferon or ribavirin.

The new hepatitis C drug, called Harvoni, is a mixture of the antiviral drugs ledipasvir and sofosbuvir. Ledipasvir (pictured) is an inhibitor of the hepatitis C virus protein NS5A, which has multiple roles in the viral replication cycle that include RNA synthesis and virus particle assembly. The mechanism of NS5A inhibition by ledipasvir is not known. Sofosbuvir is a previously licensed inhibitor that targets the viral RNA-dependent RNA polymerase. It is an analog of the nucleoside uridine, one of the four building blocks of RNA. Sofosbuvir is utilized by the viral RNA polymerase, leading to inhibition of viral RNA synthesis.

The use of single antiviral drugs (monotherapy) to treat RNA virus infections is always problematic because resistance usually arises rapidly. Dual-therapy pills like Harvoni are better, but the best are triple-therapy pills. Triple therapy formulations such as Atripla have been used successfully to treat infections with HIV-1, and presumably there will be mixtures of three antiviral drugs for treating hepatitis C.

Let’s use HIV-1 to illustrate the value of treating infections with multiple antiviral drugs. The HIV-1 viral genome, like that of HCV, is slightly less than 10,000 bases long. Assume that one mutation in the viral genome is needed for drug resistance. If the RNA polymerase mutation rate is 1 out of every 10,000 bases synthesized, then each base in the viral genome is substituted in a collection of 10,000 viruses. An HIV-1 infected person can make as many as 10,000,000,000 virus particles each day, so 1010/104 = one million viruses will be produced each day with resistance to one drug.

If we use two antiviral drugs, developing resistance to both occurs in every 104 x 104 = 108 viruses. In this case 1010/108 = 100 viruses will be produced each day with resistance to two drugs.

If we use three antiviral drugs, developing resistance occurs in every 104 x 104 x 104= 1012 viruses, which is more than what is produced each day.

This is why triple antiviral therapy has been so successful for the treatment of AIDS.

And yes, I’m sure someone has tested Sofosbuvir for inhibition of Ebola virus replication.

The Berlin patient

HIV binding CD4 and ccrSince the beginning of the AIDS epidemic, an estimated 75 million people have been infected with HIV. Only one person, Timothy Ray Brown, has ever been cured of infection.

Brown was diagnosed with HIV while living in Berlin in 1995, and was treated with anti-retroviral drugs for more than ten years. In 2007 he was diagnosed with acute myeloid leukemia. When the disease did not respond to chemotherapy, Brown underwent stem cell transplantation, which involves treatment with cytotoxic drugs and whole-body irradiation to destroy leukemic and immune cells, followed by administration of donor stem cells to restore the immune system. When his leukemia relapsed, Brown was subjected to a second stem cell transplant.

The entry of HIV-1 into lymphocytes requires two cellular proteins, the receptor CD4, and a co-receptor, either CXCR4 or CCR5. Individuals who carry a mutation in the gene encoding CCR5, called delta 32, are resistant to HIV-1 infection. This information prompted Brown’s Berlin physician to screen 62 individuals to identify a stem cell donor who carried a homozygous CCR5∆32 mutation. Peripheral blood stem cells from the same donor were used for both transplants. 

Despite enduring complications and undergoing two transplants, Brown’s treatment was a success: he was cured both of his leukemia and HIV infection. Even though he had stopped taking antiviral drugs, there was no evidence of the virus in his blood following his treatment, and his immune system gradually recovered. Follow-up studies in 2011, including biopsies from his brain, intestine, and other organs, showed no signs of HIV RNA or DNA, and also provided evidence for the replacement of long-lived host tissue cells with donor-derived cells. Today Brown remains HIV-1 free.

Although Brown’s cure is somewhat of a medical miracle, and by no means a practical road map for treating AIDS, the example of the Berlin patient has galvanized research efforts and continues to inspire hope that a simpler and more general cure for infection may someday be achieved. Clinical trials have been conducted to test a variety of strategies in which CD4+ T or stem cells are obtained from a patient, the CCR5 gene is either mutated or its translation blocked by RNA interference, and then the resulting virus-resistant cells are returned to the patient. In one case zinc finger nucleases were used to delete the CCR5 gene in a patient’s cells, a procedure that we discussed in TWiV #278.

TWiV 293: Virology Down Under

On episode #293 of the science show This Week in VirologyVincent visits Melbourne, Australia and speaks with Melissa, Alex, Gilda, and Paul about their work on HIV infection of the central nervous system, West Nile virus, microbicides for HIV, and the Koala retrovirus.

You can find TWiV #293 at www.microbe.tv/twiv.

TWiV 278: Flushing HIV down the zinc

On episode #278 of the science show This Week in Virology, Vincent, Dickson, Alan, and Kathy discuss disruption of the ccr5 gene in lymphocytes of patients infected with HIV-1.

You can find TWiV #278 at www.microbe.tv/twiv.